Female Reproductive Health

Female Reproductive Health
Female Reproductive Health

Edited by
Nikolai Manassiev
The Wand Medical Centre
Birmingham, UK
and
Malcolm I.Whitehead
Kings College Hospital
London, UK
The Parthenon Publishing Group

International Publishers in Medicine, Science 61
Technology
A CRC PRESS COMPANY
BOCA RATON LONDON NEW YORK
WASHINGTON, D.C.
Library of Congress Cataloging-in-Publication Data

Female reproductive health/edited by Nikolai
Manassiev, Malcolm Whitehead.
p. ; cm
Includes bibliographical references and index.
ISBN 1-85070-491-0 (alk. paper)
1. Gynecology. 2. Reproductive health. 3.
Women-Health and hygiene. I.Manassiev,
Nikolai. II. Whitehead, Malcolm I.
[DNLM: 1. Reproduction-physiology. 2.
Genital Diseases, Female. 3. Genitalia, Femalephysiology. 4. Infection. WQ 205 F3287 2003]
RG 133. F45 2003
618.1-dc21 2003045973
British Library Cataloguing in Publication Data
Female reproductive health
1. Gynecology 2. Generative organs, Female
I. Manassiev, Nikolai II. Whitehead, Malcolm I.
618.1
ISBN 0-203-48447-9 Master e-book ISBN
ISBN 0-203-59669-2 (Adobe eReader Format)

ISBN 1-85070-491-0 (Print Edition)
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Copyright 2004 The Parthenon Publishing Group
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Contents
List of contributors
1.
The female reproductive systemanatomy and physiology

Nikolai Manassiev and Fergus Keating
2.
Hormones in reproduction
Nikolai Manassiev and Henry Burger
15
3.
The female reproductive cycle

27
4.
Contraception
Joanna N.Raeburn, Chris Wilkinson and Nikolai Manassiev
42
5.
Infertility
Nikolai Manassiev, Naim Abusheikha and John Collins
96
6.
Menopause, hormone replacement therapy and non-hormonal

strategies
Nikolai Manassiev, Fergus Keating and Henry Burger
135
7.
Sexually transmitted infections and common genital tract infections

Alison Stirland, Chris Wilkinson and Nikolai Manassiev
176
8.
Benign breast conditions and screening for breast cancer

Nikolai Manassiev
212
9.
Sexual function and dysfunction

Nikolai Manassiev
229
Appendix I: Currently available combined oral contraceptive pills in

the UK
249
Appendix II: Prevention of pelvic inflammatory disease at the time

of IUD insertion
251
Index
253
List of contributors
Naim Abusheikha
Bourn Hall Clinic
Cambridge CB3 7TR
UK
Henry Burger
Prince Henrys Institute of Medical Research
Monash Medical Centre
Clayton
Victoria
Australia
John Collins
Department of Obstetrics and Gynecology
McMaster University
Hamilton
Ontario L8N 3Z5
Canada
Fergus Keating
Giggs Hill Surgery
14 Raphael Drive
Thames Ditton
Surrey KT7 OEB
UK
Joanna N.Raeburn
Kings College Hospital NHS Trust
Denmark Hill
London SE5 9Rs
UK
Alison Stirland
Sexually Transmitted Disease Program
Los Angeles Department of Health
Los Angeles
CA 90007
vi
USA
Chris Wilkinson
Margaret Pyke Centre and Camden &
Islington Contraceptive and Reproductive
Health Services
73 Charlotte Street
London WIT 4PL
UK
1
The female reproductive system anatomy
and physiology
Nikolai Manassiev and Fergus Keating
INTRODUCTION
The female reproductive system is composed of the internal and external
genitalia. The internal genitalia comprise the ovaries, uterine (fallopian) tubes,
uterus (including the cervix) and vagina. The external genitalia consist of the
vulva, which comprises the labia majora, labia minora, clitoris, vestibular bulbs,
mons veneris (pubis), urethral and peri-urethral gland ducts. The vulva serves as
the entrance to the vagina and in the normal state covers and protects the urethral
orifice.
The breast is not essential for reproduction. However, it poses a constant
challenge with early cancer detection and it brings misery to many women in the
form of pain. So it is essential that the breast should be included in this
discussion.
EXTERNAL GENITALIA
Labia majora
These are two skin folds overlying a condensation of fat, connective and elastic
tissue and muscle fibers (Figure 1.1). These folds continue cranially toward the
lower abdomen and fuse in the midline as the anterior commissure, or the mons
pubis. The caudal union of the labia is known as the posterior commissure. The
outer borders of the labia majora define the lateral extent of the vulva. The skin
covering the labia majora is thick, contains many sebaceous and sweat glands
and is covered with hair, except along the lower part of the inner aspect. The skin
is composed of stratified squamous epithelium with a well-vascularized dermis.
The round ligaments that emerge from the inguinal canal enter the labia in the
upper third.
2 FEMALE REPRODUCTIVE HEALTH
Figure 1.1 Components of the vulva. Reproduced from Romanes GJ. Cunninghams
Manual of Practical Anatomy, 14th edn. Vol. 11, Thorax and Abdomen. Oxford: Oxford
University Press, 1977:169, reproduced with permission of Oxford University Press
Labia minora
The labia minora consist of two cutaneous folds, which are usually concealed by
the labia majora (Figure 1.1). They directly approximate each other, thus
covering the vaginal opening. The labia minora extend from the clitoris
anteriorly to the posterior fourchette, where they join the labia majora. Sweat
glands and follicles are usually absent, but sebaceous glands are abundant. The
epithelium is stratified and squamous, with minimal keratinization. The prepuce
of the clitoris is continuous with the labia minora and is histologically similar,
except for its extreme vascularity. Usually the mons and the labia majora are the
only visible parts of the external genitals. The labia minora are in contact with
each other thus closing the vaginal opening. The space bounded by the labia
minora and the vaginal opening is called vestibule. The latter forms a junction
between the external and internal genitals. In this space are the openings of the
urethra, vagina and the greater vestibular glands (Bartholins glands). The
Bartholins glands secrete a milky lubricant during sexual arousal. Minor
vestibular glands secrete mucus around the clitoris and the urethral orifice. The
vestibular fossa is the tissue between the vaginal opening and posterior
fourchette. The vestibule has two spongy bulbs, one on each side. These bulbs
are erectile and meet in the middle thus resembling a horseshoe from an anterior
position. During sexual stimulation they become engorged. For further
THE FEMALE REPRODUCTIVE SYSTEM 3
discussion about the role of the vestibule in sexual dysfunction, see Chapter 9,
page 178.
Clitoris
The clitoris is composed of two roots that run along the lower pubic rami to unite
beneath the symphysis in the body of the clitoris. The distal part of the body is the
glans. The ischiocavernosus muscle covers the root and the body of the clitoris.
The roots, or crura, are 34 cm long in the flaccid state, but when erect are 4.55
cm long. The body is 2.33 cm long and is surrounded by a connective tissue
fascia. The covering of the glans is modified cutaneous tissue and not mucosa.
Unlike the penis, the glans clitoris contains no corpus spongiosum and does not
possess as much erectile tissue. There are numerous sensory nerve endings for
touch and pressure, such as Meissners corpuscles, on the clitoris. This little
organ has 8000 nerve fibersdouble that of the penis. The sensory supply is via
the pudendal nerve. There is also sympathetic innervation via the pelvic
sympathetic plexuses.
The clitoris seems to function as the nerve center for coitus. Sexual stimulation
causes vascular engorgement and enlargement. This makes the clitoris
exquisitely sensitive to the friction of the inserted penis. Orgasm in the female
consists of a reflex resulting in forceful contractions of both voluntary and
involuntary muscles of the pelvis and pelvic viscera. It may result from
stimulation of the clitoris even in the absence of the vagina. Once the process of
orgasm has been experienced and a conditional reflex has been established, then
the presence of the clitoris is no longer essential for orgasm. It is said that
women who have undergone vulvectomy with excision of the clitoris are still
capable of experiencing orgasm.
The arterial supply to the vulva is mainly via the internal pudendal artery. The
veins approximate the same course but also communicate with the vesicovaginal
plexus and the inferior hemorrhoidal veins. The lymph drains via the inguinal
and femoral nodes to the external iliac nodes. The nerve supply is from multiple
sources. The main contributor is the pudendal nerve, which is derived from the
second to fourth sacral nerves: the ilioinguinal and the genitofemoral nerves also
contribute.
INTERNAL GENITALIA
Vagina
The vagina is a musculomembranous canal extending from the vulva to the
uterine cervix (Figures 1.21.3). It is directed upward and posteriorly from the
vestibule toward the sacral promontory. Anteriorly, the vagina is closely related
to the bladder and urethra. The urethra lies against the lower two-thirds of the
Figure 1.2 Sagittal section of the human female pelvis. Reproduced with permission from
Bengtson J. The vagina and female urology. In Ryan KJ, Friedman AJ, Barbieri RL, eds.
Kistners Gynecology, 5th edn. Chicago: Year Book Medical Publishing, 1990:112
vagina and the bladder trigone against the upper third. The tissues separating
these structures are called the urethrovaginal and vesicovaginal septa,
respectively, and consist of supporting tissues of the endopelvic fascia. The
posterior vaginal wall is related to the peritoneal cul-de-sac (pouch of Douglas)
in its upper third, to the ampulla of the rectum in its middle third, and to the
perineal body in its lower third. The perineal body is an important structure that
provides a central area of insertion of the supporting muscles of the pelvic floor.
At the introitus, the vagina is related laterally to the bulbocavernous muscles.
Superiorly, the upper vagina fuses with the cervix, which projects into it through
its anterior wall. As a result of this arrangement, the posterior wall of the vagina
is longer than the anterior wall by about 23 cm. The recesses of the vaginal
vault above the cervix are called fornices, the deepest being the posterior fornix.
The vaginal length is usually 810 cm. The perineal muscles cause relative
constriction of the outlet diameter. The vagina is flattened when relaxed, creating
only potential space, but has a remarkable ability to distend, for example, during
the process of delivery, to accommodate the passage of the fetus. The vaginal wall
Figure 1.3 Frontal section of the uterine cervix and corpus. Reproduced with permission
from Sheets EE, Goodman HM, Knapp RC. The cervix. In Ryan KJ, Friedman AJ, Barbieri
RL, eds. Kistners Gynecology, 5th edn. Chicago: Year Book Medical Publishing, 1990:
146
possesses multiple circumferential folds, or rugae. The folds become less

prominent after the menopause. The vaginal lining is often referred to as vaginal
skin and this term is useful in everyday practice. Histologically, however, the
vagina has three layers: mucous membrane, muscular layer and adventitia. The
mucosa is composed of a non-keratinized squamous epithelium. The epithelium
is continuous onto the vaginal portion of the cervix. Vaginal epithelial cells
contain abundant glycogen, especially at midcycle, when plasma estradiol levels
are high. The vagina is well vascularized but does not contain glands. During
sexual excitement, the blood vessels engorge, the vaginal skin reddens and a
transudate is released into the vagina to aid lubrication.
The vaginal epithelium undergoes changes under the influence of estrogen.
Estrogen induces proliferation and maturation of the epithelium, enhances
glycogen storage in the superficial cells and increases the blood flow to the
paravaginal tissues. This leads to increased epithelial thickness and strengthening
of the mechanical barrier between the vagina and the outside environment.
There are three cell types present in the vaginal epithelium: parabasal cells, the
intermediate cell layer and superficial cells. Under the influence of estrogen the
superficial cells predominate during the reproduction years, while in estrogen
deprivation, i.e., after the menopause, there is a predominance of parabasal and
intermediate cells. The normal vaginal pH is 3.54.5 and this acidity is due to
conversion of the glycogen stored in the superficial and intermediate cells into
lactic acid by lactobacilli. The normal vaginal flora and physiology is discussed
in more detail in Chapter 7.
The vaginal blood supply is from the internal pudendal artery, a branch of the
internal ileac artery with wide anastomoses with the uterine, inferior vesical and
middle rectal vessels. The lymph from the upper two-thirds drains into the
external and internal iliac nodes, while that from the lower third drains into the
inguinal nodes. The sensory innervation of the vagina is from the pudendal and
ilioinguinal nerves. Sympathetic fibers from the hypogastric plexuses supply
blood vessels and the smooth muscle of the vaginal wall. The upper vagina is
said to be sensitive only to stretching.
Uterus and fallopian tubes
The uterus (Figures 1.21.4) consists of two parts: the uterine cervix and uterine
body. The cervix is cylindrical and points downward and backward. It measures
2.53 cm in length and 23 cm in diameter in adult nulligravid women, but its
size can vary considerably between women. The cervix is connected to the
uterine body by the isthmus. The vagina attaches to the cervix around its middle
(length) and divides the cervix into vaginal and supravaginal parts. In the center
of the vaginal part of the cervix there is a small openingthe external osby
which the cavity of the uterus communicates with the vagina. The cervical canal
extends from the external os to the anatomic internal os, where it connects with
the uterine cavity. The cervical canal is spindle-shaped, measuring about 8 mm
at its greatest width. The isthmus is the area of the uterus that lies between the
anatomic internal os above and the histologic internal os below. The latter
represents the area of transition from endometrial to endocervical glands. The
isthmus is referred to as the lower uterine segment during pregnancy and labor.
The cervix secretes mucus which is subject to cyclical changes. Following
menses, the amount of mucus secreted by the endocervical glands is reduced and
it is viscous. The quantity of mucus increases up to 30-fold in response to
increasing levels of estrogens during the second half of the follicular phase. The
mucus becomes thin, watery, clear and elastic and is then highly permeable to
spermatozoa. A fine thread of mucus (up to 10 cm long) can be demonstrated by
stretching a drop of secretion (spinnbarkeit) on a microscope slide. A
characteristic ferning, or palm leaf arborization, can be seen if mucus is dried on
a slide. During the luteal phase and during pregnancy, the mucus acts as a plug
between the uterus and the external environment. Progesterone secretion during
the luteal phase makes the mucus thick, milky white and a barrier for sperm and
possibly microorganisms.
The cervix is covered by two different types of epithelium: squamous and
columnar. The area of the cervix where the stratified squamous epithelium of the
vagina becomes the columnar epithelium of the endocervix is known as the
transformation zone. The position of the transformation zone is related to age,
age at first pregnancy and the degree of estrogenic stimulation. During the
reproductive years, the endocervical epithelium and glands extend to the level of
the external os or just above it. Under estrogenic stimulation, such as that
resulting from the oral contraceptive pill or from pregnancy, the endocervical
epithelium may migrate beyond the external os, appearing as a visible area on the
cervix that was known, misleadingly, as a cervical erosionmisleading, as it
incorrectly implies a pathologic change. The proper term for this condition is
cervical eversion/ectropion. During the latter half of fetal life a similar
proliferation of the endocervical mucosa may occur which can produce a
congenital eversion seen in up to 50% of female neonates. After the menopause,
as a result of waning ovarian activity, the endocervical mucosa retracts upward
and the transformation zone (squamocolumnar junction) can disappear from view.
If this occurs then obtaining a cervical smear or performing colposcopy may not
be possible unless estrogenic stimulation is applied for several weeks beforehand.
The cervical eversion (ectropion) can spontaneously disappear and the
squamocolumnar junction can move above the external os during the
reproductive years as well. This process is known as squamous metaplasia.
Squamous metaplasia
Metaplasia implies transformation of one type of differentiated tissue into another.
In the cervix, squamous metaplasia occurs when the prolapsed endocervical
epithelium (eversion/ectropion) is replaced by the more robust squamous
epithelium. The process of metaplasia probably involves the following steps:
(1) Endocervical eversion, metaplasia and stratification of the cell layer which is
underneath the eversion;
(2) Sloughing of the overlying columnar epithelium;
(3) Maturation of the underlying cells into stratified squamous epithelium.
The mature metaplastic epithelium is indistinguishable from the indigenous
squamous epithelium. However, the immature metaplastic epithelium lacks
glycogen and does not take up iodine, which can confuse the inexperienced
colposcopist. The presence of metaplastic cells on a cervical smear is thus a
normal finding.
The body of the uterus measures 77.5 cm in length, 4.55 cm in width and 2.
53 cm in thickness. It lies in the pelvis between the bladder and the rectum. The
cephalic portion is called the fundus. On both sides of the fundus are the uterine
horns where the fallopian tubes join the uterus. The uterus is composed mainly
of smooth muscle cells wrapped in peritoneum on the outside. On the inside of
the uterus there is a cavity lined with endometrium. It is slit-like and triangular in
shape. The uterus has a remarkable potential to grow. It can grow from 50100 g
in the non-pregnant state to over 1 kg during pregnancy. The uterine
endometrium also changes under the influence of ovarian hormones, developing
from less than 5 mm in thickness during the early follicular phase and in
menopausal women, to more than 10 mm under the influence of estrogen.
The fallopian tubes connect the ovaries with the uterus (Figure 1.4). They are
about 1012 cm in length. Their reproductive function involves ovum collection
and transport, the transport of sperm, aiding fertilization and early embryonic
development, and transport of the conceptus to the uterus. The fallopian tubes are
Figure 1.4 Anterior view of the uterus. Reproduced with permission from Fincker NJ,
Friedman AJ. The uterine corpus. In Ryan KJ, Friedman AJ, Barbieri RL. Kistners
Gynecology, 5th edn. Chicago: Year Book Medical Publishing, 1990:189
under the influence of ovarian hormones: their motility changes as the viscosity
of the tubal fluid and the ciliary action of mucosal cells change cyclically.
The blood supply to the uterus and the tubes is by the uterine artery, a branch
of the internal ileac artery. The venous blood drains to the internal ileac veins
and there are extensive communications with the vesical and rectal plexuses. The
main lymphatic drainage is to the external and internal iliac nodes and there are
some scanty connections to the inguinal and aortic nodes. The nerves to the
uterus and tubes are branches from the pelvic plexus. Pain from the cervix is carried
by pelvic splanchnic nerves (parasympathetic), while that from the body of the
uterus (labor pains) travels with sympathetic fibers to the lowest thoracic segments
of the cord T11-T12. The abolition of all uterine sensation requires destruction/
anesthesia above the T10 level.
Ovary
The two ovaries (Figure 1.4) are almond-shaped organs 25 cm in length, 1.53
cm wide and 0.51.5 cm thick. The combined weight is about 1520 g. Each is
suspended to the uterus via the uteroovarian ligament and to the fallopian tube
via the infundibulopelvic ligament. When the woman is standing, the long axis
of the ovary is vertical and its lateral surface lies against the pelvic side wall. The
ovary is attached to the posterior leaf of the broad ligament by a peritoneal fold
termed the mesovarium. It derives its blood supply from the ovarian artery, a
branch of the abdominal aorta just below the renal artery. The venous drainage
parallels the artery and the lymphatics drain to the para-aortic nodes, just above
the level of the umbilicus (L3/L4).
The ovary has a complex structure and function, being an organ of

gametogenesis and also an endocrine organ. It consists of three distinct regions:
the outer cortex, which contains the ovarian follicles, a central medulla
consisting of ovarian stroma, and an inner hilum around the area of attachment
of the ovary to the mesovarium. The development of the ovary involves three
distinct embryonic tissues: the primordial germ cells, the coelomic epithelium of
the urogenital ridge, and the ovarian mesenchyme. The primordial germ cells
originate from the gut endoderm and give rise to the oocytes, the granulosa cells
develop from the coelomic epithelium and the stromal and thecal cells arise from
the mesenchyme. The ovary develops from the genital ridge, which starts to form
from about the fifth to sixth week of fetal development. It consists of an inner
core of ovarian mesenchyme and a thick outer layer of proliferating coelomic
epithelium. At this stage, male and female gonads are indistinguishable and are
known as indifferent gonads (indifferent is the correct embryologic term). In
the absence of the Y chromosome, the indifferent gonad develops into an ovary.
The germ cells develop from the yolk sac and migrate and settle in the ovary, as
oogonia. They proliferate through mitosis until about 20 to 38 weeks gestation
when mitotic division ceases and meiosis starts. The oogonia differentiate into
primary oocytes, which progress into the prophase of the first meiotic division
and then become dormant until puberty. In other words, at the time of her birth, a
female has all the oocytes she will ever have. At 2528 weeks of gestation, the
number of oocytes peaks at around six to seven million and then their number
starts a steady decline, the loss being due to atresia. At birth, there are
approximately one million germ cells, and at the time of puberty, there are
between 250 000 and 400 000 oocytes. After puberty, in the oocytes that are
destined for ovulation, following the preovulatory luteinizing hormone (LH)
surge, meiosis is resumed and the first division is completed with the formation
of a big daughter cell and the extrusion of the small polar body. The oocyte
enters the second meiotic division and is arrested in its metaphase (metaphase
II). Resumption of the second meiotic division follows sperm fusion, resulting in
the formation of a second polar body and female pronucleus.
Follicles
The follicles are situated in the ovarian cortex and are either dormant or in
various stages of development (Figure 1.5). The inactive follicles are termed
primordial. In each cycle, a cohort of primordial follicles is recruited and starts
developing. The primordial follicle is composed of a single layer of granulosa
cells and a single immature oocyte arrested in the first meiotic division. The
follicle is separated from the surrounding stroma by a thin basement membrane
and does not have a direct blood supply. The developing primordial follicles go
through the following stages: primary, secondary, tertiary, graafian and atretic.
The first three stages of growth can occur in the absence of gonadotropins and
thus suggest either intraovarian control or pre-programed recruitment. During
these stages, the granulosa cells divide and grow forming multiple layers.
Granulosa cells have receptors for LH and follicle-stimulating hormone (FSH)
and their main function is the production of estrogen. During the follicular phase
the oocyte grows from 15 m to 135 m and becomes one of the biggest cells in
the body. It matures and starts secreting glycoproteins forming the zona pellucida
(pale zone). The considerable size is explained by the fact that the oocyte must
possess all machinery (mitochondria, nutrients, etc) to sustain the pregnancy
until implantation occurs. The cells outside the
Table 1.1 Some non-steroidal factors produced by the ovary
Non-steroidal factor
Proposed function
Activin
Follistatin
Inhibin
Angiogenic factors
FRP
Growth factors
FSH binding inhibitor
LH binding inhibitor
Mllerian inhibiting factor
Oxytocin (corpus luteum)
Stimulates FSH release

Suppresses FSH release
Inhibits FSH release
Vascularization of corpus luteum
Follicle atresion, aromatase inhibin
Modulation of steroidogenesis
Inhibits binding of FSH to receptor
Inhibits binding of LH to receptor
Development of reproductive tract
Modulates progesterone secretion and life span of corpus
luteum
Relaxin
Remodeling of reproductive tract
Renin-angiotensin
Ovulation; regulation of steroidogenesis
FRP, follicular-regulating protein; FSH, follicle-stimulating hormone; LH, luteinizing
hormone
follicle also grow and differentiate forming the thecal layers. The tertiary follicle
has a fluid-filled space named the antrum (hence antral follicle). The fluid
consists of plasma filtrate and secretory products of the granulosa cells.
Under the influence of FSH, the antral follicles grow further to form mature
Graafian follicles. The antral fluid increases in volume and the oocyte is
surrounded by a clump of granulosa cells called the cumulus oophorus. At this
stage, the follicle is at least 14 mm in mean diameter and is ready to release the
egg. The resumption of meiosis occurs following the preovulatory surge of LH.
The ovarian stroma consists of three cell types: contractile cells, connective
tissue cells and interstitial cells. The interstitial cells secrete steroid hormones,
mainly androgens, and undergo morphologic changes in response to LH and
human chorionic gonadotropin (hCG). As the follicle develops, the interstitial
cells differentiate and become thecal cells. After ovulation, blood vessels invade
the cavity of the follicle. Granulosa cells and thecal cells transform into
granulosa-lutein and theca-lutein cells and form the corpus luteum. The corpus
Figure 1.5 Structure of the ovarian follicle during growth and development. Reproduced
from Erickson GF, Magoffin DA, Dyer CA, Hofeditz C. The ovarian androgen producing
cells: a review of stucture/function relationships. Endocr Rev 1985;6:37199, with
permission of The Endocrine Society
luteum secretes estrogen and progesterone. In the absence of pregnancy, the

corpus luteum undergoes degeneration to form the corpus albicans. The ovary
Figure 1.6 Cross-section of the breast. Reproduced with permission from Tortora GJ,
Grabowski SR, Schmidt Prezbindowski K, eds. Principles of Human Anatomy and
Physiology, 10th edn. New York: John Wiley & Sons, 2002:1040
also produces a number of other substances in addition to steroid hormones. Some

of these are described in Table 1.1.
The pelvic floor and support of the pelvic organs
The pelvic organs and the abdominal content of a woman are supported via
intricate systems of muscles and ligaments. There is still debate among
anatomists, physiologists, urologists and urogynecologists with regard to the role
that various structures play in the support of the pelvic organs. We are not going
to join this debate but will merely list some structures which have been
universally accepted as important. The pelvic opening is closed by the perineal
body and muscles, the biggest and most important of which is the levator ani.
This muscle originates from the side walls of the pelvis and is funnel shaped.
The funnel has three orifices: urethra, vagina and anus. The uterus is held in
place largely by the uterosacral and cardinal ligaments and to a lesser extend by
the round and broad
Table 1.2 Hormonal regulation of the breast
Ductal growth
Estrogen
Cortisol
Growth hormone
Alveolar growth
Progesterone
Prolactin
Growth hormone
Cortisol
Lactation
Prolactin
Placental lactogen
Cortisol
Insulin
Insulin-like growth factor
ligaments. Prolapse of the pelvic organs depends on (1) how well developed the
support systems are (e.g., as a result of genetic endowment and exercise) and (2)
the stresses put onto them via increased intra-abdominal pressure, stretching the
tearing (pregnancy, childbirth, obesity, constipation, ascites, chronic cough, etc).
The breast
The breast is situated between the second and the sixth rib horizontally
(Figure 1.6) and between the parasternal area and the mid-axillary area
vertically. The central thickness of the breast is between 5 and 7 cm. It has
various configurations: in young nulliparous females it has a conical appearance,
and in parous women and later in life it becomes pendulous. The nipple is
situated near the summit of the breast, usually at the level of the fourth intercostal
space. The breast extends upward and laterally toward the axilla, a part of which
is known as the axillary tail of Spence. The average breast weighs about 100 g
and often there is discrepancy in size with the left breast usually being bigger. In
pregnancy, the breast increases dramatically in size and weighs three to four
times more than in the non-pregnant state. The structure of the breast consists of
skin, subcutaneous tissue and the stroma. The skin is thin, flexible and elastic,
which allows the breast to expand and shrink depending on the physiologic
condition. The breast skin has hair, sebaceous glands and eccrine sweat glands.
Below the skin, there is connective tissue which includes the fatty tissue, blood
vessels, nerves and lymphatics. Within the stroma, there is a ductal-lobularalveolar structure which resembles a river and its tributaries. Proximally, the
alveoli are very small, but distally they increase in size and open into the
lactiferous sinuses, just below the areola structure. There are 15 to 25 lobes, each
one consisting of multiple lobules, and each lobule has hundreds of
tubulosaccular secretory units. The nipple is a conical elevation where 15 to 25
milk ducts open. It has a rich sensory nerve supply and sebaceous and apocrine
sweat glands. The areola surrounds the nipple and can vary in size from 1.5 to 5
cm, and peripherally there are Morgagnis tubercles which are openings of the
sebaceous glands of Montgomery. During stimulation, the nipple becomes erect
and the areola constricts; both are caused by the underlying smooth muscle. The
breast tissue is attached to the overlying skin via a subcutaneous fascia known as
Coopers suspensory ligaments. The bottom of the breast lies on the pectoralis
fascia. The blood supply to the breasts is via the internal mammary artery (60%
of the blood), lateral thoracic artery (2530%) and the intercostal arteries (5
10%). The lymphatics of the breast are quite numerous and mainly go toward the
axilla and along the internal mammary artery. There are, however,
communications with the other breast, with subdiaphragmatic and intraperitoneal
lymph nodes and with the liver. The sensory nerve supply of the breast is derived
from the fourth, fifth and sixth intercostal nerves. The same nerves carry
sympathetic fibres with them to the breast.
The alveolar unit is the milk-producing structure of the breast and it has three
types of cells: alveolar cells, chief cells and myoepithelial cells. The alveolar
cells are stimulated by sex steroids and are responsible for milk production. The
chief cells provide the energy source for the alveolar cells. The myoepithelial
cells are of ectodermal origin, respond to oxytocin by constriction and allow the
expression of milk. The stromal tissue is quiescent until puberty, when the
breasts start developing in an orderly manner first described by Marshall and
Tanner. Breast development usually starts between 9 and 11 years of age,
together with pubic and axillary hair growth. It is difficult to outline precisely the
relative contribution of the numerous hormonal and growth factor influences on
breast growth (see Table 1.2). In vitro estrogen appears to stimulate the ductal
proliferation, while progesterone stimulates lobulo-alveolar development. The
breast undergoes cyclic changes associated with ovulation, and premenstrual
breasts can be engorged and tender probably because of tissue edema and
hyperemia.
Before pregnancy, the breast consists mainly of ducts, connective tissue and
adipose tissue. During pregnancy, lobulo-alveolar elements differentiate under
the influence of sex hormone but also placental lactogen, prolactin, insulin and
insulin-like growth factor.
2
Hormones in reproduction
INTRODUCTION
A number of hormones and hormone-like substances are involved in regulating
the reproductive process in humans. Some are well studied, others less so. It is
not our aim to discuss all of them. In this chapter we will restrict our discussion
to those hormones whose structure and function have been well studied and are
universally accepted.
LUTEINIZING HORMONE-RELEASING HORMONE
The neurohormone involved in regulating the synthesis and release of both
folliclestimulating hormone (FSH) and luteinizing hormone (LH) is
gonadotropin-releasing hormone (GnRH), also known as luteinizing hormonereleasing hormone (LHRH). It is a decapeptide secreted from the LHRH neurons
of the hypothalamus into the portal vessels. LHRH modulates both LH and FSH,
neither of them selectively. The half-life of LHRH is 24 min. It is secreted as a
pulse every hour during the follicular phase and every 3 h during the luteal phase.
Its main function is to promote synthesis, storage and release of gonadotropins.
Pulsatile secretion of LHRH leads to pulsatile release of LH and FSH. Therefore,
hypothalamic LHRH neurons regulate the synthesis and secretion of FSH and LH
by the anterior pituitary. Alteration of the output of FSH and LH can be achieved
by increasing or decreasing the amplitude or frequency of LHRH pulses.
FOLLICLE-STIMULATING HORMONE AND
LUTEINIZING HORMONE
FSH and LH are responsible primarily for the processes concerned with
follicular and germ cell development and with ovulation. LH and FSH are
secreted by the gonadotrophic cells (basophilic), which comprise about 10% of
the anterior pituitary. LH and FSH are hetero-dimeric glycoprotein hormones of
similar size, and consist of a common a chain and a distinct chain. The same
chain is present in thyroid-stimulating hormone (TSH) and human chorionic
gonadotropin (hCG). The subunit is encoded by a single gene located on

chromosome 6, while the FSH subunit is located on chromosome 11 and the
LH subunit on chromosome 19. FSH has a longer half-life than LH
(Table 2.1). Secretion of LH and FSH is under the control of LHRH, which, as
mentioned above, is secreted in a pulsatile fashion. LH is released in pulses at a
frequency of every 6090 min during the follicular phase and every 3 h during
the luteal phase. The mechanism of FSH and LH action involves binding to
specific cell membrane receptors and subsequent activation of the adenylate
cyclase system, which in turn leads to signaling steps within the cell.
FSH receptors are present only on granulosa cells. FSH stimulates the growth
and division of the granulosa cells of the ovarian follicle and controls the
aromatase responsible for estradiol formation within these cells. It also induces
the synthesis of LH receptors on the granulosa cells and is involved in the
production of inhibin, activin and insulin-like growth factor I. LH stimulates the
ovarian theca cells to produce androgens, which diffuse to the granulosa cells
where they are converted into estrogens. Plasma estradiol peaks before the LH
surge, which, in turn, triggers ovulation. Postovulation LH contributes to the
formation of the corpus luteum. Once conception has occurred, pituitary
gonadotropins are no longer required to sustain the pregnancy.
ESTRADIOL, PROGESTERONE AND FEEDBACK
CONTROL OF FOLLICLE-STIMULATING HORMONE
AND LUTEINIZING HORMONE SECRETION
The plasma concentrations of circulating FSH and LH increase markedly after
the menopause or after surgical castration. This rise is attributable to the decline
of estradiol and inhibin (mainly inhibin B) secretion. Administration of
physiologic doses of estradiol mimicking those found in the follicular phase of
the menstrual cycle in reproductive aged women leads to a decline of FSH and
LH to levels approximately 50% of the postmenopausal level. This is an example
of classic negative feedback in premenopausal women. It requires a relatively
small rise from low circulating levels of estradiol for an effect on FSH and LH to
be observed. Furthermore, the effect of estradiol is seen very quickly. However,
because inhibin is not administered in hormone replacement therapy (HRT) the
postmenopausal FSH and LH values do not return to within the premenopausal
range with HRT. In regularly menstruating women, if plasma concentration of
estradiol increases two- to four-fold and this increase is sustained over 48 h or
so, then LH and FSH secretion is enhanced, not suppressed. This is termed
positive feedback. The most important effect of progesterone is that high plasma
levels of this hormone enhance the negative feedback of estradiol and suppress
FSH and LH secretion to a very low level. By contrast, low levels may enhance
the positive feedback of estradiol.
HORMONES IN REPRODUCTION 17
Figure 2.1 Principal pathways of steroid hormone biosynthesis in the human ovary.
Reproduced from Carr BR. Disorders of the ovary and female reproductive tract. In
Wilson JD, Foster DW, eds. Williams Textbook of Endocrinology, 8th edn. Philadelphia,
PA: W.B.Saunders, 1992:73398, Copyright (1992), with permission from Elsevier
PROLACTIN
The hormone prolactin is produced by the lactotrophic cells (acidophilic) of the
anterior pituitary. It constitutes 1520% of the normal pituitary and this increases
to 70% during pregnancy. Prolactin has a single polypeptide chain containing
198 amino acids. The gene for prolactin production is on chromosome 6. The
hormone is essential for lactation and a mass of the receptors for this hormone is
present in the human breast and gonads. It may also have some function in the
regulation of steroidogenesis in the ovary. The plasma levels vary during the
day, the highest plasma concentration occurring during sleep. Under normal
circumstances, prolactin secretion is restrained by the hypothalamus and the
inhibitory factor for prolactin appears to be dopamine. Prolactin release is
stimulated by sleep, estrogen, suckling, stimulation of the nipple, thyrotropinreleasing hormone (TRH), stress, opiates and anti-dopamine medications. Some
of the properties of LHRH, LH, FSH and prolactin are summarized in Table 2.1.
OVARIAN STEROIDS
Four major classes of steroids are derived from cholesterol: the progestogens, the
androgens, the estrogens and the corticosteroids. The ovary is involved in the
synthesis and secretion of the first three (Figure 2.1).
Natural progestogens are characterized by possessing 21 carbons (C-21
steroids), androgens by being comprised of 19 carbons (C-19 steroids), and
natural estrogens have 18 carbons (C-18 steroids) in their structure. Ovarian
steroids can exert feedback on both the hypothalamus and the pituitary. Whether
estrogens and progestogens stimulate or inhibit gonadotropin release depends
upon the plasma level and the duration of exposure. The plasma concentrations,
production rates and secretion rates of the main ovarian steroids are given in
Table 2.2.
Over 9798% of the steroids secreted by the ovary are bound to plasma
proteins. Testosterone is mainly bound to sex hormone-binding
Table 2.1 Properties of human luteinizing hormone, luteinizing hormone-releasing
hormone, follicle-stimulating hormone and prolactin*
Hormone Secreted from Acts upon
Composition
Distribution
half-life in
blood (min)
Levels in
human blood
(U/l)
LHRH
Anterior
pituitary
Decapeptide
24
N/A
Thecal cells;
granulosa
cells; luteal
Glycoprotein
, a chain 89
aminoacids;
3060**
Male > 12
years 512 U/
l
LH
Hypothalam
us (preoptic
area and
arcuate
nucleus)
Anterior
pituitary
gonadotroph
Hormone Secreted from Acts upon
FSH
Composition
s
(basophilic)
cells;
interstitial
cells
chain 115
amino acids,
1
carbohydrate
chain
As LH
Granulosa
cells
Glycoprotein
, a chain
identical to
LH; chain
115 amino
acids, 2
carbohydrate
chains
Prolactin Anterior
pituitary
lactotrophs
(acidophilic)
Distribution
half-life in
blood (min)
120150**
Levels in
human blood
(U/l)
Female
Early
follicular 0.
415 IU/1
Midcycle
2070 IU/1
Luteal 0.4
15 IU/1
Menopause
2070 IU/1
Male (age
1370) 1.2
16 IU/1
Female
Early
follicular 28
IU/1
Midcycle 2.
727 IU/1
Luteal 1.27.
3 IU/1
Menopause
1893 IU/1
Male and
female 60
450 U/l
Ovarian
Polypeptide
1020
follicles;
single chain
luteal cells;
of 198 amino
mammary
acids
glands
LHRH, luteinizing hormone-releasing hormone; N/A, not available; LH, luteinizing
hormone; FSH, follicle-stimulating hormone
*Values vary from one laboratory to another
**Elimination half-life: LH, 1012 h; FSH, 17 3h
Distribution half-life and biological half-life are different concepts. For the reproductive
hormones the biological half-life is greater than the distribution half-life
globulin (SHBG). Estradiol is bound to albumin (60%) and SHBG (38%). SHBG
is a -globulin formed in the liver with a molecular weight of about 95 000. The
level of SHBG, and thus the level of free hormone, can be affected by a number
of conditions. Levels are increased by estradiol, combined oral contraceptives
(COCs) and thyroid hormones, and are decreased by androgens, hypothyroidism
and obesity.
There are number of naturally occurringgonadal steroids, all of them with
different potency. The ones that are most important for clinical practice and their
principal actions on the reproductive system are outlined in Table 2.3. In our
discussion we are going to use the terms progesterone and estrogen or estradiol
to denote all naturally occurring progestogens and estrogens.
Mechanism of action of steroid hormones
All ovarian steroids have the same basic mechanism of action. For clarity and
because the estrogen activity has been widely studied,
Table 2.2 Concentration, production rates and ovarian secretion rates of steroids in blood
Compound
Menstrual cycle Representative PR* (mg/day)

phase
concentration in
plasma (nmol/1)
SR** by both
ovaries (mg/
day)
Estradiol
Early follicular
0.08
0.07
0.51.5
0.270
0.40.8
0.250
2.1
25
0.250.5
3.2
1.5
24
0.20.5
0.81.6
Late follicular
Midluteal
Menopause
Progesterone
Follicular
Luteal
0.2 (200 pmol/

1)
1.22.6
0.7 (700pmol/
1)
< 0.11 (110
pmol/1)
3.0
30100
1.3 (0.52.8)
5.6
Testosterone
Androstenedio
ne
Dehydroepiand
17
8.0
0.33
rosterone
*PR, production rate, consisting of the sum of secretion rate and amount contributed by
interconversion of precursor steroids; SR, secretion rate, being the secretion of ovarian
steroids in units per day
Table 2.3 Relative potency and principal actions of some naturally occurring sex steroids
in females
Type of steroid and relative potency*
Estrogens
17-Estradiol (100%)
Estrone (10%)
Estriol (1%)
Progestogens
Properties
Stimulate secondary sexual characteristics
Prepare the genital tract for spermatozoal
transport
Stimulate growth and the activity of
mammary glands
Stimulate the growth of the endometrium
and prepare the endometrium for
progesterone action
Associated with sexual behavior
Regulate secretion of gonadotropins
Type of steroid and relative potency*
Properties
Progesterone (100%)
17-Hydroxyprogesterone (4070%)
Prepare uterus to receive embryo

Maintain uterus during early pregnancy
Stimulate growth of mammary glands but
suppress the secretion of milk
Regulate secretion of gonadotropins
Androgens
5-Dihydrotestosterone (100%)
Testosterone (50%)
Dehydroepiandrosterone (4%)
Induce growth of androgen-dependent

body hair
Influence sexual and aggressive behavior
? Regulate secretion of gonadotropins
*The relative potencies are approximations only. They vary with (1) the assay used; (2)
the affinity of the steroid for the steroid receptor in different tissues; (3) the
local enzymatic conversion of the steroids in the target tissues; and (4) the
differences in systemic metabolism
the mode of action described here uses estrogen as the example (Figure 2.2).
Free steroids are thought to diffuse passively to all cells because there is no
evidence as yet of an active transport mechanism. Steroids are preferentially
retained in target cells as stable complexes bound to intracellular receptor
proteins (i.e., estrogen receptorER), which are steroid- and tissue specific. The
receptor is thought to be a hormone- or ligand-activated transcription factor. The
terms are used interchangeably.
The ER has six structural domains (protein regions having some distinct feature
or role), A to F, but the important ones are the steroid-binding domain and the
DNA-binding domain. The receptor binds the hormone, i.e., estrogen, through its
steroid-binding domain. The binding of the steroid by the receptor results in the
activation of the receptor molecules, which leads to conformational changes in
the hormone-receptor complex, including its DNA-binding domain. This
activation allows the hormone-receptor complex to bind to specific sites in the
DNA, termed nuclear acceptor sites. Once bound to the DNA, the activated
steroid-receptor complex acts as a transcription factor, which switches
ongenes, coding for the production of new proteins. The newly synthesized
proteins change the metabolism of the target cell in a steroid-specific manner.
The transfer of the steroid in the cell and nuclear binding of the steroid-receptor
complex is rapid, occurring within minutes. Nuclear binding affects messenger
RNA levels and synthesis within several hours, and finally protein synthesis and
turnover happens within 1224 h. The major physiologic effects of steroids in
cells are seen in 1236 h.
There are two estrogen receptors so far described: ER (classic ER) and ER
(recently described). Classic ER was cloned and sequenced from human breast
cancer cells in 1986. The ER consists of 595 aminoacids with a molecular
weight of 66 kDa. The ER was cloned in 1996 from rat prostate and ovary. It
consists of 485 amino acids and has a molecular weight of 54.2 kDa. ER is 95%
Figure 2.2 A schematic representation of the subcellular effects of estrogen (E) in

estrogen target tissue. Estrogens dissociate from plasma proteins (P), bind to the estrogen
receptor (ER) and the complex becomes activated (ER*). Activated ER complex interacts
with the nuclear acceptor site on the DNA (A). This results in the activation of DNA
polymerase and RNA polymerase to initiate subsequent cell proliferation and protein
synthesis, respectively. The receptor is then destroyed (processed), in which case a new
cytoplasmic receptor is synthesized or recycled for subsequent ligand binding. Whether
the binding of estrogen and the receptor occurs on the cytoplasm in the nucleus has been
debated. It is currently thought that the interaction happens in the nucleus. Reproduced
from Manassiev N, Keating F, Whitehead M. Selective estrogen receptor modulators: a
review for the clinician. In Studd J, ed. The Management of the Menopause. The
Millennium Review 2000. Carnforth, UK: Parthenon Publishing, 2000:6984
homologous with ER in the DNA-binding domain and 55% in the hormonebinding domain. ER resides no chromosome 6 and ER on chromosome 14.
ER has a higher affinity for short-acting estrogens such as 17-estradiol. Tissue
distribution of ER and ER varies and is under intense scientific investigation.
Most of the work has been done on rodents, so-called estrogen receptor knockout
(ERKO) mice. A knockout mouse is a genetically engineered animal in which
the genome has been altered by site-directed recombination so that a particular
gene is deleted. The reported findings may not be directly applicable to humans.
The results depend on the sensitivity of the assays and are sometimes conflicting.
Recent reports describe ER predominance in the vagina, uterus, ovarian stroma,
breast, cardiovascular system, liver, skeletal muscle, pituitary and epididymis; in
contrast, ER is predominantly found in ovarian granulosa cells and the prostate.

Both receptors are well represented in the brain and bone, but in different
structural and functional parts. The levels of ER and ER may vary depending
on the age of the animal. The physiologic role of the different receptors is
currently being studied. For example, ER knockout mice develop to maturity,
but are infertile, do not exhibit female sexual behavior and do not respond to
estradiol.
Physiologic functions of steroid hormones
The main function of the ovarian steroids is related to reproduction. They are
instrumental in developing the secondary sexual characteristics, establishing the
menstrual cycle and in maintaining pregnancy. However, as our methods for
studying the steroid hormones have developed, so has our understanding of their
wider functions.
Estrogen
Female maturation Estrogen stimulates the growth of the vagina, uterus and
fallopian tubes and the secondary sexual characteristics during puberty. It
stimulates fat deposition, stromal development and ductal growth of the breast
and is responsible for the accelerated growth phase and the closing of the
epiphyses of the long bones that occurs at puberty. Estrogen contributes to the
growth of axillary and pubic hair and alters the distribution of the body fat so as
to produce the typical female body habitus. It stimulates the pigmentation of the
skin, most prominent in the region of the nipples and areolae and in the genital
region.
Other biological effects of estrogen Estrogen exerts effects on the
cardiovascular system, connective tissue and numerous aspects of the metabolism
such as lipids and carbohydrate metabolism. Some of those effects are well
established and important and some are less well studied and/or less significant.
Some estrogenic effects are summarized in Table 2.4.
The main sources of estrogen in women are the granulosa cells and the
luteinied granulosa and theca cells of the ovaries. Estrogen is also produced by
fat tissue and, in smaller amounts, by muscle and nervous tissue. Estrone and
estriol are mostly formed from estradiol in the liver.
Progesterone
The chief function of progesterone is to prepare the endometrium for acceptance
and maintenance of pregnancy, and the stimulation of alveolar growth of the
mammary glands. Some of the effects of progesterone are listed in Table 2.5.
Progesterone is produced by theca and granulosa lutein cells and the corpus
luteum.
Androgens
Androgen production in the female is greater than is widely appreciated. The role
of androgens in the female includes acting as precursors
Table 2.4 Biological effects of estrogen
Reproductive system
Gonadotropin regulation
Stimulation of secondary sexual characteristics
Increasing cervical mucus production
Breast development (stromal and ductal tissue)
Modulation of sexual behavior
Endometrial stimulation
Cardiovascular system
Increased cardiac output Vasodilatation
Endothelial effects
Suppression of appetite
Stimulates skin growth and wound healing
Reduces motility of the bowel
Mild anabolic effect
Metabolic effects
Higher levels of corticosteroid-binding globulin, thyroxin-binding globulin, SHBG,
renin
Reduction of cholesterol
Reduction of bone resorption
Reduction of capillary fragility
Promotion of coagulation
SHBG, sex hormone-binding globulin
for estrogen production, anabolic effects, stimulation of axillary and pubic hair
growth, sebum production, stimulation of bone formation, and stimulation of
production of erythropoietin (EPO) from the kidneys (Table 2.6).
Androgens are produced from the ovaries, the adrenal glands and from
peripheral conversion in adipose tissue. During reproductive life, the relative
contribution from these sources varies. The ovaries and adrenals produce
androstenedione, testosterone and dehydroepiandrosterone (DHEA), and the
adrenals also produce DHEA sulfate (DHEAS). Androstenedione, DHEA and
DHEAS are converted peripherally to testosterone, dihydrotestosterone (DHT)
and estrogen. Only 12% of the total circulating testosterone is free or
biologically active, the rest being bound to SHBG and albumin. In women, there
are alterations in the level because SHBG has a dramatic effect on the free levels
in plasma, binding 66% of total circulating testosterone. SHBG is increased by

increased levels of estradiol and thyroxine,
Table 2.5 Biological effects of progesterone
Reproductive system
gonadotropin regulation
endometrial decidualization
maintenance of early pregnancy
breast development (alveolar tissue)
Increase of appetite
Mild catabolic effect
Increase of basal body temperature via thermoregulatory centre of the hypothalamus
Binding to the aldosterone receptor in the kidney and promoting natriuresis
Contributes to premenstrual symptoms such as bloatedness, heavy tender breasts
Slows peristalsis in the gastrointestinal tract, which may cause constipation
Depressant and hypnotic effects on the brain
Alters the function of the respiratory centre (increases respiratory drive)
Table 2.6 Biological effects of androgens
Reproductive system
libido, sexual behavior
growth of androgen-dependent body hair
? regulation of gonadotropins
Anabolic effect
nitrogen retention
muscle growth
Stimulate bone formation
Increase serum production
Increase EPO production
Decrease HDL cholesterol
Contribute to general well-being
EPO, erythropoietin; HDL, high-density lipoprotein
and suppressed by testosterone, glucocorticoids, excessive growth hormone, high

insulin levels and obesity. The daily androstenedione and testosterone production
in premenopausal women is thought to be about 3.2 mg and 0.26 mg,
respectively.
In premenopausal women, 25% of testosterone is produced by the ovaries,
25% by the adrenals and 50% by peripheral conversion. In postmenopausal
women, 50% of testosterone is produced by the ovaries, 10% by the adrenals and
40% by peripheral conversion, and the overall androgen production decreases
with age. The age-related decrease in androgen production starts

premenopausally and testosterone levels fall by approximately 50% between the
ages of 20 and 40, and then level off. After the menopause, the process continues
and the age-related decline is particularly noticeable for DHEA and DHEAS.
Following natural menopause, the level of androstenedione is 50% of the
premenopausal value. After oophorectomy, the levels of testosterone and
androstenedione fall by 50% in previously premenopausal women and by 50%
and 21% respectively in previously post-menopausal women. Some androgenic
effects are listed in Table 2.6.
INHIBINS, ACTIVINS AND FOLLISTATINS
Inhibins, activins and follistatins are produced by the ovary and are a part of a
larger family of growth factors. Inhibins are proteins that consist of a common
subunit and one of two subunits (A or B). They are classified as inhibin A if
they contain A chain or inhibin B if they contain B chain. Activins are proteins
that have two chains (homodimersA/A, B/B; or heterodimersA/B)
butno chains.
Inhibin A is mainly produced by the dominant follicle and the subsequent
corpus luteum. It is maintained at relatively constant low levels through most of
the follicular phase, then exhibits a late follicular phase rise (in keeping with its
production by the dominant follicle), a midcycle peak, and a long peak with the
highest levels recorded during the luteal phase. Inhibin A appears to exert
negative feedback on FSH during the luteal phase of the cycle.
Inhibin B is found in the granulosa cells of antral follicles during the end of
the luteal phase of the preceding cycle and the early follicular phase of the next;
its concentration in plasma changes in parallel with FSH: it rises in the early
follicular phase, declines toward midcycle, shows a midcycle peak and reaches
its lowest level during the luteal phase. This suggests it is produced by the cohort
of small antral follicles and suppresses FSH in the follicular phase. Inhibin B is
currently being evaluated as a test for ovarian reserve (the ability of the ovary to
produce oocyte(s) in response to stimulation with fertility drugs).
Inhibin A, together with -fetoprotein and free -hCG, shows much promise in
serologic testing for Downs syndrome in early pregnancy. Activins and
follistatins are less well studied. As the names suggest, one property of the
activins is to enhance the secretion of FSH, while follistatins suppress it by
binding and inactivating the activins. Their role as gonadal feedback regulators is
still under investigation.
3
The female reproductive cycle
INTRODUCTION
From the reproductive point of view the female lifecycle can be conveniently
divided into three parts: from birth to menarche, from menarche to menopause,
and the post-menopause era. Definitions of various terms used in reproductive
medicine are given in Table 3.1. A graphical representation of some of these
definitions is shown in Figure 3.1.
HORMONE SECRETION: FROM INFANCY
THROUGH PUBERTY
In the female, luteinizing hormone (LH) and follicle-stimulating hormone (FSH)
levels are elevated at birth but fall to low levels within a few months and remain
low throughout the prepubertal years, with FSH generally slightly higher than
LH. Steroid hormones, such as dehydroepiandrosterone (DHEA), estradiol and
testosterone, are increased at birth; then they decrease to very low levels.
The adrenal androgens DHEA and DHEA sulfate (DHEAS) begin to increase
several years before puberty. This increase may be important in initiating pubic
and axillary hair growth (adrenarche) and other pubertal events.
Puberty
The sequence of events by which a child reaches sexual maturity with the
development of secondary sexual characteristics and an associated growth spurt
is called puberty. The mechanisms initiating puberty are unclear. There has been
a secular trend toward an earlier menarche in girls in Western Europe and the
USA. It is generally agreed that during the last 100 years or so, the age at which
girls first menstruate has decreased to between 12
Table 3.1 Definitions of various terms used in reproductive medicine
Puberty: the sequence of events by which a child reaches sexual maturity with
development of secondary sexual characteristics and an associated growth spurt
Menarche: first menses (mean age 13 years, range 10.516)

Precocious puberty: the onset of sexual maturation before age 8
Delayed puberty:
no breast development by age 13
no pubic hair by age 14
more than 5 years between breast development and menarche
no menstruation by age 16
Reproductive life: the period from menarche to menopause
Menopause: permanent cessation of menses (at least 12 months after last menstrual
period). In the UK the mean age at menopause is 51 years (range 4555)
Premature menopause: menopause at or before age 40
Early menopause: menopause after age 40, but before age 45
Late menopause: menopause at or after age 55
Perimenopause: period of declining ovarian function (mean age at beginning of clinical
symptoms 47 years). It begins with stage2 and ends 12 months after the final
menstrual period. It is often used interchangeably with menopause transition
Climacteric: the period from decreasing to absent ovarian function (used synonymously
with perimenopause). It is desirable to use the terms perimenopause and climacteric
only in discussion with patients and not with scientific publications
Menopausal transition: stages2 and1. It ends with patients and not in scientific
publications the final menstrual period, i.e., it can be recognized only after 12 months
of amenorrhea
Postmenopause: the years after the final menstrual period (stages+1 and+2). However,
the terms postmenopause and menopause are often used interchangeably
and 13 years. In Western Europe, the age of menarche decreased by four months
for each decade between 1850 and 1950 but has not
Figure 3.1 Graphical representation of various terms used in reproductive medicine. Data
derived from Soules MR, Sherman S, Parrott E, et al. Executive Summary: Stages of
Reproductive Aging Workshop (STRAW). Fertil Steril 2001; 76:8748
THE FEMALE REPRODUCTIVE CYCLE 29
Figure 3.2 Secular trend towards an earlier age at menarche in girls from Western Europe
and the USA. Reproduced with permission from Johnson MH, Everitt BJ. Essential
Reproduction, 2nd edn. Oxford: Blackwell Scientific Publishers, 1984:157
decreased during the last four decades (Figure 3.2). The mean age at menarche
for girls in the United States is 12.8 years. It can occur as early as 10 and as late
as 16 years. Menarche is preceded by breast budding, sexual hair growth and a
growth spurt. For several years after menarche the menstrual cycles may be
anovulatory and variable in frequency, duration and heaviness of menstrual flow.
There are a number of factors that might have contributed to the earlier
attainment of sexual maturity and that give an insight into the mechanisms
controlling the initiation of puberty.
Table 3.2 Stages of follicular development
Follicular phase: variable length, average 1117 days
(1) Recruitment: days 14
(2) Selection: days 57
(3) Dominance: days 812; ends with ovulation
Ovulation: hours
Luteal phase: relatively constant length, 1315 days
Environment
Health care and personal health have improved over the years, along with living
conditions and economic standards. These have certainly contributed to
increased longevity, but their relationship to puberty is less clear. In Western
societies, people are exposed to more light now than in the 19th century, thanks
to the advent of electricity. Increased light exposure in some species can accelerate
puberty, presumably through modulation within the central nervous system,
mediated perhaps through the pineal gland and melatonin. Interestingly, contrary
to expectation, blind girls experience an earlier menarche. Puberty occurs early
among girls living in urban areas and in those whose mothers matured early.
Nutrition and body weight
Moderate obesity is associated with earlier menarche and menarche is commonly
delayed in severely underweight and malnourished girls. Such observations
suggest that critical body weight, or more specifically critical body fat, is
necessary for menarche. In fact, the body weight at menarche over the past 100
years has remained surprisingly constant, at about 47 kg. The link between the
critical body fat and puberty may be the hormone leptin, produced by the
adipocytes. It has been suggested that a critical body leptin level is needed to
kick-start the luteinizing hormone-releasing hormone (LHRH) neurons into
activity.
The normal menstrual cycle during the reproductive years
The menstrual cycle during the reproductive years (from puberty to the
menopause) is a complex event which depends on a timely and intricate
interaction between the hypothalamus, the pituitary, the ovaries and the uterus.
Its final common pathway is pregnancy or menstruation in the absence of
pregnancy. There are numerous direct and indirect, positive and negative,
autocrine and paracrine links between the main players. This makes the task of
describing the menstrual cycle difficult. For practical purposes, it is easiest to
concentrate mainly on the changes in the ovaries and the endometrium.
Ovarian cycle
The follicle is the engine of the ovarian cycle (Figure 3.3). Follicular
development goes through several stages (Table 3.2; see also Figure 1.5) and
each of these will be discussed in turn. Serum hormone changes during the
menstrual cycle are summarized graphically in Figure 3.4.
Follicular phase The menstrual cycle begins with the first day of menstruation
but follicular growth is initiated during the last few days of the luteal phase of
the preceding menstrual cycle. Near the end of the previous luteal phase, plasma
progesterone, estrogen and inhibin A levels decline because of the demise of the
corpus luteum, and a rise of FSH occurs (days 14). FSH initiates the
recruitment of a follicular cohort (of antral follicles). These follicles start
developing and secreting steroid hormones as well as acquiring FSH and LH
receptors. From the middle of the follicular phase onward, estrogen levels rise
steadily, leading to an estradiol surge. In parallel with this increase, there is an
Figure 3.3 Developmental changes in the adult ovary during a complete menstrual cycle.
Reproduced from Carr BR, Wilson JD. Disorders of the ovary and female reproductive
tract. In Wilson JD, Braunwald E, Isselbacher KJ, et al., eds. Harrisons Principles of
Internal Medicine, 12th edn. New York, NY: McGraw-Hill, 1991:177695
increase in the levels of 17--hydroxyprogesterone, testosterone,

androstenedione and inhibin. FSH levels begin to decline because of the
negative feedback of estrogens and particularly inhibin B secreted by the
developing follicle. In response to the decline of the FSH, the development of
adjacent follicles is inhibited (days 57). This leads to the preovulatory phase
(days 812) during which FSH starts rising again. At the end of that phase LH
surges, triggering ovulation. After the surge, LH, FSH and estradiol levels fall
precipitously and progesterone and inhibin A levels start to rise. The first half of
the cycle is complete. The length of the follicular phase varies and depends on
the rate of maturation of the principal preantral follicle(s).
Ovulation Prior to ovulation, estrogen secretion by the preovulatory follicle
increases dramatically and initiates the LH surge. The prerequisite for the surge
is an estradiol level of > 650 pmol/1 or a doubling of the previous estradiol level
for 4850 h. LH initiates the process of luteinization of the granulosa cells and
progesterone secretion. During the 3436 h after the onset of the LH surge,
ovulation occurs. The peak of the LH surge is 1016 h prior to ovulation. The LH
Figure 3.4 Serum hormone levels during the human menstrual cycle. Adapted with
permission from Johnson MH, Everitt BJ. Essential Reproduction, 2nd edn. Oxford:
Blackwell Scientific Publishers, 1984:114
surge also initiates the resumption of meiosis in the oocyte, followed by the
release of the first polar body. Prior to ovulation, a small protrusion of the follicular
wall, called the stigma, appears and represents the location where a rupture
occurs with the release of the oocyte-cumulus complex. The exact mechanism of
the rupture of the follicle is unknown but it is believed to involve proteolytic
enzymes, such as collagenase, plasmin and prostaglandins. In some cycles, the
ovum is not released, which has given rise to the concept of the luteinized
unruptured follicle syndrome (LUFS), but the process appears to occur equally
often in fertile, as well as infertile, women. However, women treated with high
doses of prostaglandin synthetase inhibitors such as indomethacin may develop
luteinized unruptured follicles. Women seeking fertility are advised to avoid the
use of drugs that inhibit prostaglandin synthesis at the midcycle just prior to
ovulation.
Luteal phase Following ovulation, the follicle undergoes marked changes in
structure and function. The granulosa cells change: they enlarge and become
granulosa-lutein cells, surrounded by newly formed theca-lutein cells. They
contain a yellow pigment (lipofuscin), hence the name lutein. The luteal phase of
the cycle is characterized by rising plasma progesterone and 17-hydroxyprogesterone concentrations which peak around eight days after the LH
surge, rising luteal estradiol and estrone levels which peak for a second time, to
somewhat lesser levels, and then the preovulatory peak. In the luteal phase, inhibin
A level changes are parallel to the rise and fall of progesterone and estradiol.
FSH, LH, testosterone and androstenedione levels decline to their lowest in the
cycle. The nadir of FSH and LH is due to the negative feedback of estradiol,
progesterone and inhibin A, and stops a new cohort of follicles from developing.
Although the level of estradiol is relatively high, it does not produce a surge of
LH and FSH because of the high levels of progesterone. If pregnancy does not
occur, the corpus luteum function begins to decline rapidly nine to 11 days
following ovulation, a process known as luteolysis. It leads to the formation of
the fibrous scar, the corpus albicans. The levels of estradiol, progesterone and
inhibin A fall, FSH starts to increase and a new cohort of follicles is recruited.
The functions of the corpus luteum are (1) to secrete progesterone, (2) to
prepare the estrogen-primed endometrium for receiving a fertilized ovum, and
(3) to maintain an early pregnancy. The corpus luteum is mainly under the
influence of LH. However, LH or human chorionic gonadotropin (hCG)
administration during the luteal phase of normal women can extend the
functional life of the corpus luteum and the secretion of progesterone for up to
two additional weeks. The length of the luteal phase is relatively constant at
around 13-15 days.
Two-cell two-gonadotropin theory LH stimulates theca cells to produce C-19
steroids (mainly androstenedione and testosterone) from cholesterol. The steroids
diffuse to the nearby granulosa cells (granulosa cells do not possess a blood
supply). FSH stimulates granulosa cells to aromatize the preformed androgens to
produce estrogen (Figures 3.5 and 3.6). During the follicular stage, estrogen
levels rise and parallel the growth of the follicle and the number of granulosa
cells. After LH receptors have developed, the preovulatory granulosa cells begin
to secrete limited quantities of progesterone and 17--hydroxyprogesterone.
Estradiol and progesterone exert positive feedback on the pituitary to augment
LH release. Granulosa and theca cells change after ovulation to become the cells
of the corpus luteum. They vascularize and start producing progesterone under
the LH influence and continue the production of estradiol under the influence of
FSH.
Non-steroidal hormones and growth factors are produced by the ovary and
modulate steroid production. The concentration of ovarian steroids in follicular
fluids exceeds concentration in blood many times.
Figure 3.5 Two-cell, two-gonadotropin hypothesis of gonadotropin control of ovarian

steroid biosynthesis. LH, luteinizing hormone; FSH, follicle-stimulating hormone.
Adapted from Hsueh AJW, Adashi EY, Jones PBC, Welsh TH Jr. Hormonal regulation of
the differentiation of culture ovarian granulosa cells. Endocrine Rev 1984;5:76, with
permission of The Endocrine Society
Endometrial cycle
The hormonal changes during the cycle produce striking effects on the tissues of
the reproductive tract. The most characteristic alterations occur in the
endometrium. In the early proliferative phase, the endometrium is about 5 mm
thick. The glands are narrow and tubular. The endometrium grows under the
hormonal influence; in midcycle the thickness is 8-12 mm. Two days after
ovulation, glycogen accumulates in the glands and they start to become tortuous
and dilated. Intraluminal secretions are present, the endometrial stroma becomes
edematous and the surrounding spiral arterioles enlarge. By day 27, the upper
half of the endometrium is a solid sheet of well-developed decidual cells. In the
absence of pregnancy, corpus luteum function ceases, with a resultant drop in
estrogen and progesterone. There is now evidence that enzymes called matrix
metalloproteinases play a role in endometrial shedding which gives rise to
menstruation. Matrix metalloproteinases have the ability to degrade both
interstitial matrix and basement membranes and are activated by estrogen and
Figure 3.6 Cellular interactions in the ovary during the follicular phase (a) and luteal
phase (b). LDL, low-density lipoprotein; FSH, follicle-stimulating hormone; LH,
luteinizing hormone. Adapted from Carr BR, MacDonald PC, Simpson ER. The role of
lipoproteins in the regulation of progesterone secretion by the human corpus luteum.
Fertil Steril 1982;38:30311, Copyright (1982), with permission from American Society
for Reproductive Medicine
progesterone withdrawal. This results in necrosis of the endometrial blood

vessels, prostaglandin release, endometrial ischemia and cell death. The
endometrium breaks down and menstruation occurs. Menstrual flow consists of
blood, desquamated endometrial tissues and exudate. The cervix also undergoes
cyclical changes. Those are described in more detail in Chapter 1.
Clinical menstrual cycle
Menstruation is the cyclic uterine bleeding experienced by most women of
reproductive age. It represents the cyclic shedding of the secretory endometrium
Figure 3.7 Relative incidence of three types of menstrual cycle with age of woman.
Reproduced with permission from Johnson MH, Everitt BJ. Essential Reproduction, 2nd
edn. Oxford: Blackwell Scientific Publishers, 1984:350
because of a decline in estradiol and progesterone production caused by a

regressing corpus luteum.
The cycle length usually varies between one and two days each month, and
only 50% of women have a cycle within the 2630-day range that includes the
so-called typical 28-day interval. The cycle length varies with age and ovulation
(Figure 3.7). Anovulatory cycles tend to be shorter and occur during
reproductive age.
The length of the normal menstrual cycle varies according to different
authorities. One estimate is a mean of 2628 days with a range of 2135 days for
ages between 17 and 41 years. The duration of menstruation is between 3 and 7
days with a total blood loss of up to 7080 ml. When the menstrual blood loss
exceeds 80 ml, there is good correlation with anemia (Hb < 12 g/l) and low
plasma iron values. Since trying to determine the extent of menstrual blood loss
relying on a patients history is inaccurate, one practical way of estimating the
menstrual loss is checking for anemia.
For most women, menstruation starts at the age of 13 years (normal range 10
16 years) and stops by 51 years (normal range 4555 years).
The menopause and normal transition to menopause
The cessation of menstruation due to loss of ovarian function is called the
menopause. In most women the menopause is not a sudden event but is preceded
by a period of menstrual cycles of variable length called the perimenopause. The
perimenopause begins with the first symptoms of the approaching menopause,
i.e., vasomotor symptoms and menstrual irregularities, and ends 12 months after
the last period. The perimenopause starts on average about four years before the
last menstruation, with a mean age of 47 years. The terms perimenopause and
menopause transition are often used interchangeably.
The aging of the ovary begins even before birth. Girls are born with a finite
number of eggs. The number peaks at about 20 gestational weeks when there
may be about 7 000 000 oogonia. The process of atresia then begins and the
number is about 700 000 at birth and 250 000 to 400 000 at puberty. Atresia
continues inexorably throughout adult life, which leads to an increasingly
smaller and increasingly less responsive follicular pool. Postmenopausal ovaries
contain atretic follicles only. The menopause occurs when the remaining ovarian
follicles stop responding to FSH stimulation and the hormonal production of
estrogen by therapy ceases.
Hormonal changes during the transition to menopause
The rate of follicular decline is linear until the age of approximately 3638
years. Thereafter, the rate of depletion appears to accelerate. FSH shows a
progressive increase from the age of 2930 years onward, reflecting the
diminishing number of follicles. Inhibin B decreases as the follicular pool is
reduced. Low inhibin levels alter the negative feedback, thus allowing FSH to
rise to stimulate the development of increasingly resistant follicles and to
maintain estradiol levels. The remaining follicles mature irregularly, anovulatory
cycles occur frequently and estrogen secretion becomes variable estrogen; but
overall, the level of estrogen declines. Following the menopause, estradiol levels
are commonly below 110 pmol/1 and biochemically the menopause is said to
occur with the elevation of FSH above 2030 IU/1. In the postmenopause,
estradiol levels decrease by 90% and estrone levels by 66%, leading to a reversal
of the estradiol:estrone ratio to 1:3. The peripheral conversion of
androstenedione to estrone increases and estrone becomes the primary estrogen
of the postmenopause. The potency of this estrogen is less than 10% compared with
that of estradiol. Consequently the classic symptoms of estrogen deficiency
develop, as discussed below. Changes in androgens are more complex.
Testosterone levels change little across the menopausal transition,
androstenedione levels fall moderately and DHEA and DHEAS continue their
age-related fall without any specific relationship to the menopause transition
itself. By the age of 5055 the levels of DHEA and DHEAS are 40% and 30%
lower than young adult values, respectively, and those of androstenedione and
testosterone 50% and 70% lower than young adult values, respectively. The net
result of these changes is a relatively smaller decline in androgen as compared to
estrogen. This has the following two effects: (1) a decrease in sex hormonebinding globulin (SHBG) and relatively higher levels of circulating androgens,
and (2) the continuous exposure of the hair follicles to androgens. As a
consequence, noticeable whiskers or sideburns may appear in postmenopausal

women.
Changes in the menstrual cycle
Menstrual cycles become highly variable in regularity and flow. The median
length of the cycle shortens from 30 days at 25 years of age to 28 days at 35
years due to a shortened follicular phase. In women with regular periods, the
number of anovulatory cycles increases with age.
In the last five to six years before the menopause, only 10% of the cycles are
ovulatory.
Immediate and medium-term symptoms
Vasomotor: hot flashes and night sweats Estrogen deficiency symptoms
commonly first occur during the perimenopause when ovarian function begins to
diminish and hormone levels commonly show wide fluctuations. The most usual
estrogen deficiency symptoms are vasomotor symptoms, psychologic symptoms
and atrophic changes in estrogen-sensitive tissues. The incidence of vasomotor
and psychologic symptoms varies, and in some societies such as Japan it may be
only a third of that observed in Western Europe or North America (see
Table 3.3).
Table 3.3 Reproductive, health and other differences between North American and
Japanese women (Kobe, Kyoto, NaganoJapan; ManitobaCanada; Massachusetts
USA)
Surgical
menopause*
Menopausal
symptoms*
(reported in the last
2 weeks)
hot flashes/sweats
completely
asymptomatic
Medicine taking*
stomach remedy
herbal tea
pain killers
tranquillizers
current HRT use
Japan
10
Canada
20
USA
30
17
46
43
27
14
16
22
16
14
4
3
9
4
45
12
6
11
3
63
10
8
Breast cancer
23
96
114
incidence (per 100
000 women)
CHD deaths
9.2
34.1
33.5
Hip fracture
325
788
845
incidence (per 100
000) (per 100 000)
*The numbers shown are percentages of all women in the menopause. HRT, hormonereplacement therapy; CHD, coronary heart disease. Data derived from Kaufert
PA, Lock M, McKinlay SM, et al. In Lorrain J, ed. Comprehensive
Management of the Menopause. New York: Springer-Verlag, 1994:5965
Table 3.4 Non-menopausal causes of hot flashes
Thyrotoxicosis
Carcinoid
Mastocytosis
Anxiety
Diabetes
Pheochromocytoma
Alcohol withdrawal
Epilepsy
SERMS, selective estrogen receptor modulators
Vasomotor symptoms include hot flashes, night sweats, palpitations, headaches

and dizziness. In Western countries, 6075% of women will suffer from hot
flashes, which are believed to be a manifestation of hypothalamic
thermoregulatory dysfunction. Of these women, 85% will have them for over a
year, 2550% for up to five years and 5% for over 10 years or indefinitely. Hypoestrogenism per se does not strictly speaking cause hot flashes since these are
often absent in established postmenopausal women and premenopausal hypoestrogenic states such as Turners syndrome, anorexia nervosa and
hyperprolactinemia. Rather, it is thought that declining levels of estrogen are
responsible for the onset of symptoms.
Interestingly, around 70% of men suffer hot flashes after orchidectomy. Obese
women seem to suffer fewer hot flashes, probably due to a greater peripheral
conversion of estrogen. However, they can be provoked by alcohol, stress, hot
drinks or hot weather. The menopause is not the only cause for hot flashes in
middle-aged women and some other, albeit infrequent, causes are listed in
Table 3.4.
The hot flash is the subjective sensation of intense warmth in the upper body
and typically lasts for 4 min (range 30 s to 5 min). There may be a prodromata of
palpitations or headache. The hot flash is frequently accompanied by faintness,
weakness or vertigo. The episode ends in profuse sweating and a cold sensation,
due to the rise in the cutaneous blood flow followed by a fall in the core body
temperature. Hot flashes that happen at night (night sweats) can lead to a
reduction of REM (rapid eye movement) sleep with all its consequences, the
most important being tiredness, irritability and poor productivity.
Psychologic Over the years a number of psychologic symptoms have been
attributed to estrogen deficiency. It is important to recognize that the type of
population under study will influence the reporting of psychologic symptoms in
the menopausal transition. If the study population consists of women recruited
through menopause clinics or advertisements, it is likely that, in this self-selected
population, psychologic symptoms will be greater than in the general population
of menopausal women. If, however, the study population is unselected, a
different picture
Table 3.5 Pre-existing problems that may be accentuated after the menopause
Marital dissatisfaction
Poor health
Financial problems
Bereavementloss of parent, relative or friend
Severe social stress demanding work fear of redundancy
Educational/marital difficulties of the children
Aging and/or dependent parents
Lack of social support
Loss of partner (death, separation)
Coming to terms with aging, loss of fertility and perceived loss of femininity
Living in youth-oriented society and culture
appears. The evidence from prospective population-based longitudinal studies

suggests that there is no excess of psychologic symptoms during the enopause
transition. In particular, in some studies, no direct association between the
menopause and depression or psychologic well-being has been found, as well as
no increase of anxiety. No clear conclusion has as yet been drawn about
cognitive functions and the enopause.
There are a number of pre-existing problems and life changes that occur in
middle age (see Table 3.5) and these problems may lead to psychologic symptoms.
If, in addition, there are the added problems of hot flashes, night sweats and poor
sleep, then the feeling of an inability to cope may develop. The psychologic
symptoms may turn into psychologic morbidity, so the menopause may be the
straw that breaks the camels back. It is extremely important that the possibility
of this downward spiral is recognized and not allowed to develop. Women
should be offered the opportunity to discuss their own perception of their
problems and a much wider variety of issues, not just the physical symptoms of
the menopause. The treatment should be individualized and may include
counseling, psychologic therapy, advice on lifestyle, hormone replacement

therapy, antidepressants, or a combination of these.
Table 3.6 The menopause and the genitourinary tract
Vulval/vaginal atrophy
Vaginal dryness
Vaginal infections
Frequency/urgency, dysuria, nocturia
Predisposition to UTIs
Dyspareunia
Decreased libido/frequency of intercourse
Decreased sexual desire
Decreased intensity of orgasm
UTIs, urinary tract infections
Genitourinary and sexual Atrophic changes resulting from estrogen deficiency in

sensitive connective tissues affect the urogenital tract and, more generally, the
skin, hair and nails. Genital tract changes result in atrophic vaginitis, leading to
vaginal soreness and dyspareunia. Estrogen deficiency leads to a fall in the
number of lactobacilli with an increase of the vaginal pH. The maturation index
changes with the number of parabasal cells exceeding the number of superficial
cells. Atrophy of the cervix and uterine body and endometrial atrophy occur. The
blood flow to the pelvis decreases. The skin generally thins and loses its
elasticity and the hair and nails lose their shine and become brittle. Urinary tract
changes result in frequency, urgency, dysuria and a predisposition to urinary
infections. Changes in sexual function due to the menopause are difficult to
disentangle from those related to age. However, it has been reported that
intercourse may become painful and less frequent, with orgasm intensity
decreased. For a summary of changes in the genitourinary system see Table 3.6.
Long-term effects of the menopause
The long-term effects of the menopause include those on the cardiovascular
system, on bone and on other aspects of the metabolism. The long-term
consequences are discussed in greater detail in Chapter 6.
4
Contraception
Joanna N.Raeburn, Chris Wilkinson and Nikolai Manassiev
INTRODUCTION
Throughout history, men and women have attempted to control their fertility.
The oldest method of contraception in the world is coitus interruptus which,
while not being specifically recommended as a method by health professionals,
nevertheless remains better than nothing in situations where religious
objections or unavailability of other methods of contraception is the only
alternative. Apart from coitus interruptus, barrier methods of contraception have
been around longest. There is evidence for the use of a form of male condom
dating back at least to Roman times, although it is thought that early use of
condoms was primarily as a protection against sexually transmitted diseases
(STDs) rather than for the prevention of pregnancy. There is also evidence for
the use of female barrier methods as long ago as prehistoric Egypt.
In the middle and latter part of the twentieth century, the condom was
somewhat eclipsed by the advent of the combined oral contraceptive (COC) pill,
but with the spread of HIV infection condoms are once again one of the most
widely used methods in the developed world. The great advances of the late
twentieth century in terms of human fertility control have been in the
development of improved hormonal delivery systems and intrauterine devices
(IUDs). Frequency of use of different contraceptive methods in the UK is
summarized in Table 4.1.
The effectiveness of various contraceptive methods is measured by means of
either the Pearl index or life-table analysis. The Pearl index (named after its
inventor, an American biostatistician, and introduced in 1932) is still commonly
used, but life-table analysis is more
Table 4.1 Percentage of women aged 1549 using various methods of contraception
Method
UK
Sterilization
Hormonal
Condom
25
23
16
CONTRACEPTION 43
Method
UK
IUD
Abstinence/no partner
IUD, intrauterine device
5
16
accurate and is gaining in popularity. The Pearl index is calculated from the
formula:
The Pearl index is expressed in terms of a rate of event (i.e., pregnancy) per 100
woman-years. Although suited for scientific studies, the concept of the Pearl
index may be difficult for the patient to grasp. In everyday practice it is easier to
say that if a failure rate of a contraceptive method is quoted, for example, as 5, it
means that if 100 couples use this particular method for one year, five of them
will experience failure (pregnancy). The failure rate depends on the efficacy of
the method itself (method effectiveness or method failure) and on the ability of
the user to use the method correctly (user failure). Some contraceptive users are
very careful when using their chosen method (perfect use) and they may be able
to achieve a very low failure rate. In case of perfect use the failure rate will be
solely due to method failure. However,
Table 4.2 Failure rates for different contraceptive methods
Method
Failure rate range per 100 woman-years
Sterilization
male
00.01
female
0.30.5
Implanon (levonorgestrel implant)
00.07
Injectables
0.70.1
Combined pill (3035 g)
0.10.4
Progestogen-only pill
0.14
IUD (330380 mm2 copper)
0.30.6
IUS (Mirena)
< 0.3
Diaphragm
215
Condom
215
Coitus interruptus
817
Fertility awareness
226
Spermicides
328
Lactational amenorrhea
24
IUD, intrauterine device; IUS, intrauterine system
compliance error, intercurrent illness or some other factor may take place which
may increase the failure rate (typical use). The failure rate in this case is the sum
of method failure and user failure. Because of these considerations the failure
rate is often quoted as a range, rather than as a single number. A summary of
failure rates for various contraceptive methods is given in Table 4.2. In the USA
considerably higher failure rates have been reported for sterilization, injectables
and the pill. The effectiveness of contraception by itself does not mean very
much unless compared to natural fertility rates. Natural fertility rates vary but the
chance of getting pregnant by means of regular unprotected intercourse among
unselected couples is about 2030%, about 60% and about 90% after one, six
and 12 months, respectively. There is no reliable figure about the chance of
pregnancy after single exposure, but it varies depending on the time of the cycle.
BARRIER METHODS
Male condoms
The male condom is the cheapest and most readily available method of
contraception worldwide; it needs no intervention from health professionals, has
no adverse health effects on the user and confers undoubted health benefits on
both partners. With careful use, condoms can be an extremely effective method
of contraception, with the additional benefit of protection against sexually
transmitted infections (STIs). Failure rates are quoted as between 2 and 15% per
annum, the difference relating to that between perfect use and typical use. All
users of condoms should be aware of the availability and limitations of
emergency contraception in case of condom failure, but sadly many condom
accidents go unnoticed by the users and result in unintended pregnancies. Most
condoms available in the UK are made of latex rubber. Latex allergy
occasionally occurs and condoms made of polyurethane have been developed.
Both types of condom have their benefits and drawbacks; latex condoms may be
weakened or damaged by oil-based lubricants, including such commonly used
substances as Vaseline, baby oil, edible creams and certain medicinal products
such as several anti-candidal preparations and estrogen creams and pessaries.
Polyurethane condoms are not affected by these products and also have better
storage life than latex condoms. However, in normal use latex condoms have
lower breakage rates and lower slippage and failure rates than polyurethane
condoms, and the latter are probably best reserved for those couples suffering
from latex allergy.
Practical advice
The best way to teach condom usage is with a plastic condom demonstrator; the
principal points that need to be made are as follows:
CONTRACEPTION 45
(1) Condoms are for single use only.

(2) Avoid any mechanical damage, e.g., from sharp fingernails when the
condom is being handled.
(3) Space needs to be left at the tip of the condom for the ejaculate; this is
normally provided by the manufacturer in the form of a small teat, which
should be emptied of air prior to application.
(4) The condom should be unrolled only when placed over the tip of the erect
penis and must be put on the right way round so that the rolled-up rim can
be easily rolled down the shaft of the penis.
(5) No genital contact should take place before the condom is put on.
(6) The rim of the condom must be held firmly at the time of withdrawal, to
prevent the condom slipping off.
(7) Oil-based lubricants should be avoided when using latex condoms; waterbased lubricants such as KY jelly or a spermicidal gel should be advised
instead.
Non-contraceptive benefits of condoms
Latex condoms reduce the incidence of STIs. This is particularly so with bacterial
infections such as gonorrhea but reductions in the risk of transmitting chlamydia
and trichomoniasis have also been observed. Additionally, there is significant
protection against the blood-borne viruses HIV and hepatitis B and C, but less in
the case of conditions that may affect the vulva and shaft of penis, such as wart
and herpes viruses.
In addition, there is evidence that regular use of condoms leads to a lower risk
of cervical intraepithelial neoplasia. For many women, particularly younger ones
who may not yet be in permanent monogamous relationships, the use of
condoms is recommended as additional protection in conjunction with hormonal
or intrauterine methods of contraceptionthe so-called Double Dutch method
providing effective contraception combined with protection against STDs.
Diaphragms and cervical caps
Vaginal barrier methods have been in use throughout the last century but their
popularity has sharply declined since the immediate pre-pill era in the 1950s,
when they were the principal method of contraception available to women.
Nowadays, the most commonly used vaginal barrier is the diaphragm (originally
known as the Dutch cap) (Figure 4.1). In the UK, the diaphragm is often
popularly referred to as the cap and in our further discussion these terms are
used interchangeably. Other barriers such as the cervical cap, the Vimule and the
vault or Dumas cap (Figure 4.1) are rarely used or available nowadays. They
may have an occasional place for women who have difficulties with placement
of diaphragms or recurrent cystitis.
Figure 4.1 Female barrier devices: diaphragm and cervical caps
The diaphragm has the advantage over the condom in that firstly it is under the
womans control, and secondly it can be inserted well before intercourse and
need not therefore interrupt the spontaneity of the sex. It does not, however,
confer the same degree of protection against STIs as does the condom, although
regular users of vaginal barriers are at lower risk of cervical neoplasia and pelvic
infection.
The efficacy of the diaphragm varies according to user motivation and
consistency of use but failure rates between 4 and 18% per annum are quoted.
Undoubtedly, though, before the advent of hormonal methods of contraception,
let alone emergency contraception, there were families throughout the developed
world whose size was arrived at not by accident but by careful use of the Dutch
cap throughout the fertile years. In recent years, a number of new vaginal barrier
methods have been developed. These include the female condom or Femidom,
the sponge, Femcap and the disposable Oves cervical cap, which can stay in
place for three days.
Types of diaphragm
The diaphragm is a thin circular dome-shaped piece of rubber, edged with a
rubber-coated metal rim. The external diameter of the rim is the size of the
diaphragm, changing in increments of 5 mm. The size range is 50105 mm, the
most widely used sizes being 6580 mm. The diaphragm fits between the
posterior vaginal fornix and behind the pubic symphysis (Figure 4.2), thus
covering the cervix and isolating it from penile contact. Three types of diaphragm
are currently available: flat spring, coil spring and arcing spring. Flat spring
diaphragms have a firmer feel to the rim than coil spring ones: consequently
many women find the latter more comfortable in use. Arcing spring diaphragms
are more expensive than the other types, and combine features of both; when
squeezed prior to insertion in the vagina, they form a curved arch shape which
helps to direct the diaphragm into the right position with the leading edge in the
CONTRACEPTION 47
Figure 4.2 Insertion of the diaphragm. Reproduced with permission from Kleinman RL,
ed. Family Planning Handbook for Doctors. London: International Planned Parenthood
Federation, 1988:135
posterior fornix. This is an advantage for women who find it difficult to insert a
flat or coil spring diaphragm over an awkwardly placed cervix. In women with
poor vaginal muscle tone, a cystocoele or a rectocoele, the cervical cap may
prove more appropriate as its correct use is independent of vaginal tone.
Advice to patients
The successful use of vaginal barriers requires careful initial assessment and
fitting by a trained health professional. A correctly sized and fitted diaphragm
should be comfortable to the wearer to the extent that she should not be aware of
its presence either before, during or after intercourse; neither should it interfere
with her partners sensations (although he may be able to feel it). The size of the
diaphragm is determined by vaginal examination and is taken as the distance
from the tip of the index finger placed in the posterior fornix to the interior rim
of the pubic arch. This is not an exact science and, in practice, there is no single
size that fits an individual woman. The size of diaphragm chosen may vary
between equally experienced health professionals, according to whether a very
tight fit behind the pubic arch or a smaller device simply covering the cervix is
preferred. The use of spermicides with any vaginal barrier is always
recommended and women requesting cap fitting should be shown how to apply
spermicidal jelly and how to insert and remove the cap. It is generally good
practice to send the woman away with the cap to practice for a week, relying on
an alternative method of contraception in the meantime. At the return visit, with
the cap in place, its fit and correct placement covering the cervix can be checked
and, if all is well, the woman can then rely on it as her method of contraception.
Practical considerations
(1) The cap should not be inserted more than 2 h before intercourse; if over 2 h
have elapsed without intercourse taking place, it should be removed, further
spermicide applied and reinserted.
(2) Following sexual intercourse, the cap should be left in place for a minimum
of 6 h and a maximum of 24 h.
(3) If intercourse is repeated during the 6 h period, the cap should be left in
place but further spermicide added, either by using an applicator to apply
cream or jelly or by use of a pessary inserted high in the vagina next to the
cap.
(4) The cap can be inserted either way up but some spermicide should be in
contact with the cervix; additional spermicide can be placed around the rim
of the cap to lubricate and thus aid insertion.
It is traditionally recommended that the size of a cap should be checked after
childbirth and after gain or loss of more than 3 kg in weight; in practice it is not
common for the size to change significantly and, as stated earlier, there is no
one and only correct size at any one time. The woman herself is probably the
best judge of whether her cap is the right size, as a cap that is too large will be
uncomfortable and will not sit correctly behind the pubic symphysis, while a cap
that is too small will feel loose and will frequently be difficult to remove.
Other female barrier methods
The Femidom, or female condom (Figure 4.3), is made of lubricated
polyurethane and resembles a small plastic pouch with two soft rings, one at
either end. The purpose of the rings is to assist placement of the Femidom, the
inner ring at the closed end of the pouch being guided toward the cervix, while
the outer ring, at the open end of the pouch, is placed outside the vagina over the
labias. As it covers a greater area of the female genitalia, it is potentially a
superior barrier to STIs than male condoms but there are no reliable data to
support this assertion. Although the Femidom is not widely used in the UK it
should not be dismissed without discussion because the method does suit some
couples.
The Today sponge, which was essentially a vehicle for spermicide rather than
a barrier method, is no longer available in the UK; its high failure rate made it only
really suitable for women requiring spacing contraception or in those women
whose fertility is exceedingly low anyway (see below, under Spermicides).
The Oves cap is a single-use silicone cervical cap, which can be left in place
for up to 72 h but must not be used during menstruation. Like other types of
vaginal barrier, it is recommended to be used with a spermicide. It is available
from some pharmacies but women are advised to see their family planning
provider to fit the right size and train the woman in its use.
CONTRACEPTION 49
Figure 4.3 Female condom. Reproduced with permission from The Female Health
Company, UK
Spermicides
In general, spermicides alone are not recommended as a reliable method of
contraception, as their failure rate ranges from 3 to 28%. Spermicides should be
used in conjunction with diaphragms and cervical caps. In perimenopausal
women, particularly where the menstrual cycle appears to have ceased and
symptoms of estrogen deficiency, such as hot flashes, are beginning to appear, a
spermicidal foam or pessary may provide adequate cover. If aged under 50
years, women are advised to continue with contraceptive precautions for two
years after the last menstrual period (LMP), and if over 50, for one year after the
LMP. In all other age groups, the use of spermicides alone should be discouraged
and they should always be combined with a barrier method such as described
above.
All spermicides available in the UK contain as the active ingredient
nonoxynol-9, combined with a surfactant to aid spread in the vagina and a gel or
cream carrier compound. They are available as gels, creams, foams and also
pessaries. The first three are effective immediately after insertion while pessaries
need 10 minutes to dissolve before intercourse takes place. All spermicides
remain active in the vagina for a maximum of 2 h.
Spermicides such as nonoxynol-9 and other related compounds have been
shown in vitro to have microbicidal activity and are active against several
sexually transmitted organisms, including chlamydia, gonococcus and
trichomonas. They do not, however, provide full protection against these
infections in vivo, and there is doubt as to whether they are effective as viricides.
It is also suspected that spermicides, when used very frequently, lead to
inflammation of the vaginal epithelium which may in turn increase the likelihood
of viral transmissionsuch as HIV.
NATURAL FAMILY PLANNING
Natural family planning (also known as periodic abstinence) can be a successful
method of contraception, although widely varying failure rates, between 2 and
26%, are quoted. The greater level of success is only achieved with fairly
intensive training by an experienced teacher of the methodusually, but not
invariably, a specially trained family planning nurse; and by a very high degree
of commitment and self-control on the part of the couple.
The method relies on identifying the fertile phase of the menstrual cycle and
avoiding intercourse until the phase is over. There are a number of indicators of
fertile and infertile phases of the cycle, which can be learnt and used to identify
safe and unsafe times for sexual intercourse, depending on whether pregnancy is
sought or is to be avoided. The so-called major indicators are changes in the
quality and quantity of cervical mucus, the position of the cervix and the basal
body temperature (BBT). Minor indicators, such as ovulation pain
(Mittelschmerz), mid-cycle bleeding and breast pain, which may be readily
recognizable by some women, may also contribute to the calculation. For
successful natural family planning it is recommended that women rely on at least
twoand preferably threemajor indicators.
Mucus changes
For most of the cycle the cervical mucus is either absent or scanty, and thick,
while in the immediate pre-ovulation phase the mucus becomes profuse, thin and
stretchy (Spinnbarkeit, Figure 4.4), frequently being described as resembling raw
egg white. Properties of the cervical mucus are also discussed in Chapter 1.
These differences can be detected by the woman who examines her mucus on a
regular basis and indicate the fertile period immediately leading up to ovulation,
when intercourse should be avoided by those not wishing to conceive. One has to
bear in mind that changes in cervical mucus can be masked by seminal fluids,
spermicides or vaginal infection.
Changes in the cervix
During the fertile phase, the cervix rises higher in the vagina and the os becomes
slightly more open, whilst at other times of the cycle the cervix is lower in the
vagina and the os feels tightly closed. Again, these changes can be recognized by
those who examine themselves regularly and can contribute to knowledge of the
fertile phase.
CONTRACEPTION 51
Figure 4.4 Changes in cervical mucus and basal body temperature in relation to the
menstrual cycle. Reproduced with permission from Johnson MH, Everitt BJ. Essential
Basal body temperature

The progesterone surge produced at the time of ovulation leads to a small rise in
BBT of between 0.2 and 0.6C and the temperature remains at this higher level
until the onset of menstruation (Figure 4.4). The woman should be instructed to
take her temperature each morning before rising, using a special fertility
thermometer, which is widely graduated over a narrow temperature range to
facilitate recognition of small differences in temperature. The temperature rise
indicates that ovulation has taken place and, therefore, it has no place as a
predictor of ovulation. Once the temperature rise has been detected for three
consecutive mornings, ovulation can be considered over, the ovum no longer
viable and intercourse can take place without protection.
From the above it can readily be seen that more than one indicator is needed,
simply because the mucus and cervical changes indicate the onset of the fertile
phase, while the BBT is an indicator of the end of the fertile phase. In practice,
the mucus changes are not always as clear as described, particularly if the
woman is combining natural family planning with a barrier method of
contraception for the unsafe times. The BBT changes can be obscured by many
factors, including stress, disturbed nights, fever and alcohol, while some women
cannot easily recognize the cervical changes.
Fertility monitors
New developments to try and bring science to the aid of the determined natural
family planner include the Persona monitor. This device monitors the changes
in levels of urinary luteinizing hormone (LH) and estrogen metabolites to
indicate the start and finish of the fertile phase. It is not recommended for women
who have a cycle length outside a 2335 days range, are perimenopausal, have
polycystic ovarian syndrome have liver or kidney diseases or are breastfeeding.
The efficacy of Persona can be reduced by medications that alter LH and
estrogen metabolism, and the manufacturers instructions should be followed.
The Persona system has a quoted failure rate of about 6% for perfect use, which
is higher than many women are prepared to accept. However, it is non-invasive,
does not have side-effects, is easy to use and may appeal to couples keen to
practice natural family planning. It is not available on the NHS.
Lactational amenorrhea method
In the developing world, anovulation and amenorrhea associated with full breastfeeding is the principal method of contraception. It appears that pulsatile
secretion of gonadotropin-releasing hormone (GnRH) is suppressed by infant
suckling (via prolactin), which leads to suppression of release of LH; this in turn
causes failure of follicular development and thus of ovulation. For this to occur,
it is important that the infant should be fully breastfed, without supplements, on
demand, including during the night. If supplements are given, they should only
be given after the infant has been breastfed to maintain the maximal suckling
stimulus.
The lactational amenorrhea method (LAM) is defined as follows:
(1) The woman is fully breastfeeding, day and night, with few supplements;
(2) The woman is amenorrheic;
(3) The infant is less than six months old.
If a patient fulfills all three of the above criteria, she can be advised that her
contraceptive protection is approximately 98% and that this efficacy is comparable
to other methods of contraception available in the postpartum period. In those
rural parts of the world where women traditionally breastfeed for prolonged
periods and access to health care and family planning services may be limited,
LAM may be extended. For example, in Rwanda a program entitled LAM-9 was
introduced in which there was good efficacy up to nine months postpartum
without the use of any additional contraceptive method. In the developed world,
where food supplements are frequently introduced well before the infant is six
CONTRACEPTION 53
months old, it may be advisable to introduce additional contraceptive methods at

around three to four months.
HORMONAL CONTRACEPTION
An increasingly expanding variety of hormonal contraception is now available to
women. The common feature of all of these agents is that synthetic estrogenic
and/or progestogenic compounds are used in order to suppress ovulation and
change the endometrium, cervical mucus and tubal motility in order to prevent
pregnancy. The expansion of hormonal contraception is due to (1) the number of
chemical compounds being available; (2) various dosages; and (3) routes of
administration. In our discussion of hormonal contraception, we shall touch on
transdermal and vaginal routes, on a new progestogen (drospirene) as well as on
the first progestogen-only pill that reliably suppresses ovulation.
Combined oral contraceptives
The development of the combined oral contraceptive (COC) pill in the late 1950s
was the start of a revolution in womens reproductive health care. For the first
time, women had a reliable method of contraception that was independent of
intercourse. The original pill contained, by todays standards, huge quantities of
the synthetic progestogen, norethynodrel, and the estrogen, mestranol. Although
the pill, as the combined contraceptive pill came to be known, has been the
subject of more investigation than probably any other medicine in the twentieth
century, only one randomized prospective study of pill use, compared with a
barrier method, has ever been performed. This was carried out in Puerto Rico,
with recruitment of nearly 10 000 women between 1960 and 1969, who were
followed up until the trial was abandoned in 1976. Due to the long duration of
the study, there were very high drop-out rates during the follow-up period and
also switching of contraceptive methods between groups.
These early studies appeared to show no significant health differences between
pill users and non-users, despite the fact that the doses of synthetic hormones in
the pill at that time were vastly higher than are used nowadays. However, our
understanding of the risks and benefits of the COC pill has been refined as the
quality of research has improved. The Royal College of General Practitioners
(RCGP) study, for example, carried out in the late 1960s and early 1970s looked
at, amongst other things, the incidence and type of vascular disease in pill users,
and it was studies like this which first demonstrated the association between pill
use and venous thromboembolism (VTE). The RCGP study was also based on
pills containing much higher doses of estrogen and progestogen than are in
current use because it was not until 1974 that pills containing 30 or 35 g of the
estrogen ethinylestradiol (EE) were introduced. The development of low-dose
(30 and 35 g/day) COCs was initiated as a result of these studies, which had
suggested that some of the observed adverse effects might be related to the
amount of estrogen. In addition, there has been a progressive trend toward

reducing both the dose and the potency of the progestogen content of the pill,
with the result that all studies relating to higher-dose pills must be interpreted
with caution when considering the present-day pill user and her potential risks.
Classification of combined oral contraceptives
There are three main ways of categorizing COCs: by dose (amount of estrogen),
by generation (type of estrogen and progestogen), and by variation in dose
(phasic pills) (see Figure 4.5 and Appendix I).
Dose High-dose pills contain 50 g/day EE or more; in the UK Ovran and
norinyl-1 are the only high-dose COC licensed and are used only for women on
hepatic enzyme-inducing drugs. Low-dose pills contain 3035 g/day EE and
constitute the majority of COCs in current use in the UK. Ultra-low dose pills are
those with less than 30 g/day EE. They are not widely used and, whilst
maintaining contraceptive efficacy, tend to be associated with increased
breakthrough bleeding. It is likely that ultra-low dose pills will be refined in time
and become more widely used.
Generation Three generations of pills are currently described:
(1) First-generation pills are no longer available. They all contained 50 g of EE
or more. The original estrogen was mestranol, which is the pro-drug of EE,
and this was combined with progestogens that are no longer in use in
combined preparations, such as lynoestrenol and ethynodiol diacetate. Brand
names included Minovlar, very widely used in the early 1970s, and Minilyn
and Conova 30, both of which were still available in the early 1990s.
(2) Second-generation pills are currently the most widely used. They include the
pills containing 3035 g/day of EE in combination with one of the
following progestogens: norethisterone, norethisterone acetate and
levonorgestrel. Included in this group are the very widely prescribed
Microgynon/Ovranette and Ovysmen/Brevinor.
(3) Third-generation pills contain 2030 g/ day EE and the progestogens
gestodene or desogestrel. These exhibit less androgenic side-effects than the
second-generation progestogens. The branded names are Femodene/Minulet
and Marvelon/Mercilon. Preparations containing the progestogen
norgestimate are usu ally regarded as third-generation pills. However,
norgestimate is a pro-drug for levonorgestrel which is a second-generation
progestogen.
(4) Efforts continue to improve the metabolic effects and tolerability of the
current progestogens. Some such progestogens are: dienogest, drospirenone,
nestorone, nomegestrol and trimegestone. Dienogest is licensed in Germany
in COC pill and hormone replacement therapy formulations. Trimegestone
is available in France. The combination of drospirenone and EE is licensed
in the UK as the COC pill Yasmin. The properties of drospirenone are such
CONTRACEPTION 55
Figure 4.5 Some synthetic estrogens and progestogens used in hormonal methods of
contraception
that Yasmin cannot be classified as either second- or third-generation COC.

Drospirenone is discussed further below.
Phasic pills Monophasic pills have a constant dose of EE and progestogen
throughout the 21-day course of pills. Triphasic pills attempt to mimic the
natural menstrual cycle by varying the doses of both EE and progestogen over
the course of 21 days of pill taking. Biphasic pills have been developed but there
are no biphasic pills available in the UK at the time of writing. In general, bi- and
triphasic pills appear to offer no significant advantages over monophasic pills,
although, on an individual basis, they may suit some women better.
Efficacy, mechanism of action and metabolic effects of the pill
The contraceptive efficacy of COCs is generally quoted as between 0.1 and 0.4
pregnancies per 100 woman-years; this is with perfect use. The actual failure rate
varies in practice according to the compliance of the user and the length of time
of use. The Oxford Family Planning Association contraceptive study reported a
failure rate of 0.2 per 100 woman-years, but US data suggests a failure rate of 5
7% during the first 12 months of use. The main mechanism of action of COCs is
by inhibition of the normal secretion of LH and follicle-stimulating hormone
(FSH) from the pituitary and this results in inhibition of ovulation. The three
additional mechanisms are: (1) thickening of the cervical mucus leading to
reduced sperm penetration; (2) development of endometrial changes making it
less receptive to implantation of the blastocyst; and (3) changes in the motility
(reduced) and secretion of the fallopian tubes. Ovulation is suppressed if at the
beginning of the cycle seven pills are taken consecutively. If two or more pills
are missed from the first seven of the pack, or four or more pills are missed from
the middle of the pack, then ovulation may arise.
The use of synthetic sex steroids leads to a number of metabolic changes. Some
of them are of scientific interest only but others (coagulation, lipids, etc.) may be
of considerable clinical significance (see Table 4.3). Second- and thirdgeneration COCs show differences with regard to certain metabolic
characteristics. Third-generation COCs seem to affect coagulation more than
second-generation COCs, and users of third-generation COCs have a higher risk
of VTE than users of second-generation COCs. However, users of thirdgeneration COCs seem to have a lower risk of myocardial infarction in
comparison with the second-generation users. The picture is bound to become
more complicated with the introduction of drospirenone in Yasmin. Each Yasmin
pill contains 30 g EE and 3 mg drospirenone. Drospirenone is a derivative of
spironolactone and has mild antimineral corticoid activity and anti-androgenic
activity. One metabolic study comparing Yasmin with Microgynon showed that
in Yasmin users the systolic blood pressure decreased by 2.9 mmHg and the
diastolic blood pressure by 3.4 mmHg, high-density lipoprotein and triglyceride
levels increased and low-denisity lipoprotein levels fell; there was no change in
glucose tolerance. Whether these changes are of any clinical significance is not yet
known. Yasmin apart, in general, there is a small increase in the blood pressure
that is of no clinical significance in most women (the increase is in the range of
78 mmHg for systolic blood pressure and 56 mmHg for diastolic blood
pressure). However, regular blood pressure monitoring is very important to
identify the small minority of women who may develop clinically significant
hypertension.
Key history, indications and contraindications for combined
oral contraceptives
Medical and family history As with any other area of medicine, good
contraceptive care requires careful history taking. All methods of contraception
are safe, but for some women there are situations where the risk of complications
CONTRACEPTION 57
or failure increases. Relevant changes in medical or surgical history may mean

that
Table 4.3 Metabolic changes associated with the pill
Coagulation*
Increase in factors II, VII, VIII, IX, X. Decrease in

antithrombin and factor V
Lipids*
Increase in total cholesterol and triglycerides. Slight
decrease in HDL-cholesterol
Endocrine system
Increase in insulin, adrenal steroids, thyroxin and
prolactin*. Decrease in LH, FSH, endogenous estrogen and
progesterone. Increase in plasma renin activity and
aldosterone secretion
Liver
Increased synthesis of -2 globulin. Production of more
lithogenic bile*
Carbohydrate metabolism Increased insulin resistance
*Denotes changes of clinical significance; HDL, high-density liproprotein; LH,
luteinizing hormone; FSH, follicle-stimulating hormone
use of COCs is partially or completely contraindicated. It is the responsibility of

the doctor or nurse providing contraceptive care to take a relevant personal
medical and family history (Table 4.4) and to inform patients when the risks for
them are different from the norm. As both the medical and family history may
change, it is important to review the relevant history at each follow-up visit.
With regard to COCs, the most important areas of history to be considered are
those relating to vascular disease. Coronary heart disease (CHD),
cerebrovascular disease and VTE are very rare in the majority of young women
including those who take COCs; however, in the presence of risk factors (see
Table 4.5) this situation can be very different. The effect of risk factors on the
hazards associated with COC use is discussed later in this section. In general, the
presence of one risk factor is regarded as a relative contraindication and the
presence of two summates to become an absolute contraindication to COC use. It
is important to remember that common factors such as smoking and obesity
constitute arterial disease risks. Migraine is a recognized risk factor for ischemic
stroke. In the presence of focal neurologic symptoms preceding the onset of
headache and known as aura, these risks are increased further and COCs are
contraindicated, usually for life. The diagnosis of migraine with or without
Table 4.4 Relevant family history in first-degree relatives to be taken before prescribing
combined oral contraceptives
Venous thromboembolism and embolism
Early onset cardiovascular disease < 50 years, including
angina
myocardial infarction
hypertension
stroke
hyperlipidemia
carcinoma of the breast
Hyperlipidemia
Carcinoma of the breast
aura is made on basis of the history and the absence of other neurologic disease.
The diagnosis is usually clear but when atypical a neurologic referral may be
required to support the diagnosis of migraine. Sickle cell disease was previously
regarded as a contraindication to COCs because of the risk of thrombosis during
crises. Whilst COC is not a first-line method (Depo-Provera is associated with a
reduction in the frequency of crises), its use appears to be safe and it is widely
used in these patients as the risk of sickle cell disease in pregnancy and
associated complications far outweighs the risk of COC use; however, in the
authors opinion it is not recommendable in a patient suffering from frequent
sickle crises.
Table 4.5 Risk factors for cardiovascular disease
Venous disease risk factors
(1)
(2)
(3)
(4)
(5)
(6)
Arterial disease risk factors
(1)
(2)
(3)
Personal history of VTE*

Known thrombophilia
Severe varicose veins
Immobility, e.g., bed-bound
History of VTE occurring in first-degree
relative
History of thrombophilia in close relative
Known arterial disease

Age > 35
Current smoking (especially > 20 per day) or
ex-smoker within six months of stopping
(4)
Hypertension
(5)
Migraine (risk factor for ischemic stroke)
(6)
Hyperlipidemia/familial hyperlipidemia
(7)
Diabetes
(8)
Family history of arterial disease (ischemic
heart disease, strokes), especially occurring <
50 years old or of familial hyperlipidemia
(9)
Obesity
*Does not include phlebitis, an inflammation of the superficial veins, which according to
a number of respected journals and societies is not a risk factor for venous
thromboembolism (VTE)
CONTRACEPTION 59
Uncontrolled hypertension is an absolute contraindication to combined oral

contraceptive (COC) use; in cases of controlled hypertension without any other
additional risk factor COCs can be used with caution
A history of hormone-dependent conditions, such as pemphigoid gestationis,

cholestatic jaundice of pregnancy, certain types of porphyria or chloasma (this is
not an absolute contraindication), may contraindicate COC use. A personal and
family history of breast cancer should be noted because there is an increased risk
of having breast cancer diagnosed whilst taking COCs, compared to never users
(for more detail see page 52). Women with a strong family history of carcinoma
of the breast can use COCs, but only after having all the potential ramifications
explained, and they may need referral to a breast clinic for further advice. Current,
active liver disease or elevated liver-function tests within the previous three
months is a contraindication to COC use.
Drug history/interactions Older anticonvulsants such as phenytoin,
carbamazepine and phenobarbitone, griseofulvin and certain anti-HIV drugs, all
of which act as liver enzyme inducers, cause reduced contraceptive efficacy as a
result of increased metabolism of both the estrogen and progestogen. If COCs
are to be used, patients should be treated with a 50 g estrogen pill, possibly with
a decreased pill-free interval or tricycling (three packets taken without a break),
throughout the treatment and for up to 4 weeks after stopping it. Newer
anticonvulsants, such as sodium valproate, gabapentin and lamotrigine, do not
have this effect. Rifampicin and rifabutin are such powerful enzyme inducers
that alternative contraceptives should be used. Particular care should be taken
when short courses of rifampicin are used as prophylaxis following close contact
with meningococcal meningitis. Even just two days of treatment can lead to
decreased contraceptive efficacy for up to four weeks, and patients must be
properly advised if pregnancy is to be avoided as well as an outbreak of
meningitis.
Gynecologic history Prescribers should enquire about the menstrual cycle, in
particular its regularity, the cycle length, menstrual loss, and about the presence
of dysmenorrhea and premenstrual problems. Enquiry should be made as to
whether there have been prior episodes of amenorrhea not caused by pregnancy.
Contraceptive history should be noted, in particular the reasons for discontinuing
any previously used methods.
Social history It is important in all age groups to take a smoking history,
although smoking will not be regarded as an absolute contraindication to COC
use in women under 35 years of age unless it is associated with other
cardiovascular risk factors. However, no opportunity should be lost for life-style
advice, and young women should be helped and encouraged to give up smoking
as early as possible.
Indications The history can also identify conditions that may be indications
for COCs or that may benefit from COCs such as menorrhagia, dysmenorrhea,
uterine fibroids, acne, polycystic ovarian syndrome, recurrent functional ovarian

cysts and premenstrual syndrome (see Non-contraceptive benefits on this page).
Contraindications These can be divided into absolute and relative
contraindications to the COC pill, and are summarized in Tables 4.6 and 4.7.
Wherever a relative contraindication to prescribing is encountered, a balance
must be sought between the potential risk of prescribing COCs and both the
potential risk of pregnancy to a patient left unprotected, and unwilling or unable
to use alternative methods of contraception, and the known non-contraceptive
benefits of COCs.
Non-contraceptive benefits
In any discussion of the risks and benefits of COC use, it is very important to
convey the many non-contraceptive benefits which are not widely appreciated by
the lay public. Established benefits include a very substantial reduction in
menorrhagia, with consequent reductions in iron-deficiency anemia. It should be
noted that the most common cause of anemia in the reproductive age is
menorrhagia. Another benefit is relief of dysmenorrhea. There is a reduced
incidence of both benign breast and ovarian disease, with fewer functional
ovarian cysts, due to the prevention of ovulation and a reduction in the incidence
of pelvic inflammatory disease (PID). Perhaps of most importance, particularly
in the light of anxieties about possible increased risk of carcinoma of the breast,
is the evidence that COCs offer protection against both endometrial and ovarian
carcinoma. Specifically, there appears to be an approximately 40% reduction in
risk of ovarian cancer in ever users, this effect being apparent after just one year
of use, with greater protection with increased durations of use, and with the effect
persisting for up to 15 years after stopping COCs. With endometrial cancer, the
reduction in risk appears after two years use of COCs and persists for up to 10
years after stopping the pill.
COCs have a place in the management of acne in young women, with
improvements in this skin condition with several different preparations. The best
is Dianette, which contains 35 g/day of EE and 2 mg/day of cyproterone acetate.
This is not licensed in the UK as a contraceptive but is safe and effective for this
purpose. On the minus side is the fact that the risk of non-fatal and fatal VTE
with the EE/cyproterone combination is higher than with a third-generation COC.
Once the acne and/or hirsutism has resolved, the manufacturer advises to stop the
treatment. EE/norgestimate (Cilest) is also effective against acne and probably the
safer option. Other potential benefits of COCs are a possible role in the
prevention of osteoporosis in women and some emerging evidence of a
protective effect against rheumatoid arthritis, although results of studies are not
entirely consistent and further research in this area is required. A summary of the
health benefits of COCs is given in Table 4.8.
CONTRACEPTION 61
Table 4.6 Absolute contraindications to combined oral contraceptives (COC)

Cardiovascular
Severe hypertension > 160/100

Ischemic heart disease
Migraine with aura/transient cerebral
ischemia
Personal history of VTE
Known thrombophilia
Elective major surgery within next 4 weeks
Diabetes mellitus
Only if microvascular complications
present, > 35 years old, smoker,
hypertensive
Impaired liver function
Active hepatitis
Cholestatic jaundice of pregnancy
Liver tumors
Dubin-Johnson or Rotor syndromes
Hormone-dependent tumor
Breast cancer or hormone-dependent
tumor (although if COC is the only
acceptable and suitable method of
contraception its use may be considered in
discussion with the patient and her
oncologist)
Trophoblastic disease (until serum hCG
undetectable)
History of serious conditions related to sex Porphyria
steroids
Pemphigoid gestationis
Hemolytic uremic syndrome
Smoking
If over age 35
Severe obesity
BMI 40 kg/m2
Women over 35 years
In association with:
(1) Smoking
(2) Obesity
(3) Hypertension
(4) Diabetes
(5) Familial hyperlipidemia
VTE, venous thromboembolism; hCG, human chorionic gonadotropin; BMI, body mass
index
Health risks of combined oral contraceptives in perspective

Myocardial infarction Myocardial infarction, both fatal and non-fatal, is a very
rare event in young women of reproductive age and in non-smoking women
under the age of 35. For the everyday practice age, hypertension, smoking,
obesity and diabetes are the major risk factors for myocardial infarction and the
risk is potentiated by COC use. The case fatality rate for myocardial infarction in
pill users is 30%. In a woman with no cardiovascular risk factors, use of the
combined pill leads to little or no increase in cardiovascular risk.
In summary (see Table 4.9):
(1) Serious cardiovascular risks are very low in non-smoking women under
the age of 35 with no cardiovascular risk factors.
(2) In healthy women with no risk factors COC use increases the risk of
myocardial infarction by 12.5-fold depending on age.
(3) Smoking increases the relative risk of myocardial infarction five- to tenfold, depending on the number of cigarettes smoked.
(4) Hypertension increases the risk five- to six-fold.
(5) Obesity (body mass index (BMI) > 30) and diabetes increase the risk threeto four-fold.
Table 4.7 Relative contraindications to combined oral contraceptives (COCs)
Cardiovascular
Obesity
Migraine
Smoker of any age
Puerperal psychosis
Lactation
Undiagnosed menstrual abnormality
Family history of VTE

Family history of premature arterial
cardiovascular disease
Mild hypertension > 140/90 but < 160/100
BMI 30 kg/m2
Simple migraine without aura
> 20 cigarettes per day
COCs can be prescribed after appropriate

investigations carried out and pelvic
pathology excluded
Undiagnosed second-degree amenorrhea As above
VTE, venous thromboembolism; BMI, body mass index
Table 4.8 Benefits of combined oral contraceptives
Condition
Risk reduction (%)
Pregnancy
Ectopic pregnancy
Functional ovarian cysts
Pelvic inflammatory disease
Menorrhagia
Iron deficiency
Dysmenorrhea
Primary infertility
> 99
90
65
50
50
50
50
40
CONTRACEPTION 63
Condition
Risk reduction (%)
Ovarian cancer
Endometrial cancer
Benign breast disease
Acne
4050
4050
40
Variable
Stroke Cerebrovascular accidents are rare in young women of reproductive age;

they may
Table 4.9 Absolute risk of myocardial infarction per 106 women per annum
Non-smoker, no COCs
Non-smoker on COCs
Smoker, no COCs
Smoker on COCs
COC, combined oral contraceptive
Under 35
Over 35
<1
<4
8
40
12
40
85
485
occur as the result of ischemia or hemorrhage. Significant risk factors for both
ischemic and hemorrhagic stroke are age, hypertension and smoking, while
migraine is a risk factor for ischemic stroke only. There appears to be a small
increase in relative risk (RR=2) of ischemic stroke in women using COCs,
compared to non-users, but this must be taken in the context of the low
background risk. In contrast, there is no increase in risk for hemorrhagic stroke,
in women under 35, using COCs without any of the above risk factors. For both
ischemic and hemorrhagic stroke, there is no evidence of increased risk with
increasing duration of use, nor is there any past use effect. The data regarding the
pill and ischemic stroke are summarized in Table 4.10. The case fatality rate for
ischemic stroke is 25%.
Venous thromboembolism Despite being the commonest cardiovascular event
in COC users, the absolute risk of VTE remains low. In 1995, the Committee on
Safety of Medicines advised doctors that there was a significant difference
between second- and third-generation COCs with respect to risk of venous
thrombosis. Although the data were in fact good news because they suggested
that the risk of VTE with the second-generation pill was less (15 per 100000)
than previously thought (40 per 100 000), they were taken as being bad news. This
led to many women stopping COC. The difference between the COC generations
and VTE has been much debated both for its biologic plausibility and the
reliability of the data used, and new revised risks were published in 1999 (see
Table 4.11). No difference in the incidence of arterial disease has been observed
between second- and third-generation COCs.
The differences between second- and third-generation pills do not justify
changing the prescriptions of established pill users. However, all pill users
should have the risks explained to them in terms that they are able to understand,
with emphasis on the difference between relative and absolute risks. In the case
of first-time pill users, it is good clinical practice to commence patients on
second-generation pills. They do carry a lower VTE risk and it seems sensible to
take the safest option. It is not routine policy in the UK to screen new pill users
for coagulation disorders in the absence of a family history of thrombophilia. If a
second-generation pill is not tolerated for any reason, then it is perfectly
acceptable to change to a third-generation pill.
Where a family history of VTE exists in a first- or even second-degree relative,
some recommend screening for hereditary thrombophilias may be indicated.
Such screens look for Factor V Leiden mutations (5% prevalence in Caucasians),
protein C, protein S and antithrombin deficiencies (combined prevalence of 1
2%) and mutations in the prothrombin gene 20210 (24% prevalence in
Caucasians). One of the most well studied abnormalities,
Table 4.10 Absolute and relative risk of ischemic stroke per 100 000 women per annum
Background risk
Women with migraine
COC users, no migraine
COC users with migraine
COC users and smokers
COC users and hypertension
COC, combined oral contraceptive; RR, relative risk
4.4 (RR=1)
12 (RR=38)
9.0 (RR=2)
22 (RR=5)
31 (RR=7)
44 (RR=10)
Table 4.11 Absolute risk of non-fatal VTE in second-and third-generation pill users (per
100 000 women per annum)
Non-users
5
Second-generation COC users
15
Third-generation COC users
25
Pregnancy
60
VTE, v venous thromboembolism; COC, combined oral contraceptive
the Factor V Leiden mutation, has been shown to lead to an eight-fold increase in
VTE risk in non-users of COCs and a 35-fold increase in risk in association with
COCs. Factor V Leiden was only discovered in the 1990s, and it is likely that
there are other, as yet unrecognized inherited thrombophilic factors that will
increase the risk of VTE. It therefore may be prudent simply to recommend one
of the many excellent alternative forms of estrogen-free contraception to patients
with a relevant personal or family history of VTE, and/or positive thrombophilia
screens. Finally, it should also be remembered that the risk of fatal VTE in COC
users is exceedingly low, around 110 per million women per year for COC
CONTRACEPTION 65
Figure 4.6 Estimated cumulative number of breast cancers per 10 000 women diagnosed
in five years of use and up to 10 years after stopping combined oral contraceptives (COCs),
compared with numbers of breast cancers diagnosed in 10 000 women who had never
used COCs. Reproduced with permission from Schering Health Care Ltd., UK
users. The risk of VTE in COC users is not associated with smoking,
hypertension or small varicose veins. The case fatality rate of VTE is 12%.
Breast cancer The risk of breast cancer is strongly associated with increasing
age and is rare under the age of 40 years. Women taking COCs have a slightly
higher risk of having breast cancer diagnosed than age-matched controls: the
relative risk is 1.24 (confidence interval 1.151.33). The estimated excess
number of cancers diagnosed in the period between starting the pill and 10 years
after stopping is also age-dependent and has been estimated at 0.5, 1.5 and 4.7
per 10 000 women aged 1619, 2024 and 2529, respectively (Figure 4.6). Ten
years after stopping the pill the excess risk of breast cancer disappears and the
rate returns to the background rate. Breast cancers diagnosed in women who
have taken the pill are more likely to be localized to the breast than in women
who have not. It appears that women starting COCs before the age of 20 years
are at higher risk than those who start them at a later stage. The risk attributable
to COCs seems smallest among recent users aged 3544 years. A higher dose (>
35 g EE) seems to impart higher risk. The association between COCs and
breast cancer is not thought to be causative. It is thought that COCs may act as
growth promoters of cancers that have already arisen, or there may be earlier
detection of the cancers or both.
Effective use of COCs is achieved by providing careful, accurate instructions
to patients at the time of the first prescription, backed up by written information,
regular revision of pill rules and easy access to advice.
Cervical cancer A weak, non-causative association between COC use and
cervical cancer has been demonstrated in some studies. The relative risk is 1:1
for less than 5 years of use, rising to 2.54.0 with more than 10 years of use. The
reasons for this association are unclear. It is not known if the risk disappears if
COC use is discontinued, in a way similar to breast cancer. Cervical smears should
therefore be offered and carried out in accordance with local protocols.
Key examination
The only essentials for examination prior to prescribing the COC pill are blood
pressure, weight and height (in order to calculate the BMI). COCs would not
normally be prescribed when there is a pre-existing blood pressure equal to or
greater than 140/90; a BMI of greater than 30 would be regarded as a relative
contraindication, while one of 39 or over is generally considered to be an
absolute contraindication. There are no data to support routine breast
examination before pill prescription, nor is it necessary or desirable to carry out a
vaginal examination or cervical smear before COCs are prescribed, unless
indicated by appropriate factors in the history, e.g., irregular vaginal bleeding.
Practical prescribing points and key information for the patient
The usual time to start taking the pill is the first day of normal bleeding of the
menstrual period. When this is done, no additional contraceptive precautions are
required at all. The pill can also be started any time up to day 5 of the menstrual
cycle, but additional precautions, usually the use of condoms, are advised for seven
days thereafter. Patients should be told to take their pill at the same time each
day, ideally choosing a time at which they are most likely to remember it. If the
pill is forgotten at this time, it may be taken at any time up to 12 h later without
any loss of contraceptive protection. If the missed pill is forgotten for longer than
12 h, the missed pill rules apply, as follows:
(1) Take the most recently forgotten pill now. Discard any earlier missed pills.
Use an alternative method of contraception if intercourse occurs during the
next seven days.
(2) In addition, if there are fewer than seven pills left in the pack, start the next
pack without the usual break of a week between packs.
(3) And if there are seven or more pills left in the pack, when the pack is
finished leave the usual seven-day break before starting the next pack.
The missed pill rules also need to be known and followed in the case of
intercurrent antibiotic use, vomiting and severe diarrhea, all of which may lead to
poor pill absorption and consequent lack of effect. There are anecdotal reports of
pregnancies occurring after use of broad-spectrum antibiotics, such as ampicillin,
tetracycline and cephalosporins. There is some evidence that the enterohepatic
circulation is altered and levels of estrogen are lowered by these antibiotics
which therefore reduce efficacy of the pill. Patients should be advised to follow
missed pill rules whilst taking these antibiotics and for a week after
discontinuing. In the case of long-term antibiotic use, for instance in the
treatment of acne, extra precautions are only required for the first fortnight after
introduction of the antibiotic.
CONTRACEPTION 67
It is always a good idea to warn patients that they may experience adverse
events in the first few cycles of pill taking. These episodes are usually mild and
rarely persist beyond six months, but if they do, they may be alleviated by
changes in the pill formulation. The reported incidence of some adverse events
beyond six months is as follows: break-through bleeding 48%, breast
discomfort 13%, nausea 12% and acne 12%; amenorrhea occurs in 0.51.5%
of users. Patients should be advised not to stop their pills if one withdrawal bleed
is missed but to seek medical advice before restarting the pill if two successive
bleeds are missed. Patients also need to be advised under what circumstances
they should stop pill taking immediately, use alternative contraceptive measures
and take urgent medical advice. They should be advised of the symptoms that
might suggest an acute cardiovascular event, such as myocardial infarction,
stroke, severe migraine, pulmonary embolism or deep vein thrombosis. The
other situations that may require medical advice include development of
jaundice, newly diagnosed high blood pressure and elective surgery. With the
latter, COCs should be discontinued four weeks beforehand if a period of
immobilization is anticipated. Alternative contraception should be provided and
COC use should not be restarted until at least four weeks after full mobilization.
Follow-up of patients on combined oral contraceptives
New patients should be seen after three months, and subsequent visits can be at
six-monthly intervals provided there are no problems. Very young patients may
benefit from being seen more frequently for the first few months of pill taking.
The essentials of examination at each follow-up visit are as at first prescription,
i.e., measurement of blood pressure and weight. In addition, enquiry should be
made about the menstrual cycle, and any unusual symptoms, such as chest or leg
pain and migraine; a regular enquiry about smoking habits and family history is
also advisable and advice given where necessary.
The combined contraceptive patch
A new development in combined hormonal contraception has been the
development of the contraceptive patch. This is a thin, 20 cm2 matrix patch that
has three layers: an outer protective layer of polyester, a medicated adhesive
middle layer and a clear protective layer that is removed before application. The
patch delivers 20 g of EE and 150 g of norgestrelomine (active metabolite of
norgestimate) into the systemic circulation within 24 h. The patch is changed
weekly for 3 weeks followed by a patch-free week, thus forming a 28-day cycle.
The patch can be applied on the upper arms, torso (excluding breasts), lower
abdomen and buttocks, provided the skin is clean, dry and free of skin disorders.
Each new patch should be applied away from the site of the old patch. Users can
maintain their usual activities while wearing the patch, including swimming and
bathing, but should not apply creams or cosmetics on or around the patch. The
patch works similarly to the pill, suppression of ovulation being the main
mechanism of action. In clinical studies, the user failure and method failure rates
of the contraceptive patch were 1.24 and 0.99 per 100 women per year,
respectively. The cycle control was good, with 3% and 1% of women
experiencing breakthrough bleeding or spotting, respectively, by the end of the
third cycle. These rates are very similar to those seen with the contraceptive pill.
Compliance with the patch in a study setting was better than with the pill, with
89% of patients wearing the patch and 80% on COCs reporting perfect
compliance. Five percent of all patches (1 in 20) had to be replaced because of
partial or complete detachment. Side-effects experienced with the patch and
COCs are virtually the same, apart from breast discomfort and dysmenorrhea,
which is more common with the patch. Skin reactions severe enough to necessitate
abandoning the method occur in 23% of women in clinical trials. The overall
dropout rate with the patch is 2528% which is similar to the dropout rate
experienced with COCs (30%). In a year-long study of 770 women, the patch did
not lead to any meaningful changes in vital signs, general and gynecologic
examination patterns or laboratory parameters.
In summary, the patch is an effective method of contraception that may be
useful in cases of gastrointestinal side-effects of the pill or where compliance is
an issue. Clinical experience with the patch is limited and does not allow us to
make any broader recommendations.
Intrauterine methods of contraception
Some of the most important advances in contraception in the past 20 years have
been in intrauterine methods. Although they have the same origin, the
intrauterine methods of today are more effective and have fewer side-effects as
compared to the devices in use in the 1960s and 1970s. Intrauterine methods of
contraception can be divided into three main types: IUDs, the intrauterine implant
(IUI) and the intrauterine system (IUS) (see Table 4.12); the latter is dealt with in
a separate section. To minimize the use of abbreviations, we shall sometimes use
the term coil instead of intrauterine contraceptive device. Examples of
intrauterine devices are shown in Figure 4.7.
Worldwide, IUDs are the second most commonly used method after
sterilization, although only about 4% of British women aged 1544 choose this
method, while in most other European countries rates of up to 19% are seen.
Intrauterine methods of contraception are not only highly effective but also
safe, have high continuation rates, are fully and rapidly reversible, are simple to
use and require no action at the time of coitus. Although some appear expensive,
when considering the
CONTRACEPTION 69
Table 4.12 Intrauterine methods of contraception

Type
Devices
Active constituent
IUD
Multiload 250 Short, Multiload 250,

Copper
Multiload 375, Nova T 200, Nova T 380, TSafe Cu 380A*
IUI
GyneFix
Copper
IUS
Mirena
Levonorgestrel
The authors preferred devices are in italics; *discontinued in the UK; IUD, intrauterine
device; IUI, intrauterine implant; IUS, intrauterine system
overall cost for the duration of action, they are all cost-effective. Appropriately
trained health care professionals should fit all intrauterine methods. The traditional
IUD has a plastic T-shaped frame with a variable amount of copper in the form of
wire and/or sleeves mounted on it. The plastic frame is held responsible for the
menstrual disturbances associated with this contraceptive method. A recent
development has been the introduction of the frameless intrauterine device
GyneFix. It consists of six copper sleeves with a total surface area of 330 mm2
threaded on polypropylene suture material. The proximal end of the thread has a
knot which is buried in the fundal myometrium with an inserter for anchoring the
device. The manufacturer claims that GyneFix is as effective as the best Tshaped devices, but associated with less bleeding, pain or expulsion.
Mechanism of action
Copper-containing devices The presence of copper reduces sperm motility,
fertilization, and ovum development. In addition, should fertilization occur,
which is rare, there is a sterile inflammatory response in the endometrium that
prevents implantation. This latter mechanism is the primary effect when used for
emergency contraception.
Levonorgestrel-containing devices The presence of the progestogen
levonorgestrel within the uterine cavity leads to a profound suppression of the
endometrium (preventing implantation), thickening of cervical mucus
(preventing sperm migration) and a reduction in tubal motility. The plastic frame
induces a foreign-body reaction.
Efficacy
The efficacy of copper-containing devices is directly related to the copper content;
there is also a reduction in the rate of ectopic pregnancy in users of modern IUDs
(see Table 4.13).
Copper IUDs used for emergency contraception have a failure rate in the order
of 0.1 per 1000 women treated per cycle, which is superior to both hormonal
methods of emergency contraception and where efficacy is important in the
Figure 4.7 Examples of intrauterine devices. Reproduced with permission from Kleinman
RL, ed. Family Planning Handbook for Doctors. London: International Planned
Parenthood Federation, 1988:106
method of choice. The Mirena IUS is not effective as an emergency

contraceptive.
Assessing suitability for intrauterine methods of contraception
Intrauterine methods of contraception are suitable for most women requesting
long-term effective contraception, including many nulliparous women. There are
few absolute contraindications to their use: these and the relative
contraindications are listed in Tables 4.14 and 4.15.
Key history and examination
Intrauterine contraception is suitable for many women requesting contraception.
The history should be taken bearing in mind the absolute and relative
contraindications and should include the following.
Assessment of risk for sexually transmitted infections Risk factors for STIs
include age under 25, more than one partner in the previous year, a relationship
of less than previous six months duration and, because of the possibility of
CONTRACEPTION 71
treatment failure or reinfection, a recent STI. If the woman suspects or is aware

that her partner is unfaithful, this also should be managed as a situation where
there is an increased risk of infection. Tests for STIs may be indicated.
Assessment of menstrual problems Menorrhagia, dysmenorrhea,
intermenstrual bleeding or postcoital bleeding should be investigated
appropriately before insertion of an intrauterine contraceptive device.
Examination A full gynecologic and abdominal examination is carried out
prior to fitting an IUD.
Complications and side-effects of using intrauterine devices
Intrauterine methods of contraception are very safe, the main risks being divided
into early (i.e. at the time of fitting) and late morbidity. Mortality attributed to
IUD use is very rare, 1.6 per million insertions. All the complications listed here
should be discussed with the woman prior to insertion of an IUD.
Pain Most women having an IUD fitted will experience some pain or
discomfort, especially when the Allis forceps is applied to the cervix, when the
uterine sound is passed, and the device is inserted. Mefenamic acid 500 mg taken
30 min before fitting offers some reduction in pain. Occasionally intra-cervical
local anesthesia is required. Vagal inhibition, which may rarely lead to
circulatory collapse, occasionally occurs even without pain.
Uterine perforation This complication occurs in about 1 in 1000 insertions. It
occurs at the time of insertion, may not be associated with pain and may go
unnoticed. Perforation may be partial or complete. If not recognized at the time of
insertion, the diagnosis is usually made when, at routine follow-up, the absence
of threads is noted (see Missing threads, page 59).
Expulsion The rate of expulsion has been quoted at 315 per 100 women
during the first year of use. Rates of expulsion decrease with increased age in
women. Expulsion is more likely in the presence of a congenital uterine
abnormality. Women should be instructed to try and feel for the threads after
each period, especially during the first year of use.
Pregnancy The risk of pregnancy is greatest in the first year of use and varies
according to
Table 4.13 Efficacy of intrauterine contraceptives at 2 years (various sources)
Devices
200 mm2 copper

Copper 7
Nova T 200/
NovaGard
Pregnancies per
100 woman-years
Licensed duration of Recommended

use (years)
maximum duration
of use (years)
2.8
3.0
NA
5
NA
3
Devices
Pregnancies per
100 woman-years
Licensed duration of Recommended

use (years)
maximum duration
of use (years)
220 to 300 mm2

copper
Multiload 250
0.9
3
3
Copper T 220
0.9
NA
NA
Flexi-T 300
1.8
5
2
330 to 380 mm
copper
GyneFix*
< 0.5
5
5
Multiload 375*
0.6
5
5
T-Safe Cu 380A*
0.3
10
12
Nova T 380*
1.6
5
5
Levonorgestrel 20
g/24 h
Mirena*
< 0.3
5
5
Device recommended for routine use; discontinued in the UK; NA, not available
Table 4.14 Absolute contraindications to intrauterine contraception
Pregnancy
Unexplained genital tract bleeding
Cervical or endometrial cancer
Current benign or malignant gestational trophoblastic disease
Cervicitis due to chlamydia or gonorrhea and cervicitis where these infections have not
been excluded
Pelvic inflammatory disease current or within the previous 3 months
Pelvic tuberculosis
Distortion of the uterine cavity, for example by fibroids or congenital malformation*
Cavity length less than 5.5 cm*
Copper allergy
Wilsons disease
*Not necessarily a contraindication to the GyneFix intrauterine implant; not a
contraindication to use of the Mirena intrauterine system
the device. The most effective device is the Mirena IUS. Failure may also occur
in the event of unrecognized perforation or expulsion. Self-checking of the
threads by the patient can reduce the chance of failures due to these
Table 4.15 Relative contraindications to intrauterine contraception
At risk of sexually transmitted infections
AIDS or HIV-positive
CONTRACEPTION 73
Valvular heart disease and septal defects (See current British National Formulary for
latest advice on antibiotic prophylaxis for women at risk of endocarditis.)
Nulliparous (small increased risk of expulsion)
The following are relative contraindications to copper devices:*
Menorrhagia
Severe dysmenorrhea
Previous ectopic pregnancy
*Mirena has a beneficial effect on these conditions; not Gyne T 380 S, which is
protective
latter causes. If pregnancy occurs, it is advised that the device be removed if the
threads are visible. This carries with it a risk of mis-carriage, but this is not as
great as the risk and consequences of septic abortion if the device remains in
utero. Failure to remove the device is not an indication for termination of
pregnancy. No teratogenic effects of IUS have been reported.
Ectopic pregnancy The IUS is protective against ectopic pregnancy and has a
very low rate associated with its use. The risk of ectopic pregnancy in users of
copper devices varies between devices. The lowest ectopic pregnancy rates are in
those devices with more than 350 mm2 copper. IUDs have a greater protective
effect on intrauterine pregnancy than extrauterine pregnancywhich explains
why the rate of ectopic to intrauterine pregnancies in IUD users is greater (one in
25) than in non-users of ICCDs (one in 100200). Given these figures, should
pregnancy occur in an IUD user, it is important to exclude ectopic in the first
instance. However, IUDs do not cause ectopic pregnancies, and the risk of
having an ectopic pregnancy is reduced with some devices such as the Gyne T
380. Mirena and the Gyne T 380 are therefore the devices of choice in women
with a history of a previous ectopic pregnancy.
Actinomyces-like organisms Actinomyces is an anerobic, Gram-positive microorganism, which is normally commensal in the mouth and the gut. The microorganism is present in the genital tract only in the presence of an IUD. It is often
found on routine cervical screening and its prevalence has been quoted between
1% and 20%, depending on the duration of use of the IUD. The presence of
actinomyces-like organisms on smear does not mean that the patient has pelvic
actinomycosis, but while it is thought that there may be a small increased risk,
the absolute risk is negligible. Pelvic actinomycosis is very rare and the
discovery of actinomyces in an asymptomatic woman does not mandate removal
of the IUD. If the woman understands that she may be at a slightly higher risk of
pelvic actinomycosis and prefers to be monitored for symptoms and signs once
the situation has been explained to her, then the IUD can be left in situ. If the
woman is anxious about the possibility of infection then the device should be
removed or changed.
Effect on the menstrual cycle With the exception of the first few weeks after
insertion, irregular or intermenstrual bleeding is uncommon with copper devices.
If abnormal bleeding does occur, the presence of displacement, partial expulsion

or infection should be considered. A more usual effect is to increase the duration
of menstruation and/or the menstrual loss. In some women with previously
painless cycles, insertion of an IUD may lead to dysmenorrhea. The effect is not
predictable and appears to be greater with ordinary IUDs than with the frameless
IUI. Usual medical treatments for menorrhagia and dysmenorrhea that start after
IUD insertion can be tried but these are of limited benefit in the presence of an
IUD. Between 5 and 20% of IUD users will have the device removed because of
problematic bleeding or pain.
Pelvic infection and intrauterine contraception
The risks of pelvic infection after insertion of an intrauterine device, system or
implant are very low at approximately one case per 150200 insertions and are
only increased above the background risk in the three weeks after insertion. In
fact, the risk directly attributable to the procedure may be even less. The
presence of STIs increases the risk of developing PID after insertion. The Mirena
actually reduces the risk of developing PID, and the risk associated with the
GyneFix has not been fully evaluated but appears to be lower than that associated
with conventional coils. The importance of PID is two-fold. Firstly, every
episode of PID carries with it a significant risk of subsequent subfertility or
ectopic pregnancy secondary to tubal damage. Secondly, PID is an unpleasant
condition that causes pain and may cause a systemic illness. Because of the
association with STIs, many cases of PID post insertion are potentially
preventable. Some doctors advise screening all women for chlamydia prior to
insertion if there is a prevalence of chlamydia of 3% or greater in the local
population. However, this is not the practice of the authors as it can delay fitting
and is not appropriate for all women. It is important that all women having an
IUD fitted are informed beforehand of the risks of PID and helped to put their
own individual risk into perspective, with testing for STIs if appropriate.
Management of pelvic inflammatory disease after insertion of
an intrauterine device
PID is a clinical diagnosis (see Appendix II for details of diagnosis, investigation
and management). If the woman with PID wishes to continue to use the IUD as
her method of contraception, it should not be removed. Treatment should be
commenced and the patient reassessed after 4872 h. At this time there will be
improvement in most women; however, if this is not the case, the diagnosis
should be reconsidered and if no other cause of PID is found, the IUD should
then probably be removed to facilitate a cure.
CONTRACEPTION 75
Missing threads
If the patient reports that she cannot feel the threads or if the threads are not seen
during examination, there are four possibilities: (1) the threads are present, have
curled up and are lying in the cervical canal or the uterine cavity; (2) pregnancy;
(3) expulsion; or (4) perforation. Pregnancy can be confirmed or excluded either
by the history, a clinical examination and/or a pregnancy test. Until the position
of the IUD is confirmed, the woman should be advised to use an alternative
method of contraception. Sometimes the threads can be identified just in the os;
unless the IUD is to be removed it is not advised to try to bring the threads down
as this may dislodge the IUD. If the woman is not pregnant and the threads
cannot be found, a pelvic ultrasound scan should be performed. The result will
show the coil present either inside the uterus or outside, in the pelvis, or absent.
If the coil is in the uterus and not displaced, all that is needed are six-monthly
ultrasound scans to reassure the patient that the device is still in the uterus. The
woman should report any unusual bleeding or pain. If the coil is outside the
uterus in the pelvis, it needs to be removed surgically, usually laparoscopically,
but occasionally laparotomy is required. If the coil is absent, a plain abdominal Xray should be performed to ensure it is not intra-abdominal; if not, expulsion is
assumed and a new coil may be fitted or a different method of contraception
advised.
Timing of insertion
The usual time to insert a copper coil is just post-menstrual or during the menses.
The latter is associated with a very slightly higher expulsion rate. However, it
can be inserted at any time of the cycle, provided there is no risk that a
pregnancy has already implanted (see Intrauterine emergency contraception,
page 73).
Removal of intrauterine devices
To avoid pregnancy, IUDs are best removed during menses and when another
method of contraception has been initiated. They should not be removed midcycle if intercourse has taken place in the previous seven days because of a
theoretical risk of pregnancy.
Progestogen-only contraception
During the last 10 years, there has been a great expansion in the range of
progestogen-only methods available. At the time of writing, there are short-term,
long-term and emergency methods of progestogen-only contraception. In some
cases the efficacy of the long-term method equals or exceeds that of sterilization.
All progestogen-only methods have minimal metabolic effects that are not
significant clinically, meaning that they can be used safely in older women and
those who have contraindications to estrogen-containing contraceptives. They
often require minimal user compliance and little doctor or nurse involvement
after the initial consultation. The main side effect common to all progestogenonly methods is unpredictable bleeding: this will be discussed in more detail
under individual methods.
Progestogen-only pill
Mode of action Second- and third-generation progestogen-only pills (POPs) are
now available on the market. The second-generation POPs contain the
progestogens norgestrel, levonorgestrel, norethisterone or ethynodiol and the
third-generation POPs contain desogestrel.
The principal effect of second-generation POPs is on the cervical mucus,
causing increased viscosity and sperm impenetrability. This effect is exquisitely
sensitive to the serum progestogen concentration and therefore meticulous,
regular pill taking is required to ensure consistent serum levels. It is generally
accepted that the effect on cervical mucus wears off 27 h after taking a pill. To
be effective, at least two pills must have been taken correctly. Other effects of
second-generation POPs are on the endometrium in which normal thickening and
maturation do not occur, leading to failure of implantation if fertilization does
occur, decreased fallopian tube motility, and, in approximately 15% of women,
suppression of ovulation.
All of the above mentioned mechanisms of action apply to the third-generation
POPs as well; however, for these agents the rate of ovulation suppression is
considerably higher, i.e., over 95%.
Efficacy and drug interactions Failure rates for second-generation POPs are
age-related and range from < 1 per 100 woman-years in women over 35 years, up
to 45 per 100 woman-years in those under 25 years. This difference is likely to
be caused by a combination of factors, including falling fertility and higher pilltaking reliability in older women. Users can be advised that there are no
interactions with commonly used antibiotics. For POPs containing desogestrel,
the overall failure rate is estimated at 0.4/100 woman-years.
Some studies suggest that there may be a weight-related increase in failure
rates of hormonal methods, such as POPs and COCs. As a result, some clinicians
advise the use of two tablets daily in women weighing over 70 kg. This matter is
hotly debated, with the Summary of Product Characteristics advising against the
practice. An analysis of the Oxford Family Planning Association database did
not find a correlation between weight and failure rate either.
Key history, indications and contraindications
The following should be considered:
CONTRACEPTION 77
(1) All women requesting hormonal contraception should have a medical and
family history taken as detailed in the section on combined oral
contraception.
(2) There are in practice no absolute contraindications to POPs, although
pregnancy should be excluded before commencing treatment and
undiagnosed vaginal bleeding should always be investigated appropriately
before commencing any hormonal method of contraception.
(3) A history of ectopic pregnancy is a relative contraindication only because
ovulation is not reliably suppressed and tubal motility is reduced. Thus, if
fertilization does occur there is an increased risk of ectopic implantation; the
ectopic rate is nevertheless lower than in women not using contraception.
(4) The POP is particularly suitable for women in the following categories:
(a) Lactating women;
(b) Personal or immediate family history of VTE;
(c) Women over 35 years with risk factors for combined oral contraception,
e.g., smokers, those with cardiovascular risk factors such as diabetes or
hypertension;
(d) Migraine sufferers who experience aura or severe migraine headaches;
(e) Overweight individuals;
(f) As a matter of choice for any woman who is a reliable pill taker.
Examination, choice of pill and prescribing information Provided that the history
is normal, all that need be determined at an examination are blood pressure and
weight. Blood pressure is not generally influenced in any way by POPs but
where there is pre-existing hypertension, careful monitoring is indicated. The more
androgenic levonorgestrel (as found in Microval/Neogest) may be more likely to
increase blood pressure than norethisterone (as found in Micronor/Noriday). The
actual choice of POP for any individual patient is fairly arbitrary and is made on
an empirical basis. Any of the brands listed in Table 4.16 may be used as first
choice, with the opportunity to switch to an alternative progestogen if the
bleeding pattern or any other side-effects are unacceptable. Ethyno-diol diacetate
(the progestogen in Femulen) is a pro-drug, metabolized to norethisterone, and
has no particular advantages.
Key prescribing points are as follows:
(1) Pill-taking should be commenced on day 1 of menses; and when this happens,
no additional precautions are needed.
(2) Pills are taken continuously, without any break at any time in the cycle.
(3) Pills should be taken regularly within three hours of the same time each day.
The actual time of day is not crucial. The most important factor is the
likelihood of the woman remembering the chosen time.
(4) If a pill is taken more than 3 h later than the regular time, the effectiveness
of contraceptive cover will be reduced. Current advice is to take the
forgotten pill as soon as possible, to continue taking pills at the regular time
and to use extra contraceptive precautions for seven days.
(5) Menstrual irregularity may occur and is unpredictable, ranging from
amenorrhea, through infrequent bleeding, fairly normal regular cycles to
frequent and/or heavy bleeding. Approximately 50% of women will have a
fairly normal cycle and only a small number have bleeding problems.
(6) Minor side-effects include slight breast tenderness at the onset of pill-taking
and other progestogenic effects such as acne, headaches and bloating.
(7) Functional ovarian cysts are more common in POP users than in those not
using this hormonal method. Whilst most functional ovarian cysts are
asymptomatic and spontaneously resolve, they may present with abdominal
pain.
(8) Follow-up of POP users includes regular weighing, annual blood pressure
taking provided it remains normal, and assessment of menstrual pattern.
(9) POP use can be started 23 weeks after delivery.
Table 4.16 Progestogen-only pills
Proprietary name
Progestogen
Dose (g)
Microval
Norgeston
Neogest
Micronor
Noriday
Femulen
Cerazette
Levonorgestrel
Levonorgestrel
Norgestrel
Norethisterone
Norethisterone
Ethynodiol diacetate
Desogestrel
30
30
75
350
350
500
75
Injectable contraception
Injectable progestogen-only contraception is now widely used. There are two
such preparations available in the UKone containing medroxyprogesterone
acetate (Depo-Provera) and the other norethisterone enanthate (Noristerat; see
Table 4.17). There are no combined injectable estrogen/progestogen
contraceptives licensed in the UK. Originally both available progestogen-only
injectable contraceptives were licensed only for shortterm use, i.e., for women
whose partners had undergone vasectomy and were awaiting confirmation of
sterility, for women awaiting sterilization or following rubella immunization. A
general licence for Depo-Provera was granted in the UK in 1995.
Table 4.17 Injectable progestogen-only contraceptives
Product name Progestogen
Dose (g) Injection interval
Depo-Provera
Noristerat
150
200
Medroxyprogesterone acetate
Norethisterone enanthate
Every 12 weeks ( 5 days)

Every 8 weeks ( 5 days)
CONTRACEPTION 79
Norethisterone enanthate is still licensed for short-term use after vasectomy but
is used more widely for women who want an injectable method but who have
experienced side-effects with medroxyprogesterone acetate.
Mode of action and efficacy Injectable progestogens work primarily on the
hypothalamic-pituitary-ovarian axis to suppress gonadotropin production and
thus prevent ovarian follicular development and ovulation; they also share with
other progestogen-only methods effects on the endometrium (atrophy), fallopian
tubes (reduced motility) and cervical mucus (thickening). They have a very high
efficacy, with failure rates between < 0.01 and 1.5 per 100 woman-years, which
is at least comparable to that of sterilization and, because ovulation is inhibited,
there is no relative increase in ectopic rates.
Key history, indications and contraindications These are essentially the same
as for POPs. Caution should be used before recommending injectables for
women with a history of severe postnatal or endogenous depression as some
authorities consider that depression may recur on injectable preparations; this has
not been the authors experience. They should not be used for any woman
planning a pregnancy in the near future, due to possible delay in return of fertility
(see below); neither are they suitable for women not prepared to tolerate
menstrual irregularity or amenorrhea. However, injectables may be particularly
suitable for the following groups of women:
(1) Young women requiring long-term, reliable contraception, particularly
where difficulties exist with regard to remembering to take pills;
(2) Women with homozygous (SS) and SC sickle cell disease, in whom the
hematologic profile is improved and the frequency of sickle cell crises is
reduced by Depo-Provera;
(3) Women who cannot take estrogencontaining contraception, e.g., those with a
history of VTE or coagulation risk due to conditions such as systemic lupus
erythematosus or known thrombophilia;
(4) Women who develop hypertension on the combined oral contraceptive;
(5) Postnatally, as injectables do not diminish, and may even increase, milk
production (but see below, under prescribing details).
Examination, choice of injectable and prescribing information Blood pressure
and weight as for POPs; breast and pelvic examination and cervical smear only if
appropriate or clinically indicated.
The usual first-choice injectable is Depo-Provera; however, Noristerat does
have certain advantages over Depo-Provera. In particular, it is thought to cause
less weight gain (although hard evidence is lacking), a greater likelihood of
regular cycles and, lastly, the return of regular menstruation following cessation
of treatment is usually more rapid. Against these advantages is the drawback of
an oily preparation which is more difficult and painful to inject and has to be
repeated every eight weeks as compared to every 12 weeks.
Key prescribing points are as follows:
(1) The first injection should be given on day 1 of menses, in which case no
additional precautions are needed; if started between day 2 and day 5 extra
precautions should be used for 7 days.
(2) Postpartum, the first injection should ideally be given after six weeks. An
immediate postpartum injection may lead to unacceptably prolonged
bleeding, although in individual cases it may be appropriate to give it at 21
days postpartum.
(3) Following first-trimester termination the injection can be given
immediately.
(4) Subsequent injections should be given at the recommended intervals (see
Table 4.17).
Patients should be advised of the following:
(1) Menstrual change is very common; amenorrhea is the commonest pattern,
but frequent and/or prolonged bleeding may occur, particularly during the
first three to six months (for management, see below). Amenorrhea occurs in
30, 55 and 68% of women after 3, 12 and 24 months of use, respectively.
Prolonged heavy bleeding requiring treatment is noted in 0.54 per 100
woman-years.
(2) Regular use of Depo-Provera may lead to less premenstrual tension, less
dysmenorrhea and less anemia.
(3) Weight gain, probably due to appetite stimulation, and a reduction in the
volume of blood loss, are the commonest reasons for discontinuation of the
method. The weight gain is in the region of 23 kg after 12 years of use,
rising to 67 kg after 46 years of use.
(4) After the last injection, there may be a delay in the return of normal
menstrual cycles and possibly fertility, very rarely up to 18 months; there is
no effect on long-term fertility.
Amenorrhea owing to Depo-Provera use may also be associated in the long term
with hypo-estrogenism, which carries the theoretical risk of decreased bone
mineral density (and consequent fracture risk) and an increased risk of ischemic
heart disease. While some studies have demonstrated a reduction in bone density
in women using Depo-Provera, this has not been borne out in other studies. No
increase in ischemic heart disease has been seen in studies specifically looking at
this.
Drug interactions There is no good evidence that liver enzyme-inducing drugs,
including certain anti-epileptic therapies such as carbamazepine, griseofulvin and
rifampicin, lead to a reduced efficacy of Depo-Provera. Current medical practice,
however, is to err on the side of caution and advise injections at reduced
intervals, i.e. every 10 weeks. This reduction in interval times applies to
rifampicin, even if only a single dose is given, as hepatic enzymes can be
CONTRACEPTION 81
Figure 4.8 Size of Implanon subdermal implant in relation to a matchstick. Reproduced

with permission from Organon, UK
induced for up to four weeks. Extra contraceptive precautions should be also be

used for that period of time.
Management of prolonged bleeding on Depo-Provera In cases where there is
prolonged bleeding after a Depo-Provera injection, it is necessary to exclude
other causes of bleeding, such as pregnancy and infection. Provided estrogen is
not contraindicated, bleeding can usually be controlled by additional estrogen
therapy. This is most conveniently done by taking one packet of any low-dose
COC pill. This will frequently be effective and the next injection can then be
given at the normal time; if the next injection is due in less than four weeks, it
can be given early and the patient reassured that the bleeding will almost
invariably settle down after this next injection.
Implants
One progestogen-only implant is now available in the UK, namely Implanon.
This is a single rod system, 4 cm long and 2 mm wide (Figure 4.8). It contains a
core of 68 mg etonogestrel enclosed in an ethylenevinylacetate (EVA) membrane
which is non-biodegradable. It is designed for the slow, controlled release
of etonogestrel over a period of three years. Pre-launch studies demonstrated
Implanon to be a highly effective contraceptive with no pregnancies occurring in
over 90 000 cycles of use. The Pearl index with normal use is therefore likely to
be very low and approaching zero. A progesterone-only implant called Norplant,
which was launched in 1993, was removed from the UK market by the
manufacturer for commercial reasons in 1999, but it is still available through
some suppliers who import it.
Mode of action The principal mode of action of Implanon is inhibition of
ovulation; this occurs via suppression of LH secretion from the pituitary gland.
In one study, complete suppression of ovulation occurred during the first two
years of Implanon use, while in the last (third) year, ovulation was suppressed in
more than 95% of users. Despite the suppression of ovulation, ovarian activity
continues as FSH levels are not significantly affected, with the result that normal
estradiol levels are maintained. There are alsoin common with all progestogenonly methodseffects on cervical mucus with increased viscosity leading to
reduced sperm penetration and a reduction in the thickness of the endometrium,
both of which contribute to contraceptive efficacy.
Key history, examination and contraindications Implanon should be
considered for women wanting long-term, highly effective but reversible
contraception. As it invariably causes alteration in the menstrual pattern, it is not
suitable for women not prepared to tolerate this. It is likely to prove popular with
young women who do not wish to become pregnant for some years and want a
method that requires minimal patient or health professional involvement. It
should not be used if pre-existing pregnancy is suspected, nor in the presence of
undiagnosed vaginal bleeding or hormone-dependent tumors. It is
contraindicated in active venous thromboembolic disorders but can be given to
women with a history of VTE who wish to use hormonal contraception.
Drug interactions There may be interactions with potent enzyme inducers
such as rifampicin, griseofulvin, phenytoin and carbamazepine; nospecific
interaction studies have been performed on Implanon, and advice on its use is
based on extrapolation from studies of other progestogen-only methods. If
enzyme inducers are concurrently prescribed then an alternative method of
contraception is advisable. If only short-term use of enzyme inducers is planned,
then barrier method(s) should additionally be used when the enzyme inducer is
prescribed.
Timing of Implanon injections The following should be considered:
(1) In women previously using barrier methods of contraception or no method
at all, the injection should be given in the first five days of the cycle. If
injected later than day 2 of the cycle, extra contraceptive precautions should
be used for the first seven days.
(2) In women transferring from combined oral contraception, the injection
should be given during the pill-free week, while in women transferring from
another progestogen-only method, it can be injected at any time, provided
the patient and operator are confident that an ongoing pregnancy is not
present. In the case of transfer from the POP, extra precautions should be
used for the following seven days.
(3) In IUD users, Implanon can be injected at any time while the IUD is in
place, the IUD device then being removed with the next menstrual period.
(4) Following pregnancy, Implanon can be injected immediately after firsttrimester termination, whilst after later terminations and full-term deliveries
it is recommended that the injection should be delayed until 2128 days
after delivery.
Insertion Following infiltration of 5 ml of local anesthetic, the implant is inserted
subdermally 68 cm above the elbow in the inner aspect of the non-dominant arm
using the preloaded applicator (Figures 4.9 and 4.10) and following the
CONTRACEPTION 83
Figure 4.9 Implanon subdermal implant (with applicator). Reproduced with

permission from Organon, UK
manufacturers instructions, which should be supplemented by supervised

training. The injection site should be kept covered and dry for the first 2448 h; a
pressure bandage may help to prevent any bruising.
Bleeding pattern and side-effects Consider the following:
(1) An unpredictable bleeding pattern should be expected, both between users
and within the same user.
(2) Approximately 20% of women will have amenorrhea at some point during
use.
(3) Approximately 25% will have infrequent bleeding at some point during use.
(4) Approximately 10% will have prolonged episodes of bleeding and spotting
at some point during use.
(5) Less than 10% will have frequent bleeding or spotting (more than six
bleeding episodes in a 90-day period) at some point during use.
(6) A mean weight increase of 12% per year has been reported. This does not
differ significantly from the weight increase seen in women using nonhormonal methods of contraception over the same period.
(7) Where there is pre-existing acne, the condition generally improves with
Implanon use, but in a small (approximately 10%) proportion of women it may
worsen; in less than 15% of women acne may appear for the first time.
(8) Mood changes, breast tenderness, headaches and nausea occur in some
Implanon users, in common with all hormonal methods.
(9) Loss of libido and hair thinning or actual hair loss have also been reported.
Removal and return of fertility Implanon is removed using a small skin incision
under local anesthesia. The process may leave a small scar (23 mm). It is the
correct and careful subdermal insertion that determines the case of removal of
the rod. Excluding the duration of the anesthetic application, the mean time
needed for the insertion of Implanon is 1.1 min and for removal it is 2.6 min.
Return of fertility is very rapid and this is one of the advantages of this method
compared to injectable contraception; in studies, over 94% of women ovulated
Figure 4.10 Insertion (a, b and c) and removal (d, e, f and g) of Implanon. Reproduced
with permission from Organon, UK
within three weeks of removal of the implant. Thus, an alternative method of

contraception or a new implant should be used immediately, unless a pregnancy
is planned.
Intrauterine progestogen-only methods
The Mirena IUS is a levonorgestrel-releasing IUD which should be included in
the progestogen-only methods category rather than intrauterine devices, its
mode of action being different from that of copper IUDs, relating rather to the
progestogen content. Introduced into the UK in 1995, Mirena has rapidly become
a popular method of contraception, particularly with women requiring long-term
contraception or those considering sterilization.
Mirena intrauterine systemmode of action The Mirena IUS releases 20 g
levonorgestrel per 24 h into the endometrial cavity (Figure 4.11). It has several
different contraceptive mechanisms including: (1) profound suppression of the
endometrium with atrophy of endometrial glands and mucosal thinning; (2)
thickening of cervical mucus; and (3) inhibition of sperm motility and function.
The cumulative effect of these changes is to prevent fertilization from occurring,
with the additional safety feature of an inactive endometrium preventing
implantation should fertilization occur. Evidence from studies looking for
transient rises in human chorionic gonadotropin show that fertilization does not
occur, which indicates that there is prevention rather than interruption of
implantation. There is a variable effect on ovarian function with suppression of
ovulation being most common during the first year of use. However, with longterm use, more than two-thirds of cycles are ovulatory. The bleeding pattern that
CONTRACEPTION 85
Figure 4.11 Diffusion of levonorgestrel from the intrauterine system Mirena to the
endometrium. Reproduced with permission from Schering Oy, Finland
occurs with IUS use does not relate to ovarian function but rather to the
endometrial effects of the system. There is probably an additional foreign-body
effect of the device itself, which may play a minor part in exerting a contraceptive
effect.
Key history, indications and contraindications Many of the contraindications
to IUD (see page 56) apply equally to the IUS but there are important
differences. For example, a history of menorrhagia, with or without
dysmenorrhea, would be a contraindication to all copper-bearing coils while it
would act as a specific indication for the levonorgestrel-releasing IUS. Similarly,
an intolerance of all hormonal methods would be a contraindication to the IUS
while being, in general, an indication for a coil.
The history should be taken as though the woman was requesting hormonal
contraception (bearing in mind also any specific contraindications relating to the
use of intrauterine devices: see page 56). The IUS will be particularly suitable
for the following:
(1) Current IUD users with heavy periods.
(2) Other patients with heavy periods (if otherwise suitable for an IUD).
(3) Patients wanting long-term contraception who:
(a) Cannot remember to take pills regularly;
(b) Cannot take estrogens;
(c) Find weight gain on Depo-Provera unacceptable;
(d) Do not want an implant;
(e) Have a complete family, but find sterilization too final.
(4) Patients who will accept:
(a) The possibility of irregular bleeding in the first 3 months, and rarely
longer;
(b) Amenorrhea, should it occur.

A history of ectopic pregnancy is not a contraindication to the IUS. The rates of
ectopic pregnancy occurring with the IUS in situ are extremely low, with studies
recording a rate of 0.10.02 per 100 woman-years in IUS users, compared to 0.2
0.6 per 100 woman-years in users of copper-releasing IUDs. The rate of ectopic
pregnancy in women using no contraception is about one in 100 to one in 200,
i.e., at least ten-fold higher than in IUS users. In a major study carried out by the
Population Council, there were no ectopic pregnancies with the Mirena IUS
during 3416 contraceptive years of exposure. The possibility of ectopic
pregnancy should not be ignored, however.
Key prescribing information The IUS is associated with approximately a 40%
reduction in menstrual loss, making this method particularly suitable for women
suffering from menorrhagia. Initially, there is often frequent and prolonged light
spotting, interspersed with light regular menstrual periods. After three to six
months, as endometrial atrophy develops, the bleeding pattern usually settles to
light, regular bleeds with no intermenstrual spotting; in at least 20% of women,
amenorrhea develops by the twelfth month of use. The bleeding pattern that is
seen is related to the endometrial suppression, with concomitant lack of estrogen
responsiveness, rather than to changes in ovarian function. Estrogens and
progestogens are used in various guises to manage the bleeding should it become
troublesome for the patient; however, none has been shown to have a predictably
beneficial effect. In the longer term, in association with the marked reduction in
menstrual loss, there is a rise in hemoglobin and ferritin levels. As with all
progestogen-only methods, functional ovarian cysts may occur which are usually
self-limiting. If identified coincidentally on pelvic ultrasound scan they are
generally managed conservatively, intervention being restricted to those which
undergo complications such as torsion, hemorrhage or rupture. Other
progestational side-effects such as transient breast tenderness, hirsutism, acne
and mood changes may occur; they are commonest during the first three months
after insertion and rarely lead to discontinuation of the method. No differences in
weight gain have been seen in comparative studies of IUS and copper IUD users.
There is a suggestion that pelvic infection rates may be reduced in IUS users,
although this has not been confirmed in all studies. Some perimenopausal
women with meno-/metrorrhagia choose the IUS with the dual aim of
contraception and improved vaginal bleeding pattern. In such cases the meno-/
metrorrhagia should be investigated first, so no malignancy is missed.
Efficacy and drug interactions The IUS is a highly effective contraceptive,
which does not require user compliance and which, once fitted, requires little
medical intervention. In a variety of studies, both comparative and noncomparative, a Pearl index of less than 0.3 has been reported, indicating that the
IUS is at least as effective as female sterilization. Little is known about the effect
of hepatic enzyme inducers on the efficacy of the IUS, but because its action is
mainly local, some authorities believe that efficacy will be maintained and that,
CONTRACEPTION 87
after appropriate counseling, the Mirena IUS can be used in women taking
concurrent enzyme inducers.
Practical prescribing matters The Mirena IUS should ideally be inserted on
day 1 of the menstrual cycle and then there is no need for extra contraceptive
measures. It can be inserted up to day 7, but extra contraceptive precautions should
then be used for seven days after insertion. If there has been no sexual
intercourse in the cycle and pregnancy can definitely be excluded then the
Mirena can be inserted at any time during the cycle, with additional precautions
until the next period, the expected time of the next period or for three weeks if
these are not definable. It is not, however, suitable for use as a post-coital
contraceptive. Patients requiring emergency contraception who also wish to use
the Mirena as a long-term method should be offered standard oral emergency
contraception or fitted with a copper IUD, with the Mirena IUS being substituted
at the time of the next menstrual period. Postpartum insertion of the IUS is
recommended at 6 weeks and there is no evidence of any deleterious effect on
the breastfed infant. Following first-trimester abortion, the IUS can be inserted
immediately.
The method of fitting a Mirena IUS is by means of a special inserter which is
claimed to be easier to use. The inserter is different from those used for IUDs
and one must follow the manufacturers instructions. As the inserter tube is
wider than for the above IUDsapproximately 4.8 mm in diameterthe cervical
canal may require gentle dilatation, which can be done without anesthesia, using
standard Hegar dilators up to size 5. If anesthesia is required this is best provided
with intracervical infiltration of local anesthetic. Some use intracervical
xylocaine gel.
Follow-up is advised at four to six weeks after insertion, six months and then
yearly until it is time to replace the device, which under the present license is at 5
years. It can be replaced immediately with a new IUS if desired. At each followup visit, enquiry should be made about the menstrual pattern, any untoward sideeffects, and the patients weight should be recorded. Patients who have become
amenorrheic should have pregnancy excluded and be reassured. Return of
fertility after removal of the IUS is rapid, with the majority of women reestablishing normal menstrual cycles within one month after removal, and
conception rates during the following year are comparable with those seen after
cessation of other contraceptive methods. There have been no reports of birth
defects caused by Mirena use in cases where pregnancy continues to term with
the device in place.
New developments in hormonal contraception
A monthly vaginal contraceptive ring releasing EE and etonogestrel is in an
advanced stage of development. It is likely that in the future progestogen-only
methods of contraception based on the newer progestogens will appear. Monthly
and six-monthly injectable contraceptives are currently being developed and some
(Cyclofem, Chinese, Perlutal) are already available in some countries.
STERILIZATION
Sterilization is still the most widely used method of contraception in couples
over 40 years old in the UK. As long-acting and reversible methods such as the
Mirena, Implanon and the newer copper IUDs are increasingly recognized as
being not only highly effective but also acceptable, they are likely to challenge
female sterilization as the method of choice for women who have completed
their family. Another important point to note is that in many areas of the UK
reversal of sterilization is not available on the National Health Service.
Any person undergoing sterilization must be willing to accept that it is
permanent. The family planning provider has the responsibility to ensure that the
person considering sterilization has real expectations from the procedure, with
regard to permanence, failure rates (in comparison with other methods) and
complications. This means that the doctor or nurse giving family planning advice
must have a good understanding of all currently available long-acting methods of
contraception.
Male sterilization
Vasectomy is the most effective established method of contraception currently
available, with a failure rate ranging from 1:2000 to 1:10 000 after two
azoospermic samples. It is suitable for men who have completed their family and,
rarely, for those who have decided not to have children. It is usually carried out
under local anesthesia and has very few contraindications. Briefly, the procedure
can be described in the following way: After anesthetizing the skin, the vas
deferens is identified and immobilized through the scrotum. After that, the
scrotum is opened. In conventional vasectomy the surgeon uses a scalpel to make
two incisions in the scrotal skin, one over each vas deferens. The incisions are 1
2 cm long. The vas is brought out into the open. About a 1 cm portion of the vas
is removed and both ends are ligated. The entry incisions are then closed with
sutures. In a no-scalpel vasectomy, the scrotum is entered bluntly with a
special sharp hemostat rather than a scalpel. This creates a small puncture wound
that does not need suturing. Fewer complications and less pain are reported with
the no-scalpel vasectomy. There has been much discussion and research into a
possible link between vasectomy and prostatic cancer but such a link has now
been disproved, reinforcing the safety of this important method of contraception.
Reversal should be discussed before the surgery, in regard to both its availability
and success rates. Reversal of sterilization defined as the presence of sperm in
the ejaculate is successful in 7092% of cases depending on the technique, the
surgeons experience, the time that has elapsed since the vasectomy and the type
of vasectomy procedure. Reversal of sterilization defined as pregnancy rate is
CONTRACEPTION 89
much lower, with rates between 2580% being reported. There is also intersurgeon variation in success rates.
Vasectomy is not immediately effective, because of the length of sperm
survival. The vas distal to the vasectomy contains viable spermatozoa for weeks
after the operation. Patients must be aware of this and receive advice about
effective interim contraception. About 20 ejaculations are needed to clear the
remaining sperm. Clearance is delayed by abstinence from ejaculation. It is usual
to carry
Table 4.18 Complications of vasectomy
(1)
Wound complications
(a)
pain (significant in 8%)
(b)
bleeding/hematoma (4%)
(c)
infection (2%)
(2)
Failure, early/late*
(3)
Post-vasectomy pain syndrome (38%)
(4)
Possible psychologic effects/regret
*Early failure is defined as pregnancy occuring within six months after the operation or
before azoospermia is docmented. Late failure is defined as pregnancy
occuring after this period
out semen analyses at 12 and 16 weeks post vasectomy. After two consecutive
negative semen analyses one month apart the vasectomy can be regarded as
being successful. If the samples fail to clear, then early reanastomosis or an
additional unidentified vas is present and re-operation may be required.
Men who seek a vasectomy should be advised that:
(1) Vasectomy is not castration and does not affect sexual ability or cause
impotence.
(2) After vasectomy, the man continues to ejaculate because sperm contribute
by only 10% to the volume of the ejaculate.
(3) Vasectomy does not cause prostatic cancer or early atherosclerosis.
The complications of a vasectomy procedure are listed in Table 4.18. Sperm
granuloma is a small nodule that forms when sperm leak out of the vas deferens
or the epididymis, inducing an inflammatory reaction. Post-vasectomy pain
syndrome is defined as chronic pain in the testis following a vasectomy.
Conservative treatment with non-steroidal anti-inflammatory medication, sitz
baths or spermatic cord block may help.
Female sterilization
The convenience and efficacy of this method have made it the most commonly
used single
Table 4.19 Complications of female sterilization
Complication
Approximate frequency
Regret
Mortality
Damage to bowel or vascular tree
Thromboembolism
Wound infection
Ectopic pregnancy rate
6%
12 per 100 000
1 in 1000
Rare
12%
10% of failures
method in women over 40 who have a completed family. Recent data from the
USA indicate that the failure rate of female sterilization is higher than previously
thought: at around one in 200 over 10 years. Failure rates are highest in women
sterilized under the age of 35 or at the time of Cesarean section, in the
puerperium or at the time of termination of pregnancy. There may also be more
regret in those having sterilization in association with a recent pregnancy. The
risks of sterilization are small but quantifiable (see Table 4.19). Sterilization is
particularly suitable for women who:
(1)
(2)
(3)
(4)
Have completed their family;

Find no other long-term method acceptable;
Have no gynecologic condition that requires hysterectomy;
Have no conditions that make the procedure dangerous (for example,
obesity).
Sterilization is usually carried out under general anesthesia. It is effected by

applying clips or rings to the isthmus of the fallopian tubes. Diathermy is rarely
used now because of the risk of damaging intra-abdominal organs. Partial
salpingectomy (modified Pomeroy technique) requires a mini-laparotomy and is
particularly useful in countries where laparoscopy is not available, and it can also
be done as a day case. An important risk is that of ectopic pregnancy should
failure occur, and a woman who has previously been sterilized and who is
pregnant should have a scan at four to five weeks gestation to locate the
pregnancy.
There is usually a delay between the decision to be sterilized and the actual
operation; an effective interim contraceptive is required because some women
become pregnant while waiting for the procedure to be done. In addition, a
sterilization carried out in the luteal phase of the cycle carries a theoretical risk
CONTRACEPTION 91
of an ectopic pregnancy if a fertilized ovum is still within the tube distal to the
clip.
After laparoscopic sterilization, women can expect some abdominal
discomfort and shoulder pain for up to a week. Women who have been using a
method that makes menstruation lighter (such as the COC pill) or absent (such as
depo-medroxyprogesterone acetate) and are opting for sterilization should be
advised that their periods may appear to get heavier when that method is
discontinuedand in some cases this could be unacceptable.
As with the reversal of vasectomy, the success of the reversal of female
sterilization varies depending on the amount of tube damaged by the initial
procedure and the surgical technique used for the original operation.
EMERGENCY CONTRACEPTION
Emergency contraception is a useful means of preventing unplanned pregnancy
after unprotected sexual contact or potential contraceptive failure (see
Table 4.20). Although pregnancy is unlikely before day 7 of the cycle or after
day 17 of the cycle in a woman with a 28-day cycle, any request for emergency
contraception should be assessed for risk based on Table 4.20 andif indicated
emergency contraception offered.
Whilst having been demonstrated to be effective if commenced any time up to
72 h after sex, the efficacy of the hormonal methods (Levonelle-2 and Schering
PC4) declines with time after intercourse. Because of this, a request for
emergency contraception shouldwherever possiblebe dealt with at the time
of the request. On-call services and accident and emergency departments are
therefore important points for accessing emergency contraception. Furthermore,
Lev
Table 4.20 Indications for emergency contraception
Unprotected sex (consensual or non-consensual)
(1)
Intercourse where contraceptive method was not used or used incorrectly
(2)
Coitus interruptus
(3)
After rape or sexual assault
(4)
Ejaculation on to external genitalia
Potential contraceptive failure
(1)
COCs
(a)
two or more pills missed from first seven of the pack
(b)
four or more pills missed mid-pack
(c)
potential drug interaction
(2)
POPs
(a)
one or more pills missed (taken more than 3 h late)
(b)
potential drug interaction
(3)
IUDs
(a)
expulsion (partial or complete)
(b)
mid-cycle removal after intercourse in previous seven days
(4)
Barriers
(a)
condom split, slippage or incorrect use
(b)
diaphragm split, displacement or incorrect use
COC, combined oral contraceptive, POP, progestogen-only pill; IUD, intrauterine device
onelle-2 can be bought over the counter for emergency use. Good access to
emergency IUDs is important, and all services offering hormonal methods should
have access, by referral if necessary, to this method.
Efficacy of emergency contraception
The efficacy of emergency contraception can be expressed either as the chance
of pregnancy after using the method, or as the ratio of observed to expected
pregnancies. The latter is used in this text.
Methods of emergency contraception
There are three main methods of emergency contraception: two hormonal and one
intrauterine.
Progestogen-only hormonal emergency contraceptives
Licensed in 1999, Levonelle-2 is the most recent advance in the provision of
emergency contraception in the UK. It consists of two doses, each of one tablet
containing 750 g of levonorgestrel. The first dose is commenced within 72 h of
intercourse and the second 12 h later. A recent randomized controlled trial
involving over 4000 women showed that 1.5 mg of levonorgestrel taken as a
single dose may be as effective as the usual regimen.
Efficacy Current evidence indicates that this is the more effective of the
hormonal methods, with 86% of expected pregnancies prevented when started
within 72 h of intercourse. As with the Schering PC4, the efficacy is higher the
earlier it is started (see Table 4.21). Hepatic enzyme-inducing agents may reduce
efficacy and an IUD should be considered. Efficacy may also be reduced if the
patient vomits within 2 h of taking either dose.
It is improtant to remember that progestogen-only emergency contraceptives
have some efficacy even beyond 72 h and up to 120 h. One estimate is 5060%.
It is a better than nothing method for those women who present after 72 h, but
are unable or unwilling to have an IUD fitted.
CONTRACEPTION 93
Prescribing Levonelle-2 The manufacturers advise that pregnancy, severe

cardiovascular disease (arterial or venous), acute focal migraine and severe liver
disease are contraindicated to the use of Levonelle-2.
Follow-up of patients It is usual to advise patients after use of emergency
contraception to return in three weeks to exclude pregnancy. In practice,
however, most patients do not return. It is therefore probably more important to
ensure they are aware of what symptoms should lead them to seek medical
advice should pregnancy occur. These include
Table 4.21 The effect of the coitus-to-treatment interval on efficacy (World Health
Organization, 1998)
Interval (h) Levonelle-2 (progestogen- only
EC)
24
95
2548
85
4972
58
EC, emergency contraception
Schering PC4 (combined

hormonal EC)
77
36
31
amenorrhea, an abnormal period, morning sickness, breast tenderness, urinary

frequency, etc. After emergency contraception, the majority of women will have
a normal period on time, but about 40% will have their period either prematurely
or delayed.
Combined hormonal emergency contraceptives
Schering PC4 was licensed in 1994; its use has steadily risen since. However,
after the introduction of progestogen-only emergency contraceptives its use has
declined precipitously. Each tablet contains EE 50 g and norgestrel 500 g. The
first dose of two tablets is commenced within 72 h of intercourse and the second
two tablets are taken 12 h later.
Efficacy Current evidence indicates that this prevents between 57% and 74% of
expected pregnancies when started within 72 h of intercourse. As with
Levonelle-2, the shorter the coitus-to-treatment interval, the higher the efficacy
(see Table 4.21). Hepatic enzyme-inducing agents may reduce efficacy and an
IUD should be considered. In this situation, some advise an increase in the dose
to two doses of three tablets each but the safety and efficacy of this have not
been studied. Efficacy may also be reduced if the patient vomits within 2 h of
taking either dose.
Hormonal emergency contraception will not provide ongoing contraception,
and barrier methods should be advised for the rest of the cycle in which it is used.
Future contraception should be discussed with the patient. Hormonal methods
can be started with the next period.
Prescribing Schering PC4 The restrictions on use that apply to COCs do not
apply to Schering PC4. In fact, the World Health Organization considers that
apart from pregnancy there are no contraindications to its use. In the UK, it is
generally accepted that severe cardiovascular disease (arterial or venous), acute
focal migraine and severe liver disease are contraindications to its use.
Follow-up of patients See Progestogen-only hormonal emergency
contraceptives, page 72.
Intrauterine emergency contraception
When the earliest episode of unprotected intercourse was less than five days (120
h) previously, a copper-containing IUD can be inserted as an emergency
contraceptive. When the earliest episode of unprotected intercourse occurred
more than five days previously, a copper-containing IUD can be inserted up to
five days after the earliest calculated day of ovulation, which is day 19 of a
regular 28-day cycle. Unless ongoing contraception is required, the device is
usually removed with the next period or when an alternative method of
contraception has been established.
Efficacy This is the most effective method of emergency contraception:
therefore, unless there is a contraindication it should be the womans decision to
use it, not that of the doctor or nurse. The failure rate has been estimated to be 0.
1%.
Fitting emergency IUDs Assessment for an emergency IUD is very similar to
assessing someone for an IUD for long-term contraception, with the exception
that long-term effects such as menorrhagia are not relevant if it is to be removed
with the next menstruation. Women requesting emergency contraception by
definition have had unprotected inter-course and may be at risk of an STI.
Consideration should therefore be given to screening and prophylactic
prescription of appropriate antibiotics. IUDs should be fitted by doctors or nurses
with appropriate training.
CONTRACEPTION IN YOUNG PEOPLE
We prescribe contraception to girls under 16 years old provided we are satisfied
that the below conditions are fulfilled. These conditions are based on the test
case of Gillick versus Wisbech and West Norfolk AHA (1985). The assessment
of the young persons maturity was called the Gillick competence. The current
terminology is Fraser ruling competence or Fraser rules, named after Lord
Fraser who was one of the Law Lords who ruled in the test case.
(1) The young person understands the advice given and is sufficiently mature to
appreciate what is involved in terms of the moral, social and emotional
implications.
CONTRACEPTION 95
(2) We could not persuade the young person to inform her parents, nor to allow
us to inform them that contraception advice is being sought.
(3) The young person would be very likely to become or to continue to be sexually
active with or without contraception.
(4) Without contraception her physical and/ or mental health is likely to suffer.
(5) It is in the best interest of the young person to give contraceptive advice and/
or treatment without parental consent.
Hormonal methods can be prescribed once regular menstrual cycles have been
established. In our experience most young women prefer either COCs, DepoProvera or POPs. The new implant, Implanon, is also gaining in popularity
amongst younger women, who require, above all, contraception that is at the same
time highly effective and forgettable. We advise all young women to use
condoms for prevention of STIs. Nulliparity itself is not a contraindication for
use of IUD but the risks to future fertility associated with pre-existing or
subsequently acquired sexually transmitted disease make the IUD a less than
ideal choice for most young, nulliparous women.
5
Infertility
Nikolai Manassiev, Naim Abusheikha and John Collins
INTRODUCTION
Infertility is an important area of clinical practice. It is a common condition,
affecting between 5 and 10% of married couples worldwide. A diagnosis of
infertility is frequently obscure and few molecular causes are known. Specific
treatment is not always effective and many couples resort to empiric treatment
such as in vitro fertilization (IVF).
Knowledge of infertility is rapidly developing and changing. There are a
growing number of textbooks devoted to infertility and the two leading journals
in infertility, Fertility and Sterility and Human Reproduction, have a yearly
output of over 2400 pages each. There are numerous other infertility and review
journals, guidelines from professional bodies and fertility societies, and articles
appearing in obstetrics and gynecology and general medical journals, not to
mention the daily press, both tabloid and broadsheet. Even for the specialist it is
impossible to follow them all, while for those who only seek a basic
understanding of infertility it is unnecessary. Gaining a good working knowledge
of infertility requires (1) an understanding of normal reproductive anatomy,
physiology and pathology; (2) a good grasp of the terminology specific to
infertility; and (3) exposure to patients with infertility problems under expert
supervision and guidance. This chapter is designed to help the reader achieve the
first two tasks.
BASIC CONCEPTS OF MALE REPRODUCTIVE
ANATOMY AND PHYSIOLOGY
Brief anatomic and physiologic notes regarding the female reproductive tract
have already appeared in Chapter 1. In this section a basic description of the
male reproductive physiology is given.
The male reproductive system is composed of testes, genital ducts, accessory
glands and penis (Figure 5.1a). The testis is about 45 cm long, 23 cm wide and
over 15 ml in volume. Each testis has about 250 lobules, and each lobule is
occupied by 14 seminiferous tubules. The tubules are twisted structures about
INFERTILITY 97
Figure 5.1 The male reproductive system, (a) Schematic representation of the male
reproductive system; (b) magnification of a seminiferous tubule and interstitial tissue; (c)
diagram of a spermatozoon
150250 m in diameter and 3070 cm long, which end blindly. The epithelium
of the tubules is where spermatogenesis occurs, and it consists of Sertoli
(supportive) cells and germ cells (Figure 5.1b). The adult testis has two chief
functions: production of androgens (hormonal) and production of spermatozoa
(spermatogenesis).
Spermatogenesis is divided into two phases. The first phase consists of meiotic
divisions of the germ cells and results in the formation of round spermatids. The
second phase, termed spermiogenesis, is then devoted to a number of cytological
changes leading to the transformation of the round spermatid into structurally
and functionally fully developed spermatozoa (Figure 5.1c).
Spermatozoa are highly specialized cells that do not grow further or divide.
The spermatozoon (Figure 5.2a) consists of a head and a tail. In the head there is
a large nucleus containing the paternal DNA but very little cytoplasm. The head
is a flattened ovoid 4.55.5 mm long and 2.53.5 m wide. It has an acrosomal
region, which is like a cap and covers 4070% of it (Figure 5.2b). The acrosome
contains hydrolytic enzymes like hyaluronidase and proacrosin which are
necessary for fertilization.
The tail consists of three parts: middle piece, principal piece and end piece.
The middle piece consists of several layers of mitochondria wrapped around the
central axial core in a spiral fashion (Figure 5.2c). Its role is to provide the sperm
Figure 5.2 Ultrastructure of a spermatozoon. (a) Spermatozoon; (b) cross-section of the

head and neck region; (c) cross-section of the middle piece; and (d) cross-section of the
principal piece. Reproduced with permission from Johnson MH, Everitt BJ. Essential
with the energy that is necessary for motility. The principal piece is the longest
part of the tail. It consists of nine fibrils surrounding the inner fibrils of the axial
core. The whole principal piece is enclosed by a fibrous tail sheath consisting of
branching and anastomosing semicircular strands or ribs (Figure 5.2d). The
principal and end piece are the motile entities of the sperm. Some 40200 million
INFERTILITY 99
sperm are produced each day. Spermatogenesis takes 74 days on average, and the
passage of sperm through the epididymis requires a further 312 days (810
weeks altogether). The production of sperm is continuous but can be disrupted by
various insults, such as acute febrile illness, irradiation or medications. The role
of Sertoli cells is to provide nutrients to the germ cells, to phagocytose injured/
defective germ cells and debris, and to secrete androgen-binding protein,
estrogen, inhibin andin early fetal life -Mullerian-inhibiting factors. The
spermatogenic compartment is under the influence of follicle-stimulating
hormone (FSH) and elevated FSH levels indicate failure of this function.
The spaces between the seminiferous tubules are filled with interstitial tissue
(accumulation of connective tissue, nerves, blood vessels and lymphatics). At the
time of puberty, an additional cell type appears: interstitial (Leydig) cells. Leydig
cells are under the influence of luteinizing hormone (LH), which stimulates them
to produce testosterone. The daily testicular production rate of testosterone is 3
10 mg.
Androgens are essential for the differentiation, growth and function of the
male genital ducts (epididymis) and accessory glands (seminal vesicles and
prostate), male secondary sexual characteristics and sexual potency. Testosterone
circulates in plasma either bound to albumin (60%) or sex hormone-binding
globulin (SHBG) (38%), or unbound (2%). Estrogen, hyperthyroidism and
cirrhosis raise SHBG levels and lower the available free testosterone. The
opposite process occurs under the influence of excess exogenous androgens,
excess growth hormone or hypothyroidism.
The semen consists of seminal fluid, which is composed of secretions from the
major accessory sex glands (prostate, seminal vesicles and Coopers glands), and
sperm. The sperm are suspended in the fluid and contribute less than 10% to the
total volume of the semen. Seminal fluid is not essential for fertilization as
spermatozoa taken directly from the vas deferens can fertilize oocytes. However,
in vivo, the seminal fluid fulfills an important role in providing the optimal
environment for the spermatozoa. It provides a transport medium, nutritional
factors (fructose, sorbitol), protective factors (buffering capacity against the acid
pH of vaginal fluids) and reducing agents (ascorbic acid, hypotaurine) to protect
against oxidation.
FERTILIZATION AND CONCEPTION
During coitus, the semen is deposited in the upper vagina, notably the posterior
vaginal fornix. The semen rapidly coagulates due to the interaction between the
prostatic enzyme and the fibrinogen-like substrate derived from the seminal
vesicles. The coagulum acts as a buffer against the acidic vaginal pH and as a
spermatozoal pool. Coagulation is followed by liquefaction within 1030 min.
Spermatozoa enter the cervix and the uterus within minutes of ejaculation. It is
not clear how the spermatozoa travel within the uterus and tubes, but neither
prostaglandins nor uterine contractions are required. It is likely that the
Figure 5.3 The fertilization pathway. Reproduced with permission from Wassarman PM.
Fertilization in mammals. Sci Am 1988;259:7884
spermatozoa move by their own propulsion and by the fluid current generated by
the action of the cell cilia. The earliest that living spermatozoa can be recovered
from the fallopian tubes is 27 h after coitus, although some dead ones may
appear much sooner. At any given time, there are only several hundred
spermatozoa present in the oviducts. The survival time of the gametes in the
female genital tract is 2848 h for the sperm, and 624 h for the oocyte.
Immediately after ejaculation, the sperm is incapable of fertilization. The
ability of the sperm to attain fertilizing capacity is called capacitation. This
process takes several hours, involves stripping of glycoproteins from the sperm
surface and starts once the sperm are inside the female genital tract. Capacitation
has two consequences: the sperm (1) becomes hyperactive; and (2) undergoes a
change in the composition of the surface membrane, paving the way for the
acrosome reaction. The acrosome reaction is a process during which the surface
membrane and the outer acrosomal membrane disintegrate, the content of the
acrosomal vesicle leaks away and the inner acrosomal membrane becomes the
only envelope of the sperm head. The acrosome reaction is triggered by a
glycoprotein constituent of the zona pellucida (ZP) called ZP3, to which
capacitated sperm have the ability to bind. The exposure of the inner acrosomal
INFERTILITY 101
Figure 5.4 Schematic representation of fertilization and implantation. Reproduced from

Guillebaud J. Contraception Your Questions Answered, 2nd edn. London: Churchill
Livingstone, 1993:370, Copyright (1993), with permission from Elsevier
membrane leads to exposure of new binding sites specific for another ZP

glycoprotein, called ZP2. These binding sites hold the ZP and the sperm in
contact and allow the proteolytic enzymes on the sperm head to digest a path
through the ZP. The sperm passes along this path aided by forward hyperactive
propulsion. ZP penetration takes about 520 min. The sperm eventually reaches
the perivitelline space between the ZP and the oocyte membrane, where the oocyte
microvilli envelop the sperm head. The fusion between the surface membrane of
the oocyte and the sperm head follows, after which the sperm stops moving and
its nucleus and part of the midpiece passes into the ooplasm. The first phase of
fertilization, from entry into the cumulus mass to fusion, is completed
(Figure 5.3).
After fusion, there is a dramatic increase in the level of free intracellular
calcium, which triggers two processes lasting about 3045 min: (1) changes in the
oocyte membrane, thus preventing further sperm penetration (zona reaction); and
(2) the oocyte, which has been arrested in the metaphase of the second meiotic
division (metaphase II), is awakened. The division is completed, resulting in one
haploid chromosomal set and the despatch of the second polar body. The
chromosomes (22+X) line up in a vesicular nucleus known as the female

pronucleus. Meanwhile, the spermatozoon moves forward until it is in close
proximity to the female pronucleus. Its nucleus becomes swollen and forms the
male pro-nucleus. The tail becomes detached and degenerates. With the
successful attainment of one maternal and one paternal haploid chromosomal set,
a diploid zygote is formed and initiation of the embryo development program is
started. The second fertilization phase, between fusion and the formation of the
diploid zygote, lasts about 20 h. On average, 1824 h after fusion, the first
mitotic division occurs: the one-cell zygote becomes a two-cell conceptus. The
conceptus starts to divide rapidly and first forms a morula (mulberry, 816-cell
stage), then a blastocyst (1632-cell stage) (Figure 5.4). At blastocyst stage, the
differentiation of cells destined to become a human and those destined to become
placenta and membranes occurs. The conceptus becomes an embryo only after this
differentiation is complete (1418 days).
The blastocyst enters the uterine cavity and derives its nutrition from the
uterine secretions while preparing for implantation. The implantation process
goes through the phases of attachment and invasion. During the attachment phase
(days 45), the ZP is lostthis process is known as hatching. Early phase of
implantation starts around day 6 and by day 9, the blastocyst is buried in the
endometrium, which heals over it. The process of implantation is very complex
and involves the exchange of messages and mutual recognition between the
blastocyst and the endometrium. The implanting blastocyst starts secreting
human chorionic gonadotropin (hCG), which is released in the maternal
circulation and prevents luteolysis. The corpus luteum continues its endocrine
function and supports the pregnancy for a total of 45 weeks after conception,
after which the embryo is capable of synthesizing all steroid hormones required
for its development.
The earliest that we can recognize a developing pregnancy is about 1012
days post conception by means of sensitive hCG assays. So infertility (the
inability to achieve pregnancy) could arise from failure of the process just
described at its early stages (faulty or non-existent germ cells) to the inability to
complete the process of implantation successfully (day 9 of conception). Of
course, if in the future we are able to recognize pregnancy earlier, the
significance of infertility will change accordingly. It is very important to note that
the terminology of infertility is different from the language of embryology.
Infertility experts refer to embryo transfer (ET), when in fact it is a pre-embryo, a
morula or a blastocyst which is transferred. This distinction is paramount from an
ethical point of view, because many people consider manipulation of an embryo
wrong. However, because of the wide usage of the term embryo in infertility we
are adopting the latter in our current discussion.
INFERTILITY 103
THE EPIDEMIOLOGY OF INFERTILITY

For a pregnancy to occur the following steps are necessary: (1) a spermatozoon
fertilizes an oocyte; (2) a viable conceptus forms; (3) the conceptus travels along
the fallopian tubes; and (4) the conceptus finds a receptive endometrium where it
can bury itself and continue developing. Any break in this chain of events can
lead to infertility (Figure 5.5).
Infertility is treated medically as a problem affecting the couple. For
simplicity, the term infertile couple is used in this chapter for heterosexual pairs
engaging in procreational sexual intercourse. The normal human fecundability is
about 20%, indicating that 20 out of 100 couples will conceive in any given
month if engaged in unprotected sexual intercourse. In the general population it
can be expected that 60% of couples will become pregnant after 6 months of
regular unprotected intercourse, 8590% after a year and about 95% after two
years. Therefore a useful working definition of infertility would be inability to
conceive within two years of unprotected intercourse. This definition may need
to be modified to 1 year in couples where the woman is over 30 years of age. For
couples where the woman is over 35 years, infertility investigation is advised if
no conception has taken place after 6 months of trying to conceive. The
incidence of primary infertility varies between countries, and has been quoted
from a low 2% in Turkey and Thailand to 21% in Zaire and 32% in Gabon. In
most European countries, it is estimated to be between 3 and 7%, and about 6%
in the UK and the United States. The prevalence of infertility varies: using a 1year cut-off it is between 13 and 16%, while using a 2-year cut-off will result in
about 10%. Using a 1-year cut-off some quote that one in seven couples will
consult their doctors about infertility concerns and this is the figure most often
used in the media and by pressure groups. Strictly speaking this may be correct,
but it is misleading as it implies that one in seven couples have fertility
problems, which is untrue. It is not possible to give unified prevalence figures
about the causes of infertility. This is because the prevalence of various causes
depends on the population studied, i.e., whether the sample comes from the
general population or from primary, secondary or specialist infertility units.
Causes for infertility vary between countries and within countries. According to
some estimates from the primary care sector, infertility is caused by ovulatory
failure (26%), male infertility (20%), tubal damage (14%), endometriosis (5%),
other causes (5%) or unexplained factors (30%). The majority of couples are
subfertile, i.e., they have relative infertility and may conceive only after a longer
than normal interval. Many women become pregnant while awaiting fertility
assessment and/or treatment. One estimate puts the rate at 2.02% a month and a
cumulative rate of 19.9% a year. Follow-up of couples with unexplained
infertility shows that 64% of women with primary and 79% of women with
secondary infertility will conceive within 9 years without treatment. Sterility
(absolute infertility) affects about 12% of the population.
Figure 5.5 Overview of the fertilization pathway
CLINICAL EVALUATION AND DIAGNOSIS OF THE

INFERTILE COUPLE
During the initial interview, it is important to record the age of the female
partner, the duration of the infertility and to enquire if the infertility is primary or
secondary, as all these factors affect the prognosis. The fourth factor correlating
with prognosis is the cause of infertility. It may lie in the woman, in the man or
both, and best results are achieved if the partners are evaluated together. However,
single women and men may also request infertility evaluation and treatment.
Infertility tests are carried out to establish the cause and to guide treatment.
There are three basic infertility tests that should be done first for reasons of
simplicity, cost and good correlation with conception. These are (1) semen
analysis; (2) tests for tubal patency (preferably hysterosalpingography); and (3)
tests for ovulation (preferably midluteum serum progesterone levels). These tests,
together with any other tests deemed necessary after history and examination,
should be arranged first and further management should be guided by the results.
Male factor infertility
Assessment of male infertility is based on a patients history, physical
examination, semen analysis and other specialized investigations, such as blood
tests, testicular biopsy and
INFERTILITY 105
Table 5.1 Distribution of male infertility

Cause
Unexplained (no demonstrable cause)

Idiopathic*
Infection
Autoimmunity
Sexual (coital) factors
Congenital
Azoospermia
Endocrine
*Including idiopathic abnormal semen analysis and varicocele
4050
3540
67
34
12
12
1
1
imaging techniques. The distribution of male infertility is depicted in Table 5.1.

History and physical examination
Establishing a patients history should include specific questions covering
previous surgery in the genital area (hernia repair, scrotal trauma, torsion,
cryptorchidism or late testicular descent), infections (mumps, sexually
transmitted infections (STI) or urinary tract infection), metabolic diseases
(diabetes, chronic renal failure or liver disease), gonadal and extragonadal
neoplasia, alcohol, tobacco and recreational drugs, medications (anabolic
steroids, cimetidine, sulfasalazine, phenytoin, antineoplastic agents) and
occupational exposure to radiation, heat and toxic chemicals. It is also important
to enquire about coital frequency and the duration of the currently encountered
infertility as well as about any previous fertile periods.
Physical examination should be performed to determine general health and the
extent of masculinization and general body habitus. Poor libido, impotence or
lack of sexual hair growth are all suggestive of an endocrine problem. A genital
examination should assess the development of epi-/hypospadias or these
abnormalities would be unknown to the Peyronies disease. It is unlikely that any
of patient, but they may interfere with the intercourse or ejaculation. Scrotal
content should be palpated to determine the size of the testes, which measure 45
cm in length. Occasionally, cryptorchidism, anorchidia or a retractile testis may
be encountered. The consistency, shape and sensitivity of the epididymis should
be noted, together with any nodularity, cysts or induration. The presence of the
vas deferens should be recorded. Pampiniform plexus should be palpated and
varicocele should be looked for. Any other abnormalities, such as hydrocele,
paratesticular cysts or hernias should be noted. Rectal examination of the
prostate and the seminal vesicles may be performed if there is a history of
prostatitis or STDs. We feel that the examination should be tailored individually.
For example, in a patient with a negative history, a normal semen analysis and
adequate masculinization it may not be necessary at all.
Semen analysis
The patient is adviced to abstain from sex for 23 days and asked to provide a
sample by masturbation in a clean, wide-mouthed container for a laboratory
examination within 2 h (normal values are given in Table 5.2). Longer
abstinence increases the sperm count but adversely affects the morphology and
motility. Patients should be made aware of this relationship and should be
encouraged to have regular intercourse, 23 times a week, rather than try and time
a single intercourse around the time of ovulation. If the first semen analysis is
normal, then fertility is presumed and the analysis only needs to be repeated if
necessary (e.g., due to changes in history, operations, etc). It should be noted that
Table 5.2 lists reference values, rather than normal values. This is because there
are many fertile men with sperm paramaters below the normal range. There is a
2025% variation in the sperm count in apparently normal individuals, so if the
result is abnormal, 23 samples should be examined within a period of 3 months.
Recently, there has been much debate whether there is a trend towards a lower
sperm count in the general population. Although environmental factors cannot be
excluded as causes of male infertility, such a trend does not appear to exist.
Intercurrent febrile illness decreases the
Table 5.2 Reference values of semen analysis. Adapted from the World Health
Organization, 1992
Standard tests
Volume
Liquefaction
Sperm concentration
Motility
Morphology
White blood cells
Immunobead test
Mixed agglutination reaction test
Optional test
Fructose (total)
Normal values
1.56 ml
1030 min
20106/ml
50% with forward progression > 2 (scale of 04)
30% with normal forms
< 1106/ml
< 20% spermatozoa with adherent particles
< 10% spermatozoa with adherent particles or sperm
agglutination < 2 (scale 03)
13 mol per ejaculate
quality and/or quantity of sperm, as is exposure to lead and

dibromochloropropane.
Azoospermia If azoospermia and/or a low ejaculate volume is encountered, it
should be confirmed by two semen analyses subjected to centrifugation. The
distinction that has to be made is between damaged spermatogenesis, obstruction
INFERTILITY 107
and retrograde ejaculation. In order to arrive at the correct diagnosis, LH, FSH,
testosterone and prolactin levels should be measured. The results of the
hormonal blood tests will enable differentiation between primary hypogonadism,
prolactinoma, testicular failure and germ cell failure (Table 5.3). In cases of lowvolume ejaculate, measuring the semen fructose levels and examining a postejaculatory urine sample for sperm will help to differentiate between retrograde
ejaculation and obstruction. Retrograde ejaculation is very rare but may be
suspected if there is a low-volume ejaculate or a history of diabetes, multiple
sclerosis, retroperitoneal lymph node dissection, bladder neck surgery or spinal
cord injury. Obstruction at the level of the seminal vesicles or absence of the
vesicles and vas deferens will lead to low fructose levels. Vasectomy and failed
vasectomy reversal are the commonest causes of obstruction. Bilateral
congenital absence of the vas is the
Table 5.3 Clinical interpretation of hormonal tests in male infertility
FSH
Testosterone Prolactin Interpretation
Low
Low
Low
Low
Low
High
High
Low
Normal
High
Normal
Normal Normal
Normal
Normal
Hypogonadotropic hypogonadism, pituitary failure/

tumor
Prolactinoma (via mechanical pituitary
compression), medications
Testicular failure; if FSH > 3normal, consider
testicular biopsy
Germ cell failure (Sertoli-only syndrome)
Idiopathic/obstruction/retrograde ejaculation/
cryptorchidism/mumps/ congenital absence of vas
deferens
FSH, follicle-stimulating hormone
second commonest reason. Young syndrome obstruction in the heads of the

epididymides associated with bronchiectasiasis rare.
Germ cell failure can result from numerous causes such as cytotoxic drugs,
cryptorchidism, irradiation or be idiopathic in origin (germ-cell aplasia or Sertolionly syndrome). It is now clear that 13% of these idiopathic cases are in fact due
to a Y chromosome deletion resulting in the loss of the azoospermic factor
(AZFc). A testicular biopsy will facilitate the diagnosis. Germ cell aplasia is
found in 1020% of testicular biopsies performed for assessment of infertility. In
such cases, the seminiferous tubules are lined with Sertoli cells and there are no
germ cells. Leidig cells appear normal. In some men, areas of normal
spermatogenesis may exist next to areas of germ cell aplasia. If the hormonal
tests are normal and semen fructose is present, then the most likely diagnosis is
an obstruction at any point between the epididymis and the point where the vas
deferens joins with the seminal vesicles. Of course, it has to be bilateral such as
bilateral congenital absence of the vas deferens or vasectomy. Obstruction can be
confirmed by vasography, which is often performed at the time of testicular

biopsy.
Oligozoospermia and other sperm defects Isolated sperm abnormalities are
uncommon, and most subfertile men have a combination of defects with a
decreased sperm density, decreased motility and an increase of abnormal sperm
forms (oligoasthenoteratozoospermia, OATS). Men with significant
oligozoospermia (< 5 106/ml) should have a hormonal evaluation and further
work-up in the same way as patients with non-obstructive azoospermia, and may
also require testicular biopsy. In patients with normal gonadotropins, varicocele
should be ruled out if not already done. Most patients with sperm defects fall into
the idiopathic category. Sperm antibody testing is indicated in cases of severe
asthenospermia, but, unfortunately, there is no effective and safe medical
treatment for this condition.
Sperm leukocytes Many men thought to have leukocytes in the sperm in fact
have immature sperm forms. Even in those that have true pyospermia the
significance is unknown. Leukocytes and bacteria in vitro impair sperm motility
and sperm-egg interaction, but their importance in vivo is uncertain.
Genitourinary tract infection should be excluded by urine and prostatic fluid
cultures only in symptomatic men. Routine testing for Mycoplasma or
Ureaplasma urealyticum is not indicated, nor is empirical use of antibiotics.
Overall, with the exception of viral orchitis or bacterial epididymitis/
epididymoorchitis, infection is an uncommon cause of infertility in the developed
countries.
Endocrine evaluation
Hormonal studies are indicated for the evaluation of azoospermia or severe
oligospermia
Table 5.4 Indications for endocrine evaluation in men
Azoospermia
Significant oligospermia < 5106/ml
Oligospermia associated with:
low semen volume
testicular atrophy
gynecomastia
demasculinization/hypoandrogenism
decreased libido and/or impotence
history of cryptorchidism or hypospadias
or if there is history suggestive of endocrine disorder (Table 5.4). The

interpretation of the tests has already been discussed (Table 5.3 and above).
INFERTILITY 109
Other tests
It has been suggested that an ultrasound scan of the scrotum should be performed
routinely in patients with infertility because they seem to have a higher rate of
scrotal abnormalities, including testicular tumors. Perhaps this investigation
should be reserved for patients with grossly abnormal semen analysis or
abnormal physical examination of the scrotum. Men with undescended testes or
gonadal dysgenesis are at an increased risk for testicular malignancy.
Appropriate investigations should be undertaken for any man with painful testes
or abnormal semen cytology. Chromosomal analysis is indicated if Klinefelters
syndrome is suspected, and tests for the cystic fibrosis gene are indicated if there
is congenital bilateral absence of the vas deferens. A testicular biopsy is
indicated for the assessment of severe sperm abnormalities or atypical cells in the
ejaculate. Unless the physician is very confident in recognizing and treating
disorders of the male urogenital system, it is best to refer the patient to an
urologist with interest in andrology.
Computer-assisted semen analysis (CASA), postcoital test (cervical mucoussperm interaction test), zona-free hamster egg penetration test, zona-binding test
and reactive oxygen species assessment test have been suggested for further
investigation of infertility. CASA is no better than ordinary semen analysis. The
postcoital test has not been standardized and bears no correlation with pregnancy
rates. The other tests mentioned above are time-consuming and expensive, have
not been standardized and are mainly used for research purposes.
Treatment
Varicocele This condition is present in 2540% of men attending infertility
clinics compared with about 1015% of men in the general population. It has
been noted that the testis on the side of the varicocele has a smaller volume,
which in turn is associated with a lower sperm count. Ligation of the varicocele
has been shown to increase the sperm count and, if performed in young
individuals, even to normalize the testicular volume. There is disagreement
regarding the usefulness of varicocele repair in the treatment of infertility, but it
seems reasonable that such treatment should be offered to men presenting with
idiopathic low-sperm count and varicocele. Varicocele treatment shows better
results the earlier it is performed, the younger the patient and the more severe the
defect.
Obstruction and ejaculation disorders These cases are rare (apart from
vasectomy) and are the area of expertise of urologists. Restoring the patency of
the vas deferens after vasectomy is possible in over 90% of the cases, but the
actual pregnancy rates are 5060% because of the formation of antisperm
antibodies. The longer the period of vasectomy, the lower the success of
reversal.
Azoospermia In all patients the cause of azoospermia should be actively sought.

Azoospermia due to hypogonadism (Kalmans syndrome, brain tumor,
prolactinoma) may be treatable in some cases by correcting the offending factor
and/or pulsatile administration of gonadotropin-releasing hormone (GnRH)
analogs. In cases of obstructive azoospermia, microsurgical treatment should be
considered. If this is not possible (bilateral congenital absence of the vas
deferens) or not successful (reversal of vasectomy), sperm retrieval and assisted
reproductive techniques should be considered. Methods for sperm retrieval are:
microsurgical epididymal sperm aspiration (MESA), percutaneous epididymal
sperm aspiration (PESA) and testicular sperm extraction (TESE). In idiopathic
azoospermia, testicular biopsy may reveal islands of spermatogenesis with few
sperm. This may allow treatment with ICSI. Donor insemination (DI) should also
be offered, because it is relatively non-invasive, successful and a cheap option. The
rate of livebirths per cycle is 914%, with a cumulative rate of 50% after 6
months. When the woman is aged 40 years, the success is much less (34% per
cycle). Adoption may also be considered.
Oligoasthenoteratospermia Finally, we are left with the largest group of
patients, those affected by oligospermia and other semen defects. The treatment
options for these men are intrauterine insemination (IUI), DI, IVFET or ICSI. The
choice depends on the severity of the defect, the effect of sperm preparation and
the nature and results of any previous treatments. A summary of all treatment
options is presented in Figure 5.6.
Other treatments Bromocriptine, tamoxifen, androgens and kinin-enhancing
drugs (kallikrein or angiotensin-converting enzyme inhibitors) are ineffective
treatments for idiopathic sperm defects/low sperm count and are not currently
recommended. Antioxidant therapy with vitamin E or glutathione and mast cell
blockers (tranilast) has been tested in men with idiopathic sperm abnormalities.
These treatments require further evaluation before being considered as viable
treatment options. Corticosteroids have been used in patients with antisperm
antibodies. Reports of their effectiveness are conflicting, but evidence of their
unpleasant side-effects is unambiguous. Sideeffects include facial flushing,
bloating, folliculitis, skin rashes, irritability, insomnia and cushingoid
appearance. Several cases of aseptic necrosis of the femoral head requiring hip
replacement have been reported. Therefore, corticosteroid treatment for
antisperm antibodies is currently not recommended.
Female infertility
The main causes of female infertility are disturbances in ovulation, tubal factors,
endometriosis and unexplained (Table 5.5).
The actual numbers vary depending on the patient population. In areas where
pelvic inflammatory disease (PID) is prevalent, tubal damage may have much
higher contribution, while in areas where there is a trend towards starting a
family later in life, ovarian failure may be more prevalent.
INFERTILITY 111
Figure 5.6 Summary for male infertility treatment. IVF, in vitro fertilization; IUI,
intrauterine insemination; ET, embryo transfer; ICSI, intracytoplasmic sperm injection;
GIFT, gamete intrafallopian transfer; ZIFT, zygote intrafallopian transfer. Reproduced
from Ombelet W, Puttemans P, Bosmans E. Intrauterine insemination: a first step procedure
in the algorithm of male subfertility treatment. Hum Reprod 1995;10(Suppl. 1):90102,
with permission of Oxford University Press
Assessment of the female patient

Points that should be covered when establishing a patients history include PID
and STDs,
Table 5.5 Main causes of female infertility
Cause
Estimated prevalence (%)
Anovulation
3035
hyperprolactinemia
hypogonadotrophic hypogonadism (low FSH)
PCOS (normal FSH)
ovarian failure (high FSH)
Tubal damage
2025
Endometriosis
510
Unexplained
3035
Other causes
5
PCOS, polycystic ovary syndrome; FSH, follicle-stimulating hormone
oligo- or amenorrhea, pelvic pain, dyspareunia, galactorrhea, nutrition, body

habitus, pattern of hair growth, oily skin and acne. Pelvic examination should
follow next, with breast examination where indicated. It is sensible to discuss
some antenatal routines and advocate the testing for rubella, and to advice the
patient to increase her folic acid intake, stop smoking (if applicable) and to
reduce her alcohol consumption to a minimum. Tubal patency should be checked
via hysterosalpingogram (HSG), under antibiotic cover where history is
suggestive of past PID and/or STD. This is normally done between days 7 and
11. The risk of infection can be minimized further by (1) cancelling the
procedure if pelvic pain is present; (2) chlamydia and gonococcal screening; (3)
betadine application to the cervix before the procedure. An injection of 35 ml of
dye allows visualization of the uterine cavity and further 5 ml are injected in
order to evaluate the tubal patency. The only incontrovertible proof for ovulation
is pregnancy. All other testsbasal body temperature, LH peak measurement,
midluteal progesterone levels, follicular disappearance on ultrasound or
endometrial biopsyonly suggest that ovulation has taken place. In 95% of
women with a regular and predictable cycle, ultrasound, midluteal progesterone
testing and/or endometrial biopsy would be indicative of ovulation. However,
since ultra-sound monitoring is too labor intensive and endometrial biopsy is
inconvenient, measuring midluteal progesterone levels is the standard for routine
clinical practice. A luteal progesterone value above 25.6 nmol/1 (8 ng/ml) is
indicative of ovulation. There are commercially available kits for the detection of
the LH surge in the urine. These kits show excellent correlation with ultrasound
and serum progesterone levels and are used in some fertility clinics for the timing
of IUI and by some patients for the timing of intercourse. Day 25 serum FSH/
LH levels (basal values), testosterone levels and ultrasound of the pelvis should
be requested if there is suspicion of anovulation, polycystic ovary sundrome
(PCOS) or abnormal findings on pelvic examination. Tests for measuring thyroid
function or prolactin are of no value in the absence of galactorrhea or symptoms
of thyroid disease. Temperature charts, endometrial biopsy and sperm-mucus
interaction tests/postcoital test are of no practical value and should be undertaken
only if part of a research project. Further diagnostic testing such as laparoscopy,
ultrasound sonography, saline contrast sonohysterography and hysteroscopy is
undertaken if there is reason to suspect intra-abdominal (endometriosis, pelvic
adhesions, fibroids) or intrauterine pathology which may need treatment
(proximal tubal occlusion, resection of septum or submucosal fibroids). After the
initial evaluation is done, one should be able to arrive at a reasonable diagnosis
in most cases and should start planning treatment. Of course, there may be more
than one pathological process present, for example endometriosis and tubal
adhesions or PCOS and tubal adhesions.
Anovulation
Anovulation has many causes and is investigated by measuring prolactin and
basal FSH levels. One practical approach to anovulatory infertility is to classify
it according to the FSH and prolactin levels (Table 5.6).
INFERTILITY 113
Hyperprolactinemia Elevated prolactin levels may disrupt the cyclical release

of gonadotropin-releasing hormone (GHRH),
Table 5.6 Classification of anovulation depending on follicle-stimulating hormone (FSH)
and prolactin results
Low FSH levels/gonadotropic deficiency (WHO group 1)
Pituitary tumor
Pituitary necrosis
Kallmans syndrome
Weight loss
Exercise
Medications
Stress
Idiopathic
Normal FSH (WHO group 2)
LH and FSH and lead to anovulation. Hyperprolactinemia can be caused by a

microprolactinoma (< 10 mm in diameter) or prolactinoma, hypothyroidism,
antipsychotic medication, drug addiction or it may be idiopathic. Prolactin levels
in the blood are variable, and the test should be done in the morning (after an
overnight fast) and never after a breast examination. Prolactinomas are usually
treated with dopamine agonists. The most widely used drug is bromocriptine.
The average dose is 2.55 mg/day, usually given at bedtime to avoid the effects
of hypotension, should it occur. Other possible medications are lisuride,
pergolide or cabergoline. Cabergoline is significantly more effective than
bromocriptine in restoring normal prolactin levels and ovulatory cycles, and has
a better side-effect profile with less nausea, vomiting and orthostatic hypotension.
If ovulation does not occur despite normalized prolactin levels, these drugs can be
combined with clomiphene. If anovulation still persists, attempts to induce
ovulation can be made with FSH or pulsatile GnRH analogs. Ovulation
commonly resumes within 6 months of treatment, and pregnancy rates between
34 and 70% have been reported. If after 68 months of ovulatory cycles
pregnancy does not occur, the couple must be re-investigated. Patients with
medication-induced hyperprolactinemia and drug addicts are special cases and the
treatment should be undertaken jointly with a psychiatrist and/or a drug
rehabilitation program.
Low follicle-stimulating hormone levels The commonest type is idiopathic, but
other known causes include stress, under-nutrition, underweight and excessive
exercise, eating disorders and pituitary failure. If a specific cause is found, it
should be treated as necessary. In idiopathic cases or in pituitary failure, the
treatment is by administration of FSH, followed by hCG in order to trigger
ovulation. Pulsatile GnRH agonists is the best treatment in hypothalamic
dysfunction, but it is cumbersome and involves wearing a pump that is necessary

for intermittent administration.
High follicle-stimulating hormone levels Elevated basal FSH levels (12 IU/1)
are found in about 5% of all women aged below 45 years and signify poor
fertility prognosis. Therefore, tests should be repeated, more than once if
necessary. In some cases, the cause may be identifiable (see Premature ovarian
failure, page 127) but in most it is idiopathic. There is no need for ovarian biopsy
to confirm the diagnosis, nor does a small increase in FSH levels form a
contraindication to ovulation induction. Stimulation is a good way of establishing
that ovarian failure has occurred. It is worth noting that rare cases of pregnancy
have been reported, especially if the apparent ovarian failure was due to cancer
treatment. However, for all practical purposes, these patients should be advised
to consider adoption or attempt to get pregnant through an egg; donation program.
Normal follicle-stimulating hormone levels (normogonadotropic anovulation)
Most of these patients have PCOS which is responsible for approximately 73%
of anovulatory infertility. The most widely accepted definition of PCOS is the
association of chronic anovulation and hyperandrogenism without specific
underlying diseases of the adrenal or pituitary gland.
Polycystic ovary syndrome
PCOS is characterized by a combination of a history of chronic anovulation,
evidence of androgen excess and multiple subcortical ovarian cysts. PCOS has a
prevalence of between 49% in women of reproductive age; this increases to
20% in the infertile population. The first description of PCOS was made by Stein
and Leventhal1, who in 1935 described the classic symptoms of this condition
consisting of oligomenorrhea, hirsutism and obesity together with enlarged
polycystic ovaries with smooth and thickened capsules. Each ovary contains
multiple (8 or more) peripherally located cysts, 210 mm in diameter, scattered
around the hyperplastic stroma. Hyperandrogenism presents clinically by acne,
hirsutism and androgen-dependent alopecia, and biochemically by elevated
serum levels of androgens, particularly testosterone and androstenedione.
Obesity is common, as is hypersecretion of LH, but with normal or low serum
levels of FSH (Table 5.7).
Ultrasound features include an increase in the amount of echogenic stroma
(30% of the ovarian volume) in addition to the above pathologic features. It
should be noted that polycystic ovaries (PCO) with no increase in stroma can be
detected by ultrasound in up to 20% of apparently healthy women. These
apparently asymptomatic women (but with a diagnosis of PCO on ultrasound)
are more likely to suffer from infertility and recurrent miscarriage. If controlled
ovarian hyperstimulation (COH) is undertaken, they tend to respond in a fashion
similar to PCOS sufferers with multiple follicular development and a rapid rise
in estradiol levels. If these patients gain weight, they tend to develop clinical
features of typical PCOS.
INFERTILITY 115
The suspected pathogenesis of PCOS in overweight and obese women is as

outlined below. High body mass index (BMI) leads to insulin hypersecretion.
High insulin levels lead to decreased production of SHBG by the liver and to
hyperplasia of the ovarian stroma. The hyperplastic stroma produces increased
amounts of androgen. Increased total androgen
Table 5.7 Polycystic ovary syndrome
Feature
Affected (%)
Infertility
Hirsutism
Amenorrhea
Oligomenorrhea
Obesity
Acne
75
70
50
40
30
25
and decreased levels of SHBG (causing increased free androgen) lead to

disruption of normal follicular growth, anovulation and high LH levels. The high
LH levels additionally disrupt follicular growth and further stimulate the stroma
to produce androgens and so the process is perpetuated. It is not known how
PCOS develops in women with normal weight, but genetic predisposition and/or
environmental insult may play a role. The diagnosis is fairly straightforward from
the history, clinical examination, the ultrasound scan and the biochemical tests.
Typical findings are elevated LH, normal or low FSH and elevated testosterone/
androstenedione and free androgen index (testosterone/SHBG ratio). It is not
necessary to perform all of the biochemical tests. FSH, LH and testosterone are
commonly available and cost-effective, with specificity of 97%. Testosterone
levels between 2.5 and 4.0 nmol/1 (85150 ng/dl) point towards a benign,
ovarian cause of hirsutism. Higher levels should prompt further investigation to
exclude adrenal hyperplasia or the presence of an androgen-secreting tumor.
Late-onset adrenal hyperplasia is ruled out if the serum level of 17hydroxyprogesterone is below 6 nmol/1 (200 ng/dl) when measured in the
morning. Acanthosis nigricans, if present, reflects a more severe condition, but
its presence can be reassuring because it is indicative of PCOS and not of a
malignancy. It is now recognized that PCOS has numerous adverse metabolic
features which put the patient at an increased risk of diabetes and cardiovascular
disease (Table 5.8). It has been suggested that one of these features, i.e., insulin
resistance, should be incorporated in the diagnosis. A
Table 5.8 Metabolic features of polycystic ovary syndrome
Increased waist/hip ratio
Hyperinsulinemia/insulin resistance
Insulin resistance
Increased total cholesterol

Increased LDL cholesterol
Increased triglycerides
Decreased HDL cholesterol
LDL, low-density lipoprotein; HDL, high-density lipoprotein
ratio of fasting glucose to insulin levels of < 4.5 correlates well with the results
of the other biochemical tests. The majority of women with PCOS have
anovulation. Chronic unopposed estrogen can increase the risk of endometrial
hyperplasia and endometrial cancer. Even if anovulation is surmounted, the rate
of miscarriage is double the rate observed in normal women.
Obesity is a common feature of PCOS. The more pronounced the obesity, the
worse the clinical feature of the syndrome. Obesity increases the risk of high
blood pressure and diabetes. If such a woman becomes pregnant, there will be a
higher risk of birth defects and of a higher birth weight in her offspring; cesarean
sections are also more frequent. Perinatal mortality is also increased. In obese
patients with PCOS, impaired glucose tolerance is found in 30% of women and
diabetes in 7.5%; in non-obese women, these figures are 10% and 1.5%,
respectively. Dyslipidemia also presents at a higher rate in women with PCOS
compared to normal women and increases the risk of cardiovascular disease.
Treatment General health advice to those patients who desire fertility should
include weight loss, a healthy diet and exercise. Studies have shown that weight
loss alone allows the resumption of ovulation in a substantial number of women.
A specific treatment for anovulation is clomiphene. Clomiphene is an estrogen
receptor blocker leading to the elevation of FSH which in turn promotes further
follicular development and ovulation. It is usually started at 50 mg/day for 5
days from the second to the sixth day after spontaneous or induced bleeding. If
there is no ovulation, the dosage should be increased by 50 mg each cycle until
ovulation is induced or 250 mg/day for 5 days is reached. A 612 cycle
treatment with ovulatory dosage of clomiphene is commonly practiced. Sideeffects of clomiphene include ovarian enlargement, vasomotor disturbances,
visual disturbances, urticaria and alopecia, but they are not normally severe and
treatment needs to be stopped in only a minority of the patients. Clomiphene is
very effective and induces ovulation in 7580% of patients, with a cumulative
pregnancy rate of 80% after nine ovulatory cycles being reported. A rate of
multiple pregnancy with clomiphene of up to 10% has been reported, including
triplets (0.5%). Some observational studies have found a 3-fold increased risk of
ovarian cancer if clomiphene was used for more than 12 cycles. If clomiphene is
not effective, treatment should be discontinued after 69 cycles. The relatively
recent understanding of the central role of insulin resistance in the pathogenesis
of PCOS has prompted research on the role of insulin in the treatment of this
condition. Available insulin-sensitizing druge are metformin, rosiglitasome and
pioglitasone. When administered to insulin-resistant patients, these compounds
INFERTILITY 117
increase the responsiveness of the target tissue to insulin, thereby reducing the
need for the hormone.
The best studied compound of the three is metformin. It is usually
administered in doses of 500 mg tds or 850 mg bd. Metformin does not stimulate
insulin production or release and when given alone does not produce
hypoglycemia. Side-effects include gastrointestinal upset and in rare
circumstances lactic acidosis. Metformin should not be prescribed to patients
with (1) renal failure or in conditions with the potential to alter the renal function,
e.g., dehydration, severe infection, shock or in the presence of intravenous
iodinated contrast agent; (2) hepatic insufficiency or alcoholism; (3) cardiac or
respiratory failure; or (4) for 48 h before and after surgery.
The effectiveness of metformin in restoring the normal ovulatory cycle and in
improving the patients ability to conceive has been tested in a number of
controlled trials. Metformin is effective in normalizing the cycle in lean (BMI
24) and obese (BMI 3235) women. The reported success rates vary between
34% after 1 month of treatment, to 7882% after 36 months. The opinion on
whether to use clomiphene or metformin as first-line therapy for women with
PCOS and infertility is divided. Some practitioners start with metformin because
it seems logical to tackle the root cause of anovulation; if there is no ovulation
after 46 months, clomiphene is then added. Others prefer it the other way round
reasoning that although metformin has been used in pregnancy without an
increase in malformations or other adverse outcomes, its safety has not been fully
established. A combination of metformin and clomiphene makes a substantial
proportion of insulin non-responders ovulate.
Laparoscopic ovarian cyst reduction by means of cautery or laser
(laparoscopic ovarian drilling) does not appear to be more effective than
clomiphene and carries the risk of the anesthetic, laparoscopy, adhesion
formation and the theoretical risk of premature ovarian failure. Its advantage,
however, is that the risk of multiple pregnancies is avoided.
Tubal obstruction
Amongst the several causes of tubal obstruction (Table 5.9), PID is by far the
most common. It is estimated that 13% of women become sterile after a single
episode of PID, 36% after two and 75% after three or more. Infecundity after a
single episode of PID increases with age and with severity of infection.
Tubal infertility can be diagnosed by HSG, laparoscopy or ultrasound with
intrauterine infusion of sound contrast media. Initial evaluation with HSG seems
reasonable if there is no indication, from the patients history and examination,
of a high infection risk. In cases of proximal tubal occlusion, filmy adhesions,
sterilization, simple blockage
Table 5.9 Causes of tubal obstruction and damage

Endometriosis
Intraligamentous fibroid(s)
Ovarian/fimbrial cysts
Sterilization
of the fimbrial end and endometriosis, surgical treatment results in a 2060%

success rate, with laparoscopic and microsurgery yielding similar results. The
risk of ectopic pregnancy is about 79% of conceptions, and patients at risk
should be seen early if they become pregnant. If surgery is unsuccessful or if the
age of the patient is a consideration, IVF is the next option. Some of the patients
requiring IVF for tubal-factor infertility will have hydrosalpinx. These patients
seem to have worse pregnancy and livebirth rates in comparison to similar patients
without hydrosalpinx. It seems that surgical removal of the hydrosalpinx
improves the outcome of IVF, but the data are limited.
Endometriosis
In endometriosis endometrial tissue is found outside the uterine cavity. The
etiology is unknown but several theories exist: (1) retrograde menstruation
seeding endometrial fragments into the pelvis; (2) metaplasia of the celomic
epithelium; (3) hematogenous or lymphatic spread; or (4) immunologic defect.
The first theory is the most widely accepted.
The endometriotic lesions are variable in appearance: from non-pigmented,
white, scar-like, through pinkish or red patches and papules, to typical blue-black
spots resembling powder burns. The lesions vary in size, from microscopic to
large chocolate-colored cysts. The incidence and prevalence in the general
population is not exactly known because it is impossible and unethical to submit
a large number of women to invasive procedures (laparoscopy, laparotomy). In
asymptomatic women prevalence rates of 222% have been reported rising to 40
60% in women with dysmenorrhea. Endometriosis is more prevalent in
nulliparous women.
Table 5.10 Symptoms and signs of endometriosis
Symptoms
(% affected)
Progressive dysmenorrhea
Pelvic pain
Dyspareunia
Infertility
Premenstrual staining
Painful defecation
6080
3050
2540
3040
1020
12
INFERTILITY 119
Symptoms
(% affected)
Signs
Cul-de-sac induration
Uterosacral ligament nodularity
Fixed ovarian masses
The last 1520 years have witnessed a sharp increase in the prevalence of
endometriosis, which conspicuously coincided with the wider use of diagnostic
laparoscopy. Laparoscopy allows inspection of the peritoneal surfaces from a
distance of 12 cm with a 58-fold magnification, something which is not
generally done during open surgery. Endometriosis should be suspected from the
patients history and clinical examination (Table 5.10). Pain is not always
associated with endometriosis, even when the disease is extensive.
Endometriosis may be present even if the physical examination is negative;
rectovaginal examination may be performed to look for thickened endovaginal
septum and/or cul-de-sac induration. Diagnosis is established by laparoscopy and
the diseases is staged in four categories: minimal, mild, moderate and severe,
according to the American Fertility Society scoring system. Moderate and severe
endometriosis undeniably impairs fertility by interfering with ovulation, ovum
pick-up by the fimbria and distorted tubal/pelvic anatomy. In minimal and mild
endometriosis the link is less clear.
Treatment Treatment of endometriosis can be medical, surgical or a
combination of both (surgery followed by medication). The best initial treatment
for minimal and mild endometriosis is laparoscopic surgical ablation. With this
kind of surgery, the combined ongoing pregnancy and livebirth rate shows a
statistically significant increase (OR 1.64, 95% CI 1.052.57). Because of the
observation that endometriosis is estrogen-dependent, suppression of ovarian
function for a period of time to allow the deposits to shrink and/or disappear
seems logical. However, drug-induced ovarian suppression is no more effective
than placebo and has numerous side-effects. Drugs that have been tried and
found to be effective for pain and disease progression, but not for infertility, are:
dianazol, medroxyprogesterone acetate, gestrinone, the combined contraceptive
pill and GnRH analogs. If the surgical treatment is unsuccessful, IVF should be
attempted next. The results of both medical and surgical treatment for moderate
and severe endometriosis are unsatisfactory and priority should be given to
assisted reproductive technologies (ART).
Unexplained infertility
Unexplained infertility is present when the routine investigation of semen
analysis, tubal patency and assessment of ovulation have shown no abnormality
and the couple have engaged in regular sexual intercourse. It is a diagnosis of
exclusion. In long-term follow-up of couples with unexplained infertility,
cumulative pregnancy rates range from 27 to 79% depending on the length of

infertility and whether it was primary or secondary. The prognosis worsens if the
infertility is primary, if the duration is more than 3 years and with increasing age
of the woman. Based on three randomized clinical trials, clomiphene has a
significant but small effect: one additional pregnancy in 40 clomiphene cycles
compared with untreated control cycles. Put ina different way clomiphene
increases the baseline pregnancy rate in patients with long-standing unexplained
infertility from 12% per cycle to 24% per cycle. Clomiphene is relatively
cheap, easy to administer and has a low incidence of side-effects. Therefore,
clomiphene should be considered as first-line treatment for unexplained
infertility. IUI therapy also has a significant but small effect. Two well
conducted trials reported a conception rate of 57% or one additional pregnancy
in 2025 IUI cycles compared with control cycles. The effect of gonadotropin/IUI
treatment, based on the same trials was a conception rate of 9% or one additional
pregnancy in 14 FSH/IUI cycles compared with control cycles. Treatment with
danazol or bromocriptine are not effective and cannot be recommended. Some
studies show that treatment with gamete intrafallopian transfer (GIFT) leads to
pregnancy in over 15% of cases. GIFT, however, is handicapped because (1) it is
invasive; (2) it requires general anesthesia; (3) fertilization cannot be witnessed;
(4) its cost is similar to IVF. In recent years IVF seems to be the treatment of choice
if ovarian stimulation and IUI do not result in pregnancy after 36 cycles. Even
with the higher pregnancy rate per cycle that is typical for IVF, however, overall
pregnancy rates may not be better than with gonadotropin/IUI treatment because
many couples drop out of IVF programs.
ASSISTED REPRODUCTIVE TECHNOLOGIES
Intrauterine insemination and donor insemination
The rationale behind IUI treatment is to use a sperm preparation in order to
bypass the cervical mucus barrier and to increase the gamete density at the site of
fertilization. As already discussed, IUI is an effective treatment in cases of
abnormal semen analysis, minimal/mild endometriosis and unexplained
infertility, with best results seen when it is combined with ovulation induction.
There are situations when IUI with sperm from the husband is either impossible
or not desirable and in such cases insemination with donor sperm (DI) is
indicated (Table 5.11).
The sperm donor should have good health and no genetic abnormalities. Sperm
of individuals aged between 18 and 50 years (40 years in the US) are used, and
while established fertility is desirable, it is not an absolute requirement. The
donor undergoes rigorous screening including medical, genetic and laboratory
tests (e.g., syphilis, hepatitis B and C, HIV), physical examination and semen
INFERTILITY 121
Table 5.11 Indication for donor insemination

Azoospermia
Severe oligospermia
Immunologic infertility
Genetic disorder (e.g., Huntingdons disease, hemophilia)
Non-correctable ejaculatory dysfunction (e.g., trauma, surgery, medication)
Severe Rh-isoimmunization
Females without male partners
analysis. The sperm is quarantined for 6 months and the donor is re-tested for
HIV in order to exclude using sperm from infected, but not serum converted
individuals. The sperm to be used for IUI and DI is first subjected to special
preparation. The advantages of sperm preparation are that it removes various
unwanted substances from the sperm and concentrates the most motile sperm in a
small volume, which is then deposited in the uterus. Both IUI and DI can be
performed as part of the natural cycle but the results are better in a stimulated
cycle. Ovarian stimulation for IUI/DI is different from that for IVF treatment.
The aim of the former is to induce growth of a maximum of three follicles while
for the latter three is the bare minimum. This is achieved by daily injections
(every other day for women with PCOS) of 75 IU of FSH starting from day 3 of
the cycle. The follicular development is monitored using ultra-sound, and 5000
10 000 IU of hCG is administered when the dominant follicle reaches 1719
mm. Double insemination appears to be better than a single one. The timing of
IUI/DI is 3844 h after hCG injection if a single insemination is performed and at
2044 h if a double insemination is performed. IUI/DI is performed by inserting
a fine-bore catheter through the cervix into the uterus and 0.5 ml of the sperm
preparation is then injected. There is no need for lying down afterwards and the
patient can go home straight away if she so wishes. Luteal support with
progesterone is advised by some, but evidence from control trials is lacking.
As discussed on page 93, in cases of unexplained or male-factor infertility, IUI
is better than either natural intercourse or intracervical insemination with
pregnancy rates of 57% per cycle, up from 2% otherwise. IUI in cycles
stimulated with clomiphene or gonadotropins achieves even better results, as
more oocytes are available for fertilization or subtle ovulatory defects are
overcome. The best results of IUI are seen if after sperm preparation the sperm
concentration is 1106/ml with greater than 20% hyperactive sperm. In some
centers, however, IUI is practiced with sperm concentration of 0.5106/ml with
greater than 10% hyperactive sperm. It seems reasonable to attempt 36 of
clomiphenestimulated cycles and 36 of FSH-stimulated cycles. If pregnancy
does not follow, IVF or ICSI should be the next step. Data from the Human
Fertilization and Embryology Authority (HFEA) for the year 19992000 show
average live birth rate of 10.6% in woman aged < 38 years and 9.6% in women of
all ages, per DI treatment cycle. The average figure hides considerable variations
between centers with a range between 01.9% and 22.620.5%.
In vitro fertilization/intracytoplasmic sperm injection and
controlled ovarian hyperstimulation
In many cases of infertility treatment IVF and ICSI is necessary. In order to
improve the chances of pregnancy, more oocytes need to be made available. One
way of achieving this objective is by COH. The protocol involves abolishing the
normal cycle with the use of LHRH analog administration (downregulation) and
recruiting a number of follicles by creating an artificial cycle using exogenous
FSH and LH (stimulation). In cycles when IUI/DI is being contemplated, the aim
is to recruit 23 follicles, but in IVF or ICSI cycles more follicles are necessary.
Downregulation
During normal cycles LHRH is released in pulses of 28 min every 6090 min
but after
Table 5.12 Advantages of luteinizing hormone-releasing hormone pituitary suppression
Allows recruitment of more follicles
Leads to synchronization of development
Reduces the incidence of premature luteinization
Leads to better quality oocytes and higher fertilization rates
Abolishes natural LH surge and decreases cancellations
Reduces the need for monitoring
LH, luteinizing hormone
LHRH injection treatment the levels achieved are constant and high. LHRH
analog is administered daily from the mid-luteal phase of the previous cycle.
LHRH administration leads to a two-phase response: (1) initial flare-up between
days 2 and 4 during which preformed LH and FSH are released from the
pituitary store; and (2) decrease of LH and FSH and estradiol to castrate levels
by day 1014. LHRH acts by saturating all available receptors which are then
internalized in the cells with a net receptor loss. LHRH receptor production
continues at a very low rate, and the receptors are immediately occupied by
exogenous LHRH, so there are never enough receptors to promote a pituitary
response. The suppression of the pituitary by LHRH analogs leads to several
advantages: (1) recruitment of more follicles; (2) synchronization of follicle
development; (3) abolition of the natural LH surge and thus premature ovulation;
and (4) reduction of the need for monitoring early in the FSH administration
interval (Table 5.12). Onset of menstruation indicates suppression and
biochemical measurements are not normally necessary.
INFERTILITY 123
Recently, LHRH antagonists have been introduced into clinical practice (see
section Medications used in Assisted Reproductive Technologies below)
Stimulation
Stimulation usually begins with 150 IU of FSH daily. If there is history of
suboptimal response or the patient is in the older age group, the starting dosage
may be 225 IU. If there is history of PCOS or previous hyperstimulation
syndrome, either 150 IU are given on alternative days or 75 IU are given daily.
Monitoring in the past used to be performed by measuring serum estradiol and by
ultrasound, but currently it is done almost exclusively by ultrasound only. When
there are three follicles over 16 mm and the leading follicle is over 18 mm and if
the endometrium is over 7 mm, ovulation is triggered by 10 000 units of hCG.
FSH preparations are of either recombinant or of urinary origin. Recombinant
FSH (rFSH) is produced by inserting the fsh gene in Chinese hamster ovary
cells, which on culturing start producing human FSH which can then be purified
and made into a medicinal product. rFSH is 100% pure and free of urinary
proteins, and the supply is relatively unlimited. Urinary FSH (uFSH) is produced
by purifying the urine of menopausal women; this preparation is 99% pure, but
reactions to the urinary proteins are sometimes encountered. Although rFSH is
more expensive, the trend is towards its increased use. Although one metaanalysis shows that its use leads to higher pregnancy rates, one would have to
use rFSH in 25 IVF cycles to achieve a single pregnancy more than in 25 uFSH
cycles. Recombinant LH and hCG are now also available.
In vitro fertilization
Oocyte retrieval takes place 3435 h after hCG administration. Egg collection is
normally performed under analgesia rather than under general anesthetic. The
patient is in lithotomy position and a vaginal ultrasound probe with a long
puncturing needle is mounted on top and introduced transvaginally. The
procedure involves puncturing each follicle individually and extracting the
content by means of vacuum suction under direct ultrasound control. Cumulus
complexes consisting of granulosa cells and oocyte(s) are collected and
incubated for several hours. Granulosa cells are stripped and the oocytes are
inseminated approximately 4 h after collection, allowing 100 000 sperm per egg.
After about 1618 h of incubation, the oocytes are observed for fertilization.
Fertilization is considered normal if two distinct pronuclei containing nucleoli
are present and if the polar bodies have been extruded. Cleavage of the
conceptus is evaluated after a further 24 h, and replacement of the embryo into
the uterus is usually performed 4872 h after the insemination. The quality of the
embryo (pre-embryo) is estimated according to the percentage fragmentation of
the cells and the clarity of the cytoplasm. The embryo should have less than 20%
fragmentation and should be at the four-cell stage or more at 4448 h. It is
currently recommended that only two good-quality pre-embryos be replaced

because the pregnancy rate is the same in comparison with when three or more
are replaced, but the frequency of multiple pregnancy is reduced. After egg
collection, GnRH administration is discontinued. However, it takes 711 days
for the pituitary gland to recover and during this time there is insufficient
production of LH to support the corpus luteum and progesterone production.
Therefore, either hCG or progesterone is given as luteal support. Both are
equally effective. Luteal support is given for 812 weeks. Surplus embryos can
be frozen and kept for 5 years under the current UK legislation. Embryo freezing
appears to be safe but not all embryos survive the thawing, and the results of
frozen embryo transfer are not as good as fresh transfer (1417% versus 2030%
per cycle).
Intracytoplasmic sperm injection
A modification of IVF, called ICSI, was introduced in 1992. It followed previous
attempts to facilitate fertilization by micromanipulation of the oocyte and sperm.
Fertilization rates are very poor with IVF when the sperm count and/or motility
is very low (< 1106/ml with < 20% motility), and various treatments were
developed. These included: zona dissection (ZD), partial zona dissection (PZD),
subzonal insemination (SUZI), all of which have been made obsolete by ICSI.
ICSI was discovered accidentally when during attempted SUZI sperm was
introduced into the cytoplasm of the egg, rather than into the subzonal
space. This egg was not destroyed but monitored for fertilization. When
fertilization took place, a new chapter in ART was opened. ICSI is a very
versatile treatment, with constantly widening indications including severe sperm
defects, obstructive azoospermia and IVF failure. The main concerns about ICSI
are that the selection of gametes is arbitrary and that it may perpetuate the
original cause of male infertility in the male offspring. ICSI bypasses all natural
sperm selection and quality control systems in the female genital tract and at the
sperm-oocyte interface which might prevent defective sperm from fertilizing the
oocyte. ICSI also damages the oocyte during the injection procedure, resulting in
increased rates of cell degeneration. The clinical success of ICSI has
overshadowed the fact that it is only 11 years old and therefore it must be
practiced in conjunction with counseling, more frequent genetic testing of the
father and the offspring, and long-term follow-up of any child born via ICSI. A
fertilization rate of 6065% is achieved with ICSI with 710% of damaged
oocytes. Clinical pregnancy rates are no different from IVF and, if anything, may
be better if male infertility is the only problem and the female partner is healthy.
So far, ICSI appears to be safe, but the children born via ICSI are still very
young. It is likely that some or all of the factors that led to infertility in the father
will be inherited by some of the male offspring.
INFERTILITY 125
Blastocyst transfer
Recent advances in embryology have allowed us to pursue research in blastocyst
transfer (day-5 transfer). With modern culture methods 4060% of the fertilized
eggs reach blastocyst stage. The principal advantages of this technique are: (1)
better embryo selection and therefore better pregnancy and birth rates; (2) better
synchronization between the embryo and the uterus; and (3) an improved
potential to perform preimplantation diagnosis. Possible risks are that in some
cases no embryo will be available for transfer and that there will be fewer
embryos for cryopreservation. At present, it is not possible to recommend
blastocyst transfer.
Natural cycle IVF
IVF treatment can be carried out during the natural cycle and without COH. The
cycle is monitored with serial ultrasound scans. When the dominant follicle
reaches 16 mm, an ovulatory dose of hCG is given. The rest of the treatment is
like conventional IVF treatment. The advantages of this technique are that it is
simple, avoids the risk of OHSS and is much cheaper. The disadvantage is that
the success rate is much lower than with conventional IVF. A modification of
natural-cycle IVF is practiced in some clinics with much improved results. This
method is called in vitro maturation and is used for women with PCOS. Women
with amenorrhea are given progestogens to induce withdrawal bleeding. A
baseline scan is performed on day 2 or 3 to exclude the possibility of ovarian
cysts. Transvaginal ultrasound scans are performed on day 8 to exclude the
presence of a dominant follicle. If all follicles are 10 mm, 10 000 IU of hCG
are given via subcutaneous injection. Oocyte retrieval is scheduled 36 h later. In
in vitro maturation, hCG priming increases the percentage and rate maturation of
the immature oocytes. The oocytes are then cultured and checked for maturation
at 24 h and at 48 h. Mature oocytes are then fertilized via ICSI and suitable
embryos are transferred on day 2 or 3 after ICSI. The maturation rate is about
80%. When these mature oocytes are inseminated via ICSI, the fertilization rate
is about 75%. The clinical pregnancy rate varies with the number of oocytes
retrieved, and rates of 10% and 17% have been reported when 2 and 10
oocytes are harvested.
Results of in vitro fertilization and intracytoplasmic sperm
injection
The results of infertility treatments vary from unit to unit, but in general are
getting better with each year of experience. The success rate can be measured in
terms of overall pregnancy rates, pregnancy rates per treatment cycle or
pregnancy rate per embryo transfer. A number of pregnancies may end with miscarriage, and therefore, the best way to measure success is by live birth rate.
Figure 5.7 Correlation between age and pregnancy rates. IVF, in vitro fertilization; ICSI,
intracytoplasmic sperm injection. Reproduced from The Patients Guide to IVF Clinics.
London: Human Fertilisation and Embryology Authority, 2000. Human Fertilisation and
Embryology Authority
Figure 5.8 Live birth rates by duration of infertility. Data derived from the Human
Fertilisation and Embryology Authority, 1999
Other issues that need to be considered are the rate of ovarian hyperstimulation
syndrome and multiple pregnancy.
The major factors that affect the chance of achieving pregnancy are the age of
the woman (Figure 5.7), duration of infertility (Figure 5.8), cause of infertility
and whether the infertility is primary or secondary (secondary having a better
prognosis). A summary of results based on HFEA 1999 data is presented in
Table 5.13 and Figure 5.9. There is considerable variation in results with some
units reporting success rates about one-third of the average and others over twice
the average. For women under 38 years of age there is no significant difference
in pregnancy rates if two embryos are transferred instead of three but there is a
reduced risk of multiple pregnancy. The miscarriage rate is about 15% of the
clinical pregnancy rate and the chance of an ectopic pregnancy is approximately
24%. Cancellation rates of 520% are reported, varying between centers and
between countries.
INFERTILITY 127
Estimation of the ovarian reserve

Some women do not respond at all to ovulation induction or respond by
developing less than four follicles. These poor responders are thought to have
decreased ovarian reserve. The term ovarian reserve describes the patients
reproductive potential in terms of ovarian follicle number and oocyte quality.
Typical features are age > 35 years, basal values of FSH > 12 IU/1, LH > 5 IU/1
and estradiol > 250 pmol/1 (80 pg/ml). Basal FSH levels correlate very well with
pregnancy rates. It has been shown that where the basal FSH level is > 12 IU/1,
the fertility prognosis is poor and if the FSH level is > 20 IU/1 the live birth rate
is between 0 and 3%. It is currently recommended that basal FSH levels should
be a screening tool in the initial infertility assessment. Some authorities advocate
the clomiphene challenge test hoping to unmask patients with diminished ovarian
reserve, who might not be detected by basal FSH screening alone. The value of
the clomiphene test has not been fully established, but it is used by some
infertility centers for women over 35 years of age prior to committing to COH. The
test involves measuring basal (day 3) FSH levels, administering 100 mg of
clomiphene per day on cycle days 59 and then measuring
Table 5.13 Live birth rates from in vitro fertilization/intracytoplasmic sperm injection
treatments
Variable
Below age 38 years
All ages Range (all ages)
Per treatment cycle started (%)

19.6
17.4
6.037.0
Per egg collection (%)
21.2
19
6.937.8
Per embryo transfer (%)
23.6
21.1
7.440.7
Per frozen embryo transfer (%)
13.4
12.3
024.4
Abandoned treatment cycles (%)
16
Multiple birth rate (%)
28.6
Birth rate, twins (%)
25.5
Birth rate, triplets (%)
3.1
Data derived from the Human Fertilisation and Embryology Authority, 2000
FSH levels again on day 10. If either of these FSH readings are abnormal (above
the upper limit for the laboratory) the test result is considered abnormal.
Egg donation
There will be occasions when the use of a womans own eggs during IVF will not
be possible or desirable. Such cases arise with ovarian failure, poor-quality
oocytes, poor responders, persistent IVF failure or with genetic disorders.
Women in this predicament can still get pregnant if they use donor eggs. Healthy
women under 35 years of age can donate eggs; these are inseminated with the
sperm of the infertile womens husband and the embryo(s) is (are) transfered into
Figure 5.9 Live birth rates in in vitro fertilization (IVF) and intracytoplasmic sperm
injection (ICSI) between 1985 and 1998. Data derived from the Human Fertilization and
Embryology Authority, 1998, 1999
the uterus of the infertile woman. The child will have a different genetic make-up
from that of the woman who carries and delivers the child. The prospective
donor is screened for genetic or acquired diseases in much the same way as
sperm donors. Screening includes, but is not restricted to, a donors history,
blood group, infectious diseases (hepatitis B and C, HIV, syphilis,
cytomegalovirus), karyotype and cystic fibrosis. The donor undergoes usual IVF
treatment up to the stage of egg collection. The recipients cycle is coordinated
with HRT or GnRH agonist and HRT and the embryos are transferred to her
uterus in the normal way. The live birth rate with donor eggs in the UK for the
year 2000 was 21% for fresh transfers.
Medications used in assisted reproductive technologies
It can be said that modern ART is only possible because of the advances made in
basic sciences and especially pharmacology. The medications used for infertility
treatment can be derived from (1) natural sources, i.e. human menopausal
gonadotropins; (2) be produced using recombinant technology, i.e., FSH or LH;
or (3) be of purely synthetic origin, i.e., GnRH agonists/antagonists. A major new
development has been the introduction of recombinant gonadotropins (FSH, LH,
hCG). The recombinant technology is discussed on page 96. Recombinant FSH
(r-FSH) is more expensive than urinary FSH (u-FSH). Based on current data rFSH is more effective than u-FSH in achieving clinical pregnancy and is more
cost-effective as well because less of it is used in the course of an IVF treatment
cycle. Recombinant LH and r-hCG have not been used long enough to compare
them to the urinary products. As mentioned earlier in the chapter, GnRH agonists
are used to suppress the endogenous production of FSH and LH. This takes 714
INFERTILITY 129
days to achieve and involves initial flare-up during which preformed and stored
FSH and LH are released. The flare-up is used in some clinics with a so-called
short protocol but the pregnancy rates are lower. Therefore, the long protocol
is preferred. In recent years, GnRH antagonists have been developed. Unlike
GnRH agonists, the antagonists do not induce an initial stimulation of
gonadotropin release. The reason is that GnRH antagonists competitively bind to
the GnRH receptor without receptor activation or initial stimulation. Rapid
(within a few hours) and reversible suppression of gonadotropin secretion ensues.
Stopping the agonist leads to a quick recovery of the pituitary function. During
COH, administration of GnRH agonist is required only around the time of the
expected LH surge. This allows a switch from the long protocol to the short
protocol. In the short protocol FSH is started from day 23 of the menstrual
cycle and after 6 days GnRH antagonists are started. Both are administered for a
further 45 days, until the day of hCG trigger. The average length of this protocol
is 111 days and a lower total dose of FHS is required. The overall length of the
COH cycle using GnRH antagonists instead of GnRH agonists is about 710
days less. The experience with GnRH antagonists is limited and it is not possible
to tell if they are superior in terms of live birth rates or complications like OHSS.
Some medications used in ART are listed in Table 5.14.
Complications of controlled ovarian hyperstimulation
Well-established complications of ovarian stimulation, whether it is used for IUI,
DI, IVF or ICSI, include ovarian hyperstimulation syndrome (OHSS;
Table 5.15) and multiple pregnancy.
Ovarian hyperstimulation syndrome
Ovarian hyperstimulation syndrome (OHSS) is a iatrogenic complication of
gonodotropin treatment with potentially severe and even fatal consequences.
Mild forms of OHSS occur in 810% of cycles and severe forms in 0.51%. The
pathophysiological hallmark of OHSS is a sudden increase of vascular
permeability, which results in development of extravascular exudate. Loss of
fluid and protein into the third space leads to a fall in the intravascular volume,
loss of oncotic pressure, hemoconcentration, low urinary output and edema. A
high estrogen level is a predictor and a marker of the condition, but it is not
considered the direct cause. It is thought that OHSS is triggered by (1) activation
of the ovarian renin-angiotensin system; and (2) secretion of vascular endothelial
growth factor from the ovary. Mild and moderate OHSS presents with nausea,
vomiting, lassitude, diarrhea, abdominal pain and distension. Severe forms may
present with the same symptoms as above, plus ascites, hydrothorax and signs of
hypovolemia and oliguria. Complications of OHSS include ovarian torsion,
thromboembolism, liver dysfunction and ARDS. OHSS starts 38 days after the
hCG injection. It should be anticipated if risk factors are present (Table 5.16),
and hCG should not be administered. Prophylaxis of OHSS with intravenous

infusion of albumin has not been effective.
Mild cases and some moderate cases of OHSS subside in 23 weeks, and can
be safely
Table 5.14 Medications used in assisted reproductive technologies
Medication
Trade name
Description
Dose
Buserelin
Suprecur
150 g as a nasal
spray four times a day
Nafarelin
Synarel
Synthetic GnRH
agonist 100 times
more potent than the
natural hormone
As above
Triptorelin
Cetrorelix
Decapeptyl
Cetrotide
Ganirelix human
menopausal
gonadotropins (hMG)
Orgalutran
Menogon
Menopur
As above
Synthetic GnRH
antagonist
200 g nasal spray

three times a day
3.0 mg SC one a day
3.0 mg SC as a single
dose or 0.25 mg/day
SC
0.25 mg/day SC
75225 IU SC or IM
daily
As above
Purified extract from
menopausal urine
containing FSH and
LH in a ratio of 1:1
Urofollitropin, high
Metrodin HP Extract from
75225 IU SC or IM
purity (HP)
menopausal urine
daily
containing FSH but
virtually no LH
Follitropin alpha
Gonal-F
Recombinant FSH
37.5150 IU SC daily
Follitropin beta
Puregon
As above
50200 IU SC daily
human chorionic
Choragon
An extract from the
10 000 IU SC for
gonadotropin (hCG)
Pregnyl
urine of pregnant
triggering of ovulation
Profasi
women containing
15002000 IU SC
hCG secreted from
every 23 days for
the placenta
luteal support
Lutropin alpha
Luveris
Recombinant LH for
75 IU SC daily
use in patients with
severe (< 1.2 IU/1)
LH deficiency
Progesterone
Crinone
Vaginal gel
One applicator of 8%
containing 8%
gel daily for luteal
progesterone
support
delivering 90 mg of
progesterone per
application
Gestone
Progesterone for
50100 mg daily IM
injection (50 mg/ml)
FSH, follicle-stimulating IM, intramuscular hormone; GnRH, gonadotropin-releasing
hormone; LH, luteinizing hormone; SC, subcutaneous;
INFERTILITY 131
managed at home. The patients should be advised to keep well hydrated and to
avoid intercourse because of the risk of ovarian rupture and adnexal torsion.
Patients who develop severe forms of OHSS need to be hospitalized.
Thorough clinical examination should be performed, including weight and
abdominal girth, but bimanual pressure on the ovaries should be avoided. Blood
tests should include full blood count, urea and electrolytes, liver function tests
and hematocrit. An ultrasound scan is useful for monitoring the size of the
ovaries and ascites, if present. Treatment is by bed rest, rehydration, antithromboembolic stocking and perhaps subcutaneous heparin. Paracentesis
(abdominocentesis) is advised if there is tense ascites which leads to abdominal
Table 5.15 Classification of ovarian hyperstimulation syndrome
Mild
Chemical
Chemical and ovarian enlargement
Moderate
Abdominal distension, nausea, vomiting, diarrhea and ovarian enlargement (512 cm)
Severe
Nausea, vomiting, diarrhea, abdominal distension, ascites and/or pleural effusion and
ovaries > 12 cm
Hematocrit > 55%, coagulation abnormalities and/or acute renal failure
discomfort and difficulties in breathing and/or if the urinary output is poor.

Severe OHSS takes 2040 days to resolve but may
Table 5.16 Risk factors for ovarian hyperstimulation syndrome
Estradiol > 10 00018 000 pmol/1 (30006000 ng/dl)
> 2025 follicles present
Thickened ovarian stroma
Ovaries > 8 cm
Fluid in the POD
Polycystic ovary syndrome
Young age (< 35 years)
Low weight
Pregnancy, especially if multiple
take longer if conception occurs. Several mortalities have been reported,

including one in the UK.
The potentially very serious consequences of OHSS and the lack of specific
treatment make prevention paramount. Several strategies are available and these
are (1) abandoning the cycle with or without early follicular aspiration; (2)
coasting (stopping the gonadotropin stimulation, continuing with GnRH
suppression and not administering hCG until estadiol levels decline); (3)
intravenous infusion of albumin or hydroxyethyl starch at egg collection; (4)
shifting the cycle to cryopreservation of the embryos; or (5) two follicular
aspirations in the same cycle. Not all of these methods have been rigorously
tested. The first three have been and are proven to be effective.
Multiple pregnancy
One complication of ovarian stimulation that is frequently overlooked is multiple
pregnancy. The incidence of multiple pregnancy and delivery in developed
countries has increased dramatically over the last 15 years. In England and
Wales between 1980 and 1993, the number of twin pregnancies has increased by
25% and the number of triplet and higher-order pregnancies has more than
doubled. Latest figures show that the multiple birth rate following ART is 37%
in the UK and 35.5% in the US. The complications of twin and higher-order
pregnancies affect the
Table 5.17 Established maternal complications arising form assisted reproductive
technologies
Allergy/erythema/injection complications
Ovarian cysts
Sedation/anesthetic complications
Vaginal bleeding
Vaginal/abdominal infection
Perforation of the bowel or iliac vessels at egg collection
Ovarian hyperstimulation syndrome
Multiple pregnancy
pregnancy itself, neonatal health and function in early childhood, which can
make the couple forever regret seeking infertility treatment. Some complications
are spontaneous abortion, preterm labor and delivery, pregnancy-induced
hypertension, low birth weight, increased prevalence of congenital
malformations and neurological impairments. In comparison with single
pregnancies, in twins and higher-order births the perinatal mortality and the rate
of cerebral palsy are both increased 510 times. Multiple pregnancy in IVF and
ICSI cycles is almost entirely preventable and the current recommendation is to
transfer only two good-quality embryos to the uterus.
Safety of assisted reproductive technologies
The issue of safety of ART relates to the mother and her offspring. Short-term
complications for the mother are listed in Table 5.17. Posssible long-term
complications are an increased incidence of cancer of the reproductive system.
INFERTILITY 133
Many epidemiologic studies have looked into a possible connection between

infertility treatment and cancer of the breast, ovary or uterus. So far the results
have been reassuring with the exception of two early studies suggesting a
possible link between ovulation induction and ovarian concer. These findings
have not been confirmed by later research. However, for the moment it seems
prudent to restrict the use of clomiphene to 69 cycles and COH to 912 cycles.
ART involves manipulation of the gametes and in many (perhaps most) cases
bypassing the mechanisms of natural selection. Mindful of this, researchers have
focused their attention on the health of children born as a result of IVF treatment.
The data show that the main danger is not so much the technology itself, but the
rate of multiple gestation. In summary, IVF leads to an increased rate of
prematurity, low birth weight and higher rates of stillbirth and perinatal mortality
(8.2% versus 6.6%). The rate of low birth weight among singletons is increased
more than two-fold, from 2.5% in the general population to 6.5% after IVF/ICSI
treatment. There is an increased rate of congenital malformation in IVF babies,
even after excluding prematurityrelated undescended testis, unstable hip and
hydrocele. The malformations that occurred with higher frequency among IVF
babies include spina bifida, anencephaly, hydrocephalus and esophageal atresia.
In one study, major birth defects were identified in 9% of 1 -year-old ARTderived babies as compared to 4.2% of naturally conceived ones. It has been
reported that the risk of cerebral palsy and developmental delay is increased by
24 fold. However, it is important to rembember that the majority of couples will
not be affected and will have a healthy baby
New developments and other issues
It is beyond the scope of this book to cover the whole field of infertility. The
authors would like to point out that there are many other medical, ethical and
legal considerations related to infertility treatment. Here we list some of them:
counseling; living with infertility; giving up fertility treatment; adoption; welfare
of the child; treatment of single or gay/lesbian people; egg donation/surrogacy;
cryopreservation of ovarian/testicular tissue, male/female gametes or embryos;
posthumous treatment; preimplantation diagnosis; the question of when does the
embryo/blastocyst become a person; fertility of the offspring; ooplasmic transfer;
semicloning and cloning. The list will keep on expanding as medicine and
society continue to evolve.
CONCLUSION
Of the specific treatments for infertility, two therapies could be considered very
successful, namely gonadotropin therapy for group I (World Health Organization
classification) ovulation disorders and DI for azoospermia. Although
developments in the treatment of infertility have been exciting and promising, an
important barrier to effective treatment is the failure to identify the molecular
and membrane defects that must exist in many other cases of infertility which are
unexplained or do not respond to specific treatment. Less than 50% of infertile
couples are successful in having a child, and less than 5% undergo the most
effective treatment for persistent infertility, which is IVF with ICSI when needed.
Continuing research is necessary to reduce the cost and complexity of these
treatments in order to make them more accessible.
References
Stein IF, Leventhal ML. Amenorrhoea associated with bilateral polycystic ovaries. Am J
Obstet Gynecol 1935; 21:181
6
Menopause, hormone replacement therapy
and non-hormonal strategies
Nikolai Manassiev, Fergus Keating and Henry Burger
INTRODUCTION
Taken at face value, the menopause should be viewed as a normal life event. The
last menses simply signifies the beginning of a new era in the womans life cycle:
the postmenopausal phase. Since all women will undergo the menopause (or die
beforehand), it cannot be regarded per se as abnormal. The menopause marks the
cessation of the female reproductive potential and is characterized by markedly
decreased estrogen levels and very low progesterone levels. The roles of these
hormones are quite varied. The physiologic function of progesterone appears to
be confined mainly to pregnancy, but that of estrogen reaches far beyond with
effects on various organs and systems; and this, coupled with the confirmed
relationship between the decline in estrogen and hot flashes and sweats, has
undoubtedly contributed to the definition of the menopause as an estrogen
deficiency state. The menopause coincides with an age-related increase in
incidence of a wide variety of potentially serious medical conditions. It is little
wonder that research into the relationship, if any, between the reproductive
hormones, especially estrogen, and cardiovascular disease (CVD), osteoporosis
and Alzheimers disease, for example, has attracted so much attention.
There is a tendency, however, to concentrate on the decline in estrogen levels
and to describe the menopause as an estrogen deficiency state or ovarian
failure. Although these terms can be used to define the menopause, this
approach is simplistic and creates an impression of pathology. The association of
the menopause with, for example, CVD, osteoporosis and urinary incontinence
gives an impression of causality, which may or may not exist. It can be argued that
the menopause is only one of many factors which together with life-style, diet,
genetic predisposition and the process of agingcan be blamed for various
diseases that occur with higher frequencies during the postmenopausal phase of
the womans life. Inevitably, low estrogen levels, hormonal changes and
hormonal replacement figure prominently in discussions of the menopause,
partly because of the causality theory and partly because there are numerous data
and research studies to draw from. However, we believe in a balanced, wider,
Figure 6.1 Average life span at various times in history
holistic approach to the menopause. We hope that in future non-hormonal

strategies will figure in chapters on the menopause more prominently.
Life expectancy in the developed world has increased steadily during the
twentieth century, and women commonly live more than one-third of their life in
a postmenopausal state (see Table 6.1 and Figure 6.1). In the UK, 18% of the
entire population comprises women over 50 years of age. There are over 10
million women in the UK in a low estrogen state (Table 6.2).
The impact of these statistics upon health resources has recently begun to be
understood more fully because of the greater knowledge of the effects of
estrogen deficiency on the various organ systems. As discussed below, estrogen
deficiency has been linked to osteoporosis and coronary heart disease (CHD).
The financial impact of osteoporosis alone has been estimated to amount to 1.7
billion
Table 6.1 Life expectancy in the UK for people of various ages
Men
Women
Age (years)
1911
1971
1991
2011
1911
1971
1991
2011
0
20
40
60
80
50.4
44.0
27.5
13.7
4.9
68.8
50.9
31.8
15.3
5.5
73.2
54.2
35.2
17.7
6.4
77.4
58.0
39.0
21.0
77.0
53.9
46.4
29.8
15.3
5.6
75.0
56.7
37.3
19.8
6.9
78.8
59.6
40.0
21.9
8.4
81.6
62.0
42.5
24.1
9.1
Data derived from the Office for National Statistics, 2003
in the UK with some 70 000 hip fractures each year, leading to 40 premature
deaths every day. CHD is the leading cause of death in women in the UK and
MENOPAUSE, HRT AND NON-HORMONAL STRATEGIES 137
USA: it accounts for the death of 17% of all women and 27% of women under
the age of 75 years in the UK. CHD presents an enormous financial burden to the
economies of the developed world, currently estimated at 10 billion per year in
the UK alone (total including both direct and indirect costs to the economy). It is
thus important to define precisely the link between the effects of estrogen
deficiency and CHD, and preventive strategies need to be developed, if possible.
This chapter presents an overview of the current understanding of hormonal and
especially estrogen deficiency on various target organs, outlines the principles of
hormone replacement therapy (HRT) and describes non-hormonal interventions
which may improve the health of postmenopausal women.
ESTROGENS
Estrogen describes a group of steroid hormones produced primarily in the
ovaries during reproductive life, but additionally in extra-gonadal sites such as
adipose tissue. Estradiol is the primary estrogen during reproductive life, and is
secreted by the granulosa cells of the developing follicle in response to folliclestimulating hormone (FSH) and luteinizing hormone (LH)
Table 6.2 UK population: women aged 4585+(in millions)
Age band
1991
2001
4559
6064
6574
7584
85 +
Total
4.8
1.5
2.8
1.9
0.7
11.7
5.6
1.5
2.6
2.0
0.8
12.5
secretion from the anterior pituitary gland. The estradiol concentration varies
throughout the menstrual cycle, with low levels in the early follicular phase (150
200 pmol/1), a peak at mid-cycle (12001500 pmol/1) and intermediate levels
(500 pmol/1) in the luteal phase. A small amount of estrone is also produced,
derived mainly by peripheral conversion of androstenedione in adipose tissue,
and the ratio of estradiol:estrone in the premenopausal woman remains at around
3:1. The daily production of estradiol during the reproductive years is 0.070.8
mg, dependent upon the phase of the cycle. In the serum, 38% of estradiol binds
to sex hormone binding globulin, a -globulin. About 60% of estradiol binds
with lower affinity to albumin. A small fraction (23%) remains unbound.
Following the menopause, estradiol levels are commonly below 110 pmol/1, but
the peripheral conversion of androstenedione to estrone increases. In the
postmenopause, estradiol levels decrease more relative to estrone levels, leading
to a reversal of the estradiol:estrone ratio to 1:3. Estrone becomes the primary
postmenopausal estrogen, but its potency is only 130% compared with estradiol.
Potency is measured in vivo and in vitro using a variety of assays (thus

explaining the breadth of the potency range above), e.g., inducing estrus in
animals, cornification (maturation) of vaginal epithelial cells, uterine weight in
rodents and studying effects on cell cultures. Consequently the classic symptoms
of estrogen deficiency develop, as discussed below. Endogenous estrogens are
primarily metabolized in the liver where they are conjugated with glucoronide
(and sulfate) to form water-soluble products, and then excreted in the bile and
urine in an inactive form. In the bowel, bacteria are able to remove the
glucoronide and the sulfate groups. This frees some estrogen for reabsorption
which then re-enters the liver through the portal vein. This process is known as
the enterohepatic cycle.
MENOPAUSE, HORMONE REPLACEMENT
THERAPY AND THEIR EFFECTS ON THE BODY
Vasomotor symptoms and mood
The activity of the hypothalamus in the regulation of temperature, satiety/
appetite and blood pressure, and of the limbic system in regulation of mood and
psychologic well-being, seems to be influenced by estrogen. Estrogen deficiency
at these specific sites in the central nervous system (CNS) is thought to be
responsible for the vasomotor symptoms of hot flashes, night sweats, palpitations
and mood swings experienced by over 60% of climacteric women. The hot flash
of heat is a subjective sensation associated with cutaneous vasodilation and a
subsequent drop in core body temperature. The hot flash may be accompanied by
visible redness in the neck and face area, sweating or even panic. It is typically
described as starting from somewhere around the mid-torso and moving upwards
to the face. This intensely unpleasant sensation can last from seconds to minutes,
usually within the range of 34 min. The precise mechanism underlying hot
flashes is unclear, but altered thermoregulatory control from the hypothalamus is
believed to be partially responsible. These manifestations of vasomotor
instability show a diverse range of intensity between women, and at worse can be
extremely disruptive to a womans quality of life. The symptoms associated with
the surgical menopause are more abrupt and severe and can last longer than those
associated with the natural menopause. Smoking, lack of exercise and being
underweight are associated with an increased risk of hot flashes. Hot flashes
and their differential diagnosis are discussed in more detail in Chapter 3.
Estrogen therapy is an effective treatment in reducing both the frequency and
intensity of these vasomotor symptoms, and higher estrogen doses may be
required in hysterectomized women. Medroxy-progesterone acetate (MPA) and
norethisterone acetate (NETA) are moderately effective in treating hot flashes in
women who do not want to take estrogen or in whom estrogens are
contraindicated. Tibolone (synthetic compound with estrogenic, progestogenic
and androgenic activity) is also effective against hot flashes and is used as an
alternative to HRT. Recent randomized controlled trials produced data showing
that long-term HRT may not be as safe as originally thought. This may lead to
renewed interest in clonidine. The latter is moderately more affective than
placebo in relieving hot flashes but it can cause sedation or dry mouth in some
patients. It is licensed for treatment of hot flashes and the usual dose is two
tablets of 25 mg twice a day. Phytoestrogens have been studies as a natural
remedy for hot flashes as well. The results from controlled trials suggest that the
effect is moderate at best and tends to be more pronounced in women with more
severe hot flashes. New treatments for hot flashes are now being tested. In small
controlled clinical trials, gabapentin, venlafaxine and fluoxetine were found to be
more effective than placebo. However, their use in daily clinical practice is not
yet established. Up to 40% of the female population experience adverse affective
symptoms during the climacteric, ranging from mild anxiety states to depressive
disorders, and a reduced sense of well-being. Although no definite hormonal link
has been demonstrated, a beneficial effect of estrogen on quality of life measures
has been demonstrated.
Urogenital system
Lower genital tract
Estrogen receptors (ERs) occur in the tissues of the vagina, urethra, bladder and
pelvic floor, consistent with the fact that the lower parts of the female genital and
urologic tracts share a common embryologic origin from the primitive urogenital
sinus. Prolonged estrogen deficiency leads to vaginal atrophy and the classic
symptoms of vaginal dryness, itching, burning and dyspareunia. Apart from the
unpleasant feeling of dryness, vaginal atrophy predisposes to vaginal infection
and sexual dysfunction. Estrogen replacement, whether local or systemic, has
been shown to be effective in treating atrophic vaginitis, vaginal dryness and
infection. Estrogen replacement leads to improved lubrication and enhancement
of the pleasurable sensations experienced during sexual stimulation.
Lower urinary tract
Estrogen deficiency has been linked to urologic complaints such as frequency,
nocturia, incontinence, urinary tract infections and the urge syndrome. The
increase in prevalence of urinary incontinence with age may be related to the
menopause and diminishing estrogen levels. ERs have been demonstrated in the
urinary tract. Stress incontinence arises when the urethral closure pressure is
exceeded by the intravesical pressure. Estrogen may exert beneficial effects on
the positive urethral closure pressure by a combination of increased urethral cell
maturation and periurethral collagen production, increased blood flow and
increased -adrenoreceptor sensitivity in the urethral smooth muscle. However,

recent studies have shown that the menopause has not been specifically linked to
the onset of stress incontinence and may be only one of several contributing
factors. Contrary to popular belief, estrogen replacement does not appear to help
with stress incontinence. Estrogens may help in the urge syndrome and urge
incontinence by raising the sensory threshold of the urethra and bladder. It is not
clear if estrogens reduce the incidence of lower urinary tract infection.
Skin, connective tissue and cartilage
The menopause may affect all organs containing connective tissue. Estrogen
and
Table 6.3 Effects of estrogen on the cardiovascular system
Beneficial effect on blood lipids and lipoproteins
Positive effect on endothelial cell function
Relaxation of the vascular smooth muscle
Decreased platelet adhesion and aggregation
Effects on coagulation and fibrinolysis
Effects on inflammatory markers
Promotion and maintenance of gynecoid body fat distribution
Improved glucose and insulin metabolism
androgen receptors have been found on dermal fibroblasts, and further work has
demonstrated the presence of receptors in the epidermis, hair follicles, sebaceous
glands and eccrine glands and vessels. Postmenopausal atrophy of the dermis
results from a decrease in the dermal skin collagen content, which declines in the
first five years after the menopause by up to 30%. It has been demonstrated that
skin collagen content and skin thickness are increased in women on HRT
compared to age-matched women on no treatment.
Middle-aged women commonly complain of polyarticular symptoms and this
has fueled speculation that there may be a connection between arthritis and the
menopause. The term menopausal arthritis has been used to describe such
complaints. ERs have been found on articular chondrocytes, but their
significance is not clear. Population surveys and hospital-based studies have
found that the prevalence of generalized osteoarthritis is three to ten times higher
in middle-aged women than in men. Rheumatoid arthritis also shows a striking
age and sex disparity. It appears earlier in women than in men and the female/male
ratio is 2.33.7:1. HRT seems to improve arthritic symptoms, and may be a
useful intervention in maintaining bone health in patients with rheumatoid
arthritis who have an increased risk of osteoporosis. Although it may seem
logical that HRT should be beneficial in maintaining joint health because of the
abundance of ERs in connective tissue, there is no agreement on the role of

HRT, if any, in these two types of arthritis.
Cardiovascular system
ERs have been demonstrated in canine peripheral and coronary arteries, in
cultured rat aortic smooth muscle cells, in baboon myocardium and aorta, and in
human endothelial cells. Vasodilatation in response to estrogen administration
was first noted in the rabbit ear artery and later in primate coronary arteries,
human umbilical and human coronary arteries. It appears that the effect of
estrogen on the cardiovascular system (CVS) is complex, acting via at least eight
different mechanisms that are outlined in Table 6.3.
Progesterone receptors are present in myocardium but the effect of
progesterone on the CVS is less well studied. The influence of estrogen on the
CVS will be discussed in further detail below.
Blood vessels
The response of vessels to estrogen is largely one of vasodilatation. Under the
influence of estrogen, cardiac output increases, systemic vascular resistance
decreases and blood pressure remains unchanged or falls slightly. In healthy
pregnant women estrogen causes increased angiotensinogen levels and renin
activity, and these lead to increased blood volume by a direct effect on volume
through enhanced sodium retention. In the cerebrovascular circulation, there are
gender differences. Before the menopause, cerebrovascular blood flow is greater
in women than in men of the same age. Cerebrovascular blood flow is increased
during pregnancy, when estrogen levels are also increased, but decreases after
the menopause. Estrogen affects the reactivity of cerebral arteries to vasoactive
stimuli such as serotonin.
As yet, the mechanism of estrogens effects on the vasculature has not been
fully elucidated, but several explanations have been proposed, involving either
immediate or delayed effects. Immediate effects are likely to result from nitric
oxide (NO) production and prostaglandin formation from the endothelium and
effects on calcium channels
Table 6.4 Lipid and lipoprotein changes at the menopause
Total cholesterol
by 6%
LDL
by 10%
HDL
by 6%
Triglycerides
by 11%
Apolipoprotein B
Lipoprotein (a)
in the smooth muscle cells of the vessel wall. Longer-lasting effects may involve
reducing angiotensin-converting enzyme activity, inhibition of smooth muscle cell
proliferation and increasing the smooth muscle cell prostaglandin production by
increasing prostacyclin synthetase and cyclo-oxygenase.
The normal effect of endogenous estrogen in premenopausal women, as
described above, is found in postmenopausal women given physiologic doses of
estrogen. Angiographic and ultrasound studies have shown enhancement in the
coronary, brachial and internal iliac artery blood flows and in the
cerebrovascular circulation in response to estrogen. There are reports that
estrogen decreases the size of atherosclerotic plaques in the common carotid
artery as measured by ultrasound scan (USS). The results of angiographic studies
of coronary arteries affected by atherosclerosis are not consistent: after treatment
with estrogen some studies show either no progression or reversal of the disease,
while other fail to demonstrate any effect.
Lipids and lipoprotein metabolism
Premenopausal women have an overall more favorable lipid profile than men,
with lower low-density lipoprotein (LDL) until the sixth decade, lower very lowdensity lipoprotein (VLDL) throughout life, and higher highdensity lipoprotein
(HDL) during postpubertal life. The differences are due to increased
apolipoprotein B100 receptor activity in the cell membrane leading to lower LDL,
more efficient clearance of VLDL, an increased rate of synthesis and a reduced
clearance of HDL. Hepatic lipase activity is higher in men than in women, hence
HDL is lower in men. Estrogen deficiency following the menopause is associated
with adverse changes in blood lipids and lipoproteins. Many studies examining
these changes have shown that there is a significant increase in total cholesterol,
LDL cholesterol and triglycerides and a decrease in HDL cholesterol after
adjustment for age, body mass index and smoking, though not all studies are
consistent. The important HDL2 subfraction was found to be reduced as a direct
result of the menopause and there is an age-related increase of lipoprotein (a) (Lp
(a)) after 50 (Table 6.4).
There are over 50 randomized studies on the effect of estrogen or estrogen/
progestogen on lipid and lipoprotein metabolism in healthy women and in
women with risk factors for (or with clinically established) coronary artery
disease. Some of the studies have compared HRT with a placebo and some with
statins (simvastatin). The studies have consistently demonstrated the ability of
estrogen replacement therapy (ERT) to improve the cholesterol profile
significantly. Typical percentage changes in lipids are given in Table 6.5. There
is little difference between oral conjugated equine estrogens (CEE) and oral
estradiol. Progestogens have to be added on a cyclical or continuous basis in
order to protect against endometrial cancer. Progestogens have an effect on lipids
that, like estrogens, depends on their chemical structure, dose, regiman and route
of administration. Well designed control trials in menopausal women show that
progesterone and dydrogesterone do not oppose the favorable changes in lipid

metabolism induced by estrogen. The antagonism of norethisterone is minimal
and the effect of levonorgestrel seems most pronounced. On this basis, it seems
preferable to use HRT combinations containing dydrogesterone or norethisterone.
The case of medroxyprogesterone is peculiar. In clinical controlled trials where
the endpoint was changes in lipid metabolism, it
Table 6.5 Typical changes in blood lipids (%) following oral hormone replacement
therapy
Estrogen
Estrogen/progestogen
Total cholesterol
510
38
LDL
1520
1015
HDL
1015
310
Triglycerides
2030
1015
showed minimal antagonizing effect on the entrogen-induced lipid changes. In

trials where the end point was cardiovascular morbidity and mortality, the group
treated with CEE and medroxyprogesterone fared significantly worse than those
on placebo, so preparations with medroxyprogesterone are best avoided. We
believe that HRT prescribing should be individualized according to the clinical
condition and the nature of the dyslipidemia, to maximize the benefits and
improve compliance. For example, transdermal estradiol/norethisterone may be
preferable in diabetics, and continuous combined HRT is best avoided in patients
with established ischemic heart disease.
Body fat distribution
Estrogen promotes and maintains the deposition of adipose tissue in the classic
gynecoid pattern of postpubertal females. The ideal waist-to-hip ratio is 0.8 or
less, while a ratio over 1 is abnormal. A waist circumference for women of 89
cm and for men of 102 cm is considered healthy. Based on cohort studies some
researchers suggest lower number ( 80 cm for women and 94 cm for men).
Waist-to-hip ratio measurements and dual-energy X-ray absorptiometry (DXA)
measurements show that there is a postmenopausal shift in fat deposition, with a
significant increase in abdominal (android) and intra-abdominal fat distribution.
This may result from the decline in the estrogen:androgen ratio after the
menopause. This increase in waist-to-hip ratio over time has been shown in women
to be associated with a significant increase in cardiovascular morbidity and
mortality. Reversal of these unfavorable changes has been observed in
randomized controlled trials of HRT.
Glucose and insulin metabolism

Estrogen deficiency leads to decreased insulin output from the pancreas,
decreased insulin elimination and an increase in relative insulin resistance. While
hyperglycemia itself may cause injury to the vascular endothelium, it is insulin
resistance with accompanying hyperinsulinemia that may be a pivotal metabolic
disturbance in the pathogenesis of CHD. Fasting blood glucose and glycated
hemoglobin do not change after menopause. However, HRT decreases insulin
resistance and circulating insulin levels and therefore may be beneficial.
Coagulation and fibrinolysis
It has been shown that increased levels of Factor VII and fibrinogen are risk
factors for cardiovascular disease. The association of those two factors with
cardiovascular death appears to be at least as strong as the association between
cholesterol and cardiovascular death. The menopause itself leads to a 6%
increase in the level of Factor VII and a 10% increase in fibrinogen. Orally
administered 17-estradiol decreases the level of fibrinogen. Estrogen enhances
fibrinolysis in postmenopausal women by reducing plasminogen activator
inhibitor-1 (PAI-1) by 50%. Little is known about the effect of the menopause on
platelet function, but it appears that exogenous estrogen, or HRT, decreases
platelet aggregation adenosine triphosphate release. Transdermal HRT does not
appear to lead to any detrimental changes in the coagulation profile. The effects
of the menopause and HRT on coagulation and fibrinolysis are summarized in
Table 6.6.
The complex relationship between estrogen and coagulation is not fully
understood, and the studies of coagulation are frustrated by:
Table 6.6 Menopause, HRT and coagulation and fibrinolysis
Factor
Menopause
HRT
Fibrinogen
Increase 6%
Decrease
Factor VII
Increase 7%
No change
Factor VIII/von Willebrand Increase
Increase
Antithrombin
Increase
Decrease
Protein C
Increase
Increase
Protein S
Increase
Decrease
PAI-1
Increase
Decrease
t-PA
Decrease
Increase
Platelets
No change
Decrease aggregation
HRT, hormone replacement therapy; PAI-1, plasminogen activator inhibitor-1; t-PA,
tissue plasminogen activator
(1) The use of different laboratory methods;
(2) The effect of tourniquet on sampling;

(3) Disagreement between researchers on the relative importance of coagulation
variables;
(4) Difficulties in dissociating the effects of aging from the menopause;
(5) The participation of some coagulation factors in the acute phase response;
(6) The continuous stream of new discoveries, such as Factor V Leiden,
prothrombin gene mutation, etc.;
(7) The effects of progestogens; and
(8) Differences betwen synthetic and natural estrogens, route of administration
and doses.
Markers of inflamation
The current understanding is that the process of atherosclerosis is to a large
extend an inflammatory process. Some blood markers of inflammation are Creactive protein (CRP), interleukins 1 and 6, E-selection, serum amyloid protein
A and adhesion molecules. These markers correlate well with the severity of
CHD, the transition of stable into unstable angina and the rate of myocardial
infarction (MI) and stroke. The best studied marker is CRP. The reasons for that
are as follows: (1) the development of highly sensitive assays for this protein
allowing the stratification of subjects within the normal range; (2) the fact that
CRP levels are stable over long periods of time with the exception of the time
during an acute infection (approximately 2 weeks); (3) there is no diurnal
variation. CRP was found to be a strong independent predictive factor for
cardiovascular events in healthy women, in women at risk of CVD and in women
with established CVD. In studies, the relative risk of events for women in the
highest as compared to the lowest quartile of CRP was 2.3. It is now accepted
that the predictive values of CRP blood levels for cardivascular events is at least
as good as that of low-density liproprotein. CRP is synthesized in the liver in
response to inflammation. The signal for synthesis is usually mediated via
inflammatory cytokines. The level of CRP in apparently healthy subjects
correlates with the body mass index (BMI). The effect of age and menopause on
CRP is not known. However, the effect of estrogen or HRT is well studied. In all
studies so far 0.625 mg of CEE and 2.5 mg of MPA per day invariably lead to a
substantial (8085%) increase in CRP levels. Oral CEE increase the levels by 48
65% and transdermal estrogen by 310%. It is not clear if HRT stimulates
hepatic synthesis of CRP or systemic inflammation or both. In any case the
effect of HRT on inflammation may help explain the increase in cardiovascular
events observed in HRT users during the first few years of treatment.
Summary
CVD is the main cause of death in the UK: more than one in three people (40%)
die from it. The main forms of CVD are CHD and stroke. About half of all
deaths are caused by CHD and about a quarter by stroke.
A 50-year-old woman has a 31% lifetime probability of developing CHD and
a 17% lifetime probability of dying from CHD. This is the leading cause of death
in postmenopausal women. The prevalence of CHD increases progressively with
age and this may be partly due to estrogen deficiency. This assumption is
biologically plausible and supported by experimental and epidemiologic
evidence. A large meta-analysis of observational epidemiologic data showed a
35% reduction in the incidence of CHD and a 37% reduction in mortality from
CHD in users of ERT. Moreover, this protective effect seemed greater in women
who already had CHD. This wealth of encouraging data prompted a number of
randomized controlled trials. The designs, endpoints and regimens were varied:
some were primary prevention studies, others were secondary. Some used
surrogate endpoints such as changes in coronary artery diameter, others
incidence, morbidity and mortality of CHD. Oral or transdermal estradiol or CEE
were used as the estrogen component either alone or as sequential or continuous
combined HRT with MPA or NETA. In all but one study ERT or HRT were no
better than placebo. In the one trial with positive results, new cases of CHD in
the HRT group were observed. These studies are summarized in Table 6.7. What
are we to make of this divergent results between observational and controlled
studies? In randomized controlled trials subjects are randomly assigned to
treatment and thus possible biases are minimized. In observational trials subjects
who choose to take the treatment may be very different from those that do not.
This fundamental methodologic difference helps to explain the results at least
partially. One possible bias is the so-called healthy-user effect. This means that
observational trials fail to control fully for lifestyle and other health-related
factors that may differ in hormone users and not-users. In observational studies
subjects who choose to take ERT or HRT may be generally healthier and/or have
healthier lifestyles than non-users and this imbalance may lead to an
overestimation of the effect of the treatment and an underestimation of its risks.
Observational studies are also susceptible to compliance bias. It is known that
subjects who are compliant with their treatment tend to have improved outcome
even if the tretment is placebo. It is possible that hormone taking is simply a
marker for better compliance with other lifestyle advice and/or treatments of
CVD. It is also possible that cohort studies do not capture fully early clinical
events. Let us imagine that women are enrolled in a cohort study, information is
collected at baseline and update questionnaires are sent to them every 2 years.
The subject is not on HRT and returns the questionnaire saying so. If she starts
taking HRT shortly after that, say in 23 months time, and proceeds to have an
MI within the next 1218 months for the purpose of the study she would be
misclassified as a non-user having had an MI thus underestimating the hazard of
the treatment. As the Womens Health Initiative (WHI) and Heart and Estrogen/
Progestin Replacement Therapy Follow-up (HERS) trials show, the risk for MI
early in the treatment is higher than overall. There are also biological
explanations that may account for some of the discrepancy in the data between
randomized controlled and observational studies. One explanation is that
different regimens may have different effects. In the nurses Health Study mose
hormone users were on estrogen and those that were on estrogen/progestin were
taking progestins for 1014 days. The estrogen arm of the WHI trial continues.
The implication is that estrogen may still be beneficial and that further research
into different regimens and preparations is necessary. Another biological
explanation is that estrogen may need to be taken early after the menopause in
order to prevent the development of atherosclerosis, rather than after the
establishment of atherosclerotic plaques when estrogen may raise the levels of
inflammatory markers, especially CRP, and destabilize the plaques leading to
clinical events. This possibility is supported by randomized controlled trials on
monkeys. Whatever the explanations are for the current data on HRT and CHD
we have to accept the supremacy of experimentation over observation. On the
basis of this, HRT regimens cannot be prescribed for primary or secondary
prevention of CHD in the populations specified in Table 6.7. However,
randomized controlled trials did not show any benefit in women with established
heart disease. Postmenopausal estrogen use does not affect the blood pressure
and is safe to be administered to hypertensive women, when the hypertension is
under control.
Osteoporosis
One in three women and one is 12 men over the age of 50 years have low bone
density or osteoporosis. It is the major factor for the 70 000 hip, 50 000 wrist and
40 000 spinal fractures seen annually in the UK. As discussed earlier,
postmenopausal osteoporosis represents a major public health issue.
Osteoporosis has been defined as a disease characterized by low bone mass and
micro-architectural deterioration of bone tissue, leading to enhanced bone
fragility and a consequent increase in fracture risk. The development of
osteoporosis depends upon both the peak bone mass attained and its subsequent
rate of loss. Peak bone mass is achieved in early adulthood and is largely (80%)
genetically determined. This has been confirmed in studies comparing bone mass
in twins and in studies of racial groups that have migrated. To some extent, peak
bone mass is influenced by diet, exercise, alcohol consumption, smoking, drugs
(e.g., corticosteroids, contraceptive pills, liver enzyme inducers), parity and the
presence or absence of estrogens. Estrogens seem to have a central role in
regulating bone mass and estrogen-deficient states such as anorexia nervosa,
secondary amenorrhea due to strenuous exercise, use of luteinizing hormonereleasing hormone (LHRH) analogs and the menopause have all been shown to
lead to bone loss.
The development of osteoporosis results from an imbalance between bone

resorption and bone formation and also depends on the peak bone mass. Loss of
gonadal function and aging are the two most important factors. Starting around
the fourth or fifth decade of life, men and women lose 0.30.5% of their bone
mass every year. This is increased in women by up to ten-fold in the early years
following surgical or natural menopause, due to an increase in bone turnover and
bone resorption in excess of bone formation. Women may eventually lose up to
50% of their cancellous bone and 30% of their cortical bone. The speed of bone
loss in later life decreases but continues inexorably into old age. The quality of
bone is impaired, because the bone loss leads to disruption and perforation of the
bone trabeculae which provide strength. After the trabeculae are disrupted
treatment does not lead to their restoration, but merely thickens the remaining
bone. The lifetime risk of osteoporotic fracture for women aged 50 is between 30
and 40% (Table 6.8).
There are several reasons for this gender difference. Women have a lower
peak bone mass than men, lose more bone than men after the menopause and
women fall more often than men. Women have lower muscle mass and lower
agility to prevent the consequences of falls.
Currently, bone density is measured using DXA scanning. The method is
accurate and reproducible with a margin of error of between 0.5 and 1%.
Importantly, because many interventions increase bone density between 0.5 and
3% per year, one year of treatment may not be enough to show treatment-related
changes in the bone density. Bone density varies across different ethnic groups
and geographically and therefore there should be separate reference ranges for
different racial groups. The mean and standard deviation (SD) are established by
measuring bone density in healthy young women. One SD decrease in bone
density leads to doubling of the risk of
Table 6.8 Estimated lifetime risk of osteoporosis (%) in 50-year-old Caucasian men and
women
Site
Men
Women
Hip
6
17.5
Distal forearm
2.5
16
Clinically diagnosed
5
15.6
vertebral fracture
Any of the above
13.5
39.1
Data derived from Melton LJ, Atkinson EJ, OFallon WM, et al. Long-term fracture risk
prediction with bone mineral measurements made at various skeletal sites. J
Bone Min Res 1991; 6(Suppl.1):S136
fracture. The DXA scan results are expressed in two ways, as T-scores and Zscores. Both scores are the standard deviation by which an individual bone
density differs from a reference group. T-scores represent the bone density of the
RR, relative risk; CI, confidence interval; CEE, conjugated equine estrogens; MPA, medroxyprogesterone acetate; HRT,
hormone replacement therapy; MI, myocardial infarction; NETA, norethisterone acetate; CHD, coronary heart disease
Table 6.7 Results of studies investigating the effect of estrogen replacement therapy and hormone replacement therapy
on cardiovascular disease
individual compared with the mean value of young healthy controls, while Zscores represent the bone density of the individual compared to the mean value
of their own age group. In our practice, we tend to use the T-score (young
healthy controls) to assess bone density up to the age of 75. It can be argued that
using the T-score results in too many women being classified with low bone
density or osteoporosis. However, we think that such an argument is not in line
with the measurement of the ventricular ejection fraction of the heart or the
measuring of blood pressure, for example, and does little to increase the
awareness in women of their bone health. Bone density and osteoporosis have
been linked via the following classification from the World Health Organization
(WHO):
(1) Normal bone density: mean 1 SD (T-score l);
(2) Low bone mass (osteopenia): between 1 SD and 2.5 SD below the mean (-1
> T-score > 2.5);
(3) Osteoporosis: 2.5 SD below the mean (T-score 2.5);
(4) Severe osteoporosis: 2.5 SD below the mean (T-score 2.5) plus one or
more fractures.
In the absence of screening for osteoporosis, a case-finding strategy is
recommended.
Qualitative ultrasound is increasingly being used for bone density
measurement. Studies show that there is good correlation between ultrasound
assessment of the bone density and the risk of fracture. Qualitative ultrasound
equipment is much cheaper than DXA scanning, requires no special room for
installation and its maintenance is easier. As clinical data accumulate, it is likely
that qualitative ultrasound will play a much bigger role in the future.
Another way of assessing fracture risk is by monitoring biochemical indices of
bone turnover. There are two types of biochemical markers: of bone resorption
and of bone formation. The markers for bone resorption are hydroxyproline and
the pyridinium crosslinks with their associated peptides. The markers for bone
formation are alkaline phosphatase (total and bone-specific), osteocalcin and the
protocollagen propeptides of type I collagen. In a state of predominant bone
resorption, the markers of resorption increase and with treatment they decrease.
The markers of bone formation are low in osteoporoiss and increase with
treatment. The markers of bone turnover connot be used alone for diagnosing
osteoporosis but in conjuction with BMD measurement could improve fracture
prediction in postmenopausal women. Bone markers are useful in monitoring the
response to treatment in the early stages. Bone density measurement should be
offered to those women who are at increased risk for osteoporosis (Table 6.9) or
for monitoring the response to treatment.
Treatment for osteoporosis

Estrogen therapy is now well established as a prophylaxis for the prevention
of osteoporotic fracture and is also effective in women with established
osteoporosis. Estrogens are thought to affect the bone both directly and
indirectly. The direct actions include: (1) decreasing the number of resorption
pits; (2) stimulating osteoblast activity to produce more type I collagen and
transforming growth factor-; and (3) suppressing production of interleukin-1
Table 6.9 Risk factors for osteoporosis
Family history of osteoporosis
Hip fracture in first-degree relative
Low body mass index (< 19 kg/m2)
Early menopause (under the age of 45 years) (prolonged periods of oligo-amenorrhea
during the reproductive years)
Smoking
Alcoholism
Low-calcium diet
Prolonged immobilization
Rheumatoid arthritis
Chronic liver disease
Malabsorption syndromes
Hyperthyroidism
Hyperparathyroidism
Chronic steroid use (prednisolone 7.5 mg/day or equivalent)
Long-term (> 5 years) inhaled corticosteroids
Cushings syndrome
Radiographic evidence of osteopenia
Previous fracture of spine or wrist with minimal trauma
Table 6.10 Antifracture activity of the most frequently used treatments of
postmenopausal osteoporosis as derived from placebo-controlled randomized trials
Drug
Vertebral fracture
Hip fracture
HRT
Alendronate
Etidronate
Risedronate
Parathyroid hormone
Raloxifene
Calcitonin
Fluoride
Vitamin D
+++
+++
++
+++
+++
+++
+
+
+
++
++
+
++
0
0
0
0
0
Drug
Vertebral fracture
Hip fracture
HRT, hormone replacement therapy; + + +, strong evidence; + +, good evidence; +, some

evidence; 0, no evidence
and -6 and tumor necrosis factor-. All of these actions promote bone resorption.
Indirectly, estrogen is thought to: (1) reduce the level of parathyroid hormone; (2)
enhance the absorption of calcium from the intestine; and (3) increase the
secretion of calcitonin. The minimum daily estrogen doses associated with bone
preservation in early postmenopausal women are 0.625 mg of CEE, 1 mg of
estradiol and 25 g of transdermal estradiol. Apart from estrogen, there are a
number of strategies which are useful in combating this scourge in older women,
with bisphosphonates, calcium and vitamin D, weight-bearing exercise, selective
estrogen receptor modulators (SERMs), calcitonin (parathyroid hormone),
sodium fluoride and testosterone all being employed. There is good evidence
from controlled clinical trials in favor of these treatments, and this is summarized
in Table 6.10. Advice regarding osteoporosis prevention and treatment should be
individualized, according to the patients circumstances, bone density,
preferences and beliefs.
The central nervous system, cognition, Alzheimers disease
and stroke
The brain is a key target organ for gonadal steroids. The gonadal steroids start
exerting their effect on the CNS from the antenatal period onwards, and the effect
probably continues throughout life. The CNS consequences of absolute
menopausal loss of progesterone, the severe depletion of estrogen and the high
levels of LH and FSH that last for 40% of the womens adult life are poorly
understood. However, the permanent changes of the levels of these hormones
may have bearing on both normal and pathologic brain functions.
Estrogen and the central nervous system
ERs have been demonstrated in many parts of the brain, i.e., the cortex, limbic
system, hippocampus, cerebellum and hypothalamus. Estrogen is both
neurotrophic and neuro-protective and able to modify the synthesis, release and
metabolism of neurotransmitters in these areas. It is also believed to influence
dynamic processes whereby neurites are extended, synaptic connections are
formed and neuronal circuits are modeled. Studies of cross-gender hormone
therapy in trans-sexual men and women imply that sex hormones exert effects on
cognition, with estrogen associated with enhanced verbal fluency and
testosterone with better visuo-spatial abilities. Several small observational
studies in healthy women during different phases of the menstrual cycle and of
postmenopausal women receiving HRT have suggested that estrogen can benefit
a number of skills including fine motor abilities, verbal fluency and creativity.
Interventional studies seem to support beneficial effects of estrogen on verbal
memory. The effect is strongest in those with severe menopausal symptoms. The
magnitude of such putative estrogen effects, although modest, may nevertheless
be clinically relevant.
Estrogen and Alzheimers disease
Attention has recently been focused on the role of estrogen deficiency in
cognitive function, and the link, if any, between estrogen deficiency and
Alzheimers disease. Alzheimers disease is a neurodegenerative disease
characterized by cerebral (notably cortical) atrophy, which leads to progressive
memory loss, confusion, disorientation, inability to live normal everyday life
independently and death. Alzheimers disease is the commonest form of
dementia, accounting for 70% of all cases of dementia. Its incidence increases
with age. Its prevalence is 1% at 60 years of age, 3% at 6574 years of age, 19%
at 7584 years of age and 3040% in over 85-year-olds. Alzheimers disease is
the fourth leading cause of death in the USA and represents a huge burden on the
healthcare system.
It is thought that Alzheimers disease is more prevalent in women than in men
(2.5:1), though some studies do not find any gender difference. The key
biochemical and pathologic features of Alzheimers disease are (1) the formation
of senile plaques consisting of amyloid in brain cells; (2) neurofibrillary tangles
where the leading role is played by tau protein and apolipoprotein; and (3)
deficiency of the neurotransmitter acetylcholine. Experimental evidence from
cell cultures and laboratory animals shows that estradiol protects the neurons
from oxidative damage, enhances cholinergic nerve cell survival, promotes
glucose uptake in the brain and protects against -amyloid toxicity. Estrogens
have been demonstrated to increase cholinergic metabolism, which is positively
linked to memory performance. The decline in short-term memory following the
menopause may be attributable to the effects of estrogen deficiency on the
neurotransmitter acetylcholine. Estrogen increases levels of acetyltransferase, the
enzyme involved in acetylcholine synthesis, and thus estrogen deficiency may
lead to reductions of this critical transmitter involved in many cognitive processes
such as attention processing, learning and memory. Estrogen deficiency may also
lead to decreased cerebral blood flow, as discussed above. If estrogen has such
favorable effects on brain cells, then women using estrogen during menopause
would be expected to have a lower risk of Alzheimers disease. Epidemiologic
data, however, are inconclusive. Of the longitudinal studies, the Rancho
Bernardo study found no differences in Alzheimers disease between users and
non-users after 15 years of follow-up. The Manhattan Study of Aging and the
Baltimore Longitudinal Study of Aging found that estrogen use was associated
with a decreased risk of Alzheimer disease after follow-up of 15 years and 16
years, respectively. Case-controlled studies were similarly inconclusive. A meta-
analysis published in 1998 found that estrogen may have some protective effect,
and noted the heterogeneity in the studies. The authors went on to conclude that
estrogen cannot be recommended for the prevention or treatment of Alzheimers
disease.
More data have become available since. The Cash County Memory Study, a
prospective study of incident dementia, followed a cohort of 1889 women for a
mean of 3 years. It found that women who had used estrogen for 310 years
(former users) had a markedly decreased risk of Alzheimers disease (the longer
the use, the bigger the decrease). Among current users, there was no such effect,
event for those taking estrogen for over 10 years. The authors suggest that
estrogen may be effective if taken early in the menopausal years. The effects of
estrogen on women with Alzheimers disease have also been studied. Four
recent controlled trials published in 2002 and 2003 did not demonstrate any
beneficial effect of estrogen compared to placebo. Three of the studies recruited
women with mild to moderate Alzheimers disease and used unopposed CEE 0.
6251.25 mg for 12 weeks to 1 year. In none of the studies did estrogen slow the
disease progression or improve global cognitive or functional outcomes. The
WHI reported on continuous combined HRT (0.625 mg of CEE plus 2.5 mg of
MPA) or placebo and its effect on the incidence of dementia. It recruited 4532
women, 65 years or older and free of dementia, and the follow-up was for a mean
of 4 years. The group on HRT had twice the incidence of dementia than those in
the placebo group. For the moment, despite the biological plausibility and early
promise, the present data indicate that estrogen cannot be recommended for either
the prevention or the treatment of Alzheimers disease. Evidence for a cause and
effect relationship between estrogen deficiency and Alzheimers disease remains
inconclusive and further work will hopefully establish the precise nature of any
relationship.
Estrogen and stroke
Stroke is the third leading cause of death in women, after CHD and cancer. The
incidence of stroke increases with age and is higher in women than in men.
Eighty percent of all strokes are caused by ischemic cerebral infarction, most
often due to emboli arising from atherosclerotic changes in the major arteries
supplying the braincarotids and vertebrals. Stroke shares many risk factors
with CHD: age, hypertension, smoking, diabetes and high cholesterol. Because
observational studies suggested that the risk of CHD in women decreases with
HRT, researchers started to look into a similar association between HRT and
cerebrovascular disease and stroke. Experimental studies using Doppler
ultrasound showed that the cerebral blood flow increases with estrogen
administration. The thickness of atherosclerotic plaques in the carotid arteries as
measured by ultrasound seems to decrease with estrogen treatment. Despite the
similarities between CHD and cerebrovascular disease, the effect of estrogen on
stroke was inconsistent across studies, most showing no effect, while in some
either an increased or decreased risk was noted. Results from randomized

controlled trials show that (1) oral estradiol taken for secondary prevention does
not have any effect on the incidence of new stroke; (2) continuous combined
HRT (0.625 mg of CEE and 2.5 mg of MPA) used by menopausal women with
known CHD for over 4 year did not change significantly the incidence of stroke
although there were more new strokes in the treatment arm; and (3) continuous
combined HRT of the same regimen as above led to a significant increase in the
stroke rate when taken for an average of 5.6 years by previously healthy women.
The results are summarized in Table 6.11. HRT use does not affect the incidence
or severity of hemorrhagic stroke.
The conclusion is that continuous combined HRT (0.625 of CEE and 2.5 of
MPA) leads to more strokes whether given to healthy women or women who
suffered a previous stroke. On current evidence, estradiol seems at best neutral
when taken for secondary prevention.
Colorectal cancer
Colorectal cancer has an incidence of 38 per 100 000 in England and Wales and
is the second most common cancer in women in the UK. It is the third leading
cause of cancer death and constitutes 15% of all cancers. Although colorectal
cancer can occasionally occur at a younger age, most patients are in their sixth or
seventh decade at diagnosis.
The cause of colorectal cancer is unknown but diet, genetic factors,
adenomatous polyps and secondary bile acids have been implicated. The Nurses
Health Study and other cohort studies suggested that postmenopausal hormone
replacement use appeared to decrease the risk of cancer by about 35%, with
current use affording more protection than past use. The protective effect
disappeared five years
Table 6.11 Estrogen replacement therapy/hormone replacement therapy and stroke
Study
Regimen and
mean duration
of follow-up
Treatment arm
(events)
Control arm
(events)
RR (CI)
Viscoli CM, et
al. (2001)8
1 mg oral
estradiol; 2.8
years
0.625 mg CEE
and 2.5 mg
MPA; 4.1 years
0.625 mg CEE
and 2.5 mg
MPA; 6.8 years
339 (99)
327 (93)
1.1 (0.81.4)
1380 (82)
1383 (67)
1.23 (0.891.
7)
1156 (59)
1165 (55)
1.09 (0.751.
57)
Hulley S, et al.
(1998)4
Grady D, et al.
(2002)5
Study
Regimen and
mean duration
of follow-up
Treatment arm
(events)
Control arm
(events)
RR (CI)
Wassertheil0.625 mg CEE
8506 (151)
8102 (107)
1.31 (1.021.
Smoller S, et al. and 2.5 mg
68)
(2003)9
MPA; 5.6 years
CEE, conjugated equine estrogens; MPA, medroxyprogesterone acetate
Table 6.12 Absolute contraindications to hormone replacement therapy
Active
breast cancer
endometrial cancer
other estrogen-dependent tumors
Acute thromboembolic disorder
Acute myocardial infarction
Undiagnosed vaginal bleeding
Undiagnosed breast mass
Severe liver disease
Severe cardiac disease
after discontinuation of hormone use. Possible mechanisms explaining this effect

on bowel cancer include the ability of estrogen to decrease the secondary bile
acid production and its ability to suppress the growth of colonic epithelial cells.
These results have been since confirmed in a randomized controlled trial, the
WHI study. In this trial the incidence of bowel cancer was 10 per 10 000 womanyears on treatment and 16 per 10 000 woman-years on placebo, or absolute risk
reduction was 6 per 10 000 woman-years and relative risk reduction was 37%.
Gums, teeth, wound healing and postural balance
The effects of the menopause and HRT on oral health, wound healing and
balance are less well studied. The data so far show that
Table 6.13 Relative contraindications to hormone replacement therapy
History of
breast cancer
endometrial cancer
liver disease
Previous thromboembolic disorder
Enlarging uterine fibroids
Endometriosis (recurrence)
Estrogen-dependent migraine
ERT prevents tooth loss and gum disease, enhances wound healing and improves
postural balance in postmenopausal women.
CONTRAINDICATIONS AND RISKS OF HORMONE
REPLACEMENT THERAPY
There are remarkably few absolute (Table 6.12) or relative contraindications to
HRT (Table 6.13).
There are many other contraindications and special precautions to be found on
the HRT prescribing data sheets. Usually these are included on the basis of data
from studies of the oral contraceptives or from purely theoretical considerations.
In the view of most experts HRT is not contraindicated for those conditions listed
in Table 6.14. This view was endorsed by the British Menopause Society in a
recent publication.
Table 6.14 Conditions no longer considered contraindications to hormone replacement
therapy
Controlled hypertension
Coronary heart disease*
Varicose veins
History of superficial thrombophlebitis
Otosclerosis
Malignant melanoma
History of cervical cancer
History of ovarian cancer
Benign breast disease
Certain regimens may be contraindicated. Data derived from Rees M, Purdie DW.
Management of the Menopause. The Handbook of the British Menopause
Society. London: BMS Publications, 1999:39
Risks of hormone replacement therapy

Breast cancer
The widely discussed possibility that HRT leads to an increase in the risk of
breast cancer has been responsible for much of the controversy surrounding the
treatment. The data available from observational studies are widely disparate. A
recent meta-analysis of 90% of the available world breast cancer data (over 52
700 cases and 108 000 controls) has to a large extent overridden the individual
studies and has made counseling women easier (Table 6.15). The study has
estimated the background risk of breast cancer incidence in 50- to 70-year-old
women at 45/1000 women and has shown significant increases in breast cancer
incidence among HRT users. However, this increased risk returned to
background levels within five years after discontinuation of therapy. The study
reported that body mass index is an independent risk factor for breast cancer: the
higher the body mass index, the higher the risk. An important but often
overlooked finding was that the excess risk of breast cancer attributed to HRT
was confined to women with a BMI of less than 25 kg/m2. The two findings
above have subsequently been confirmed in another study. The increase in the
relative risk of breast cancer with HRT can be calculated for each year of HRT
use. It would seem prudent, therefore, to assess both the potential benefit of
using HRT and the risk of developing breast cancer in the case of each
individual woman. The addition of a progestogen does not decrease the risk of
breast cancer and if anything it may lead to slight increase in the risk. HRT
increases the density of the breast tissue and may decrease the sensitivity of
screening mammography. The Nurses Health Study reported an increase in risk
of dying from breast cancer among users in comparison to non-users, but many
studies have reported exactly the opposite. It is conceivable that HRT use may
lead to lower death rate because (1) women taking HRT may be healthier at the
outset, (2) HRT users tend to have lower all-cause mortality than non-users, and
(3) breast cancer striking women on HRT may behave differently with less
incidence of lymph node involvement and distant spread. The WHI trial had a
secondary endpoint, i.e., the incidence of breast cancer. There was a 26%
increase (38 versus 30 per 10 000 woman-years) in the HRT group and no
difference in the risk of in situ cancer or breast cancer mortality between the
groups.
Endometrial hyperplasia and endometrial cancer
Unopposed use of estrogen increases the risk of endometrial hyperplasia and
endometrial carcinoma. The longer the duration of treatment and the higher the
estrogen dosage, the higher the risk. The incidence of endometrial hyperplasia is
20, 50 and 62% after one, two and three years use of 0.625 mg/day of CEE,
whereas the background rate of this condition is between 0.5 and 2% a year.
Similarly, there is a three- to ten-fold increase in the incidence of endometrial
cancer with unopposed estrogen, depending on the duration of use. Sufficient
doses of progestogen, given cyclically for 1214 days, largely eliminate the risk
of endometrial hyperplasia and cancer, but there are studies suggesting that the
risk is not completely abolished. Continuous combined HRT offers the best
endometrial protection and may even decrease the risks of endometrial
Table 6.15 Relative and absolute risks of breast cancer with hormone replacement therapy
(HRT)
Current HRT users: RR=1.023 per year of use
Long use (~ 11 yrs): RR=1.35
For each year of delayed menopause: RR=1.028
Absolute risk: age 5070

Year]s of use
Cases per 1000
Extra cases per 1000 HRT

users
Never used
45
0
5 years of use
47
2
10 years of use
51
6
15 years of use
57
12
RR, relative risk. Data derived from Collaborative Group on Hormonal Factors in Breast
Cancer. Breast cancer and hormone replacement therapy: collaborative
reanalysis of data from 51 epidemiological studies of 52 705 women with
breast cancer and 108 411 women without breast cancer. Lancet 1997;350:
104759
hyperplasia and carcinoma to below those seen in an untreated population.

Therefore, in women with a uterus, progestogens must always be prescribed for
at least 1214 days every month or continuously. Recommended oral doses for
endometrial protection in sequential regimens are:
(1)
(2)
(3)
(4)
Norethisterone: 0.72.5 mg;

Norgestrel: 75150 mg;
Dydrogesterone: 1020 mg;
Medroxyprogesterone: 510 mg.
Endometrial protection can be achieved by inserting a levonorgestrel-releasing

intrauterine device (Mirena) or by intravaginal progesterone administration
(Crinone gel). Progesterone pessaries (Cyclogest) and oral micronized
progesterone (Utrogestan) can also be used, but are not licensed for this
indication in the UK. With monthly sequential HRT, 7090% of women will
have vaginal bleeding, which commonly starts after the ninth day of progestogen
and should be no heavier than a normal period. With continuous combined HRT,
about 5080% of women will stop bleeding after 12 months of treatment.
Irregular bleeding associated with HRT use is a common cause of anxiety among
women and their doctors and often leads to discontinuation of HRT. The initial
approach should include assessment of the problem via history taking and clinical
examination. Although the causes of vaginal bleeding are numerous
(Table 6.16), in most cases the bleeding is caused by HRT and not by disease, or
can be due to poor compliance, altered gastrointestinal absorption or a drug
interaction.
When pathology is absent, a change of regimen, medication or dose may be
enough to eliminate the problem. However, endometrial assessment is advised if
there is:
(1) Heavy withdrawal bleeding;
(2) Prolonged withdrawal bleeding;

(3) Breakthrough bleeding for two or more consecutive cycles;
(4) Bleeding in women on continuous combined HRT starting after a period of
amenorrhea;
(5) Bleeding continuing for six months after starting continuous combined
HRT.
Endometrial assessment is by means of vaginal USS and endometrial biopsy, but
occasionally hysteroscopy may be necessary. On USS, endometrial thickness,
double layer, of 4 mm or less excludes endometrial carcinoma. Endometrial
biopsy is an outpatient
Table 6.16 Causes of postmenopausal bleeding
(1)
(2)
(3)
Malignant lesions
(a) Endometrium
cancer
endometrial hyperplasia
(b) Other malignancy of the genital tract
vagina
vulva
uterine sarcoma
rarely associated with fallopian tube or ovarian cancer
Non-malignant lesions of the genital tract
atrophic endometrium, vagina and/or cervix
polyps
fibroids
endometritis, cervicitis
vulvar lesions
trauma
parasitic infections
Other sources of bleeding outside the genital tract
urethral (urologic system: urethral cruncle, cystitis, etc.)
rectal (and intestinal diseases): hemorrhoids, rectal neoplasm, etc.
Table 6.17 Hormone replacement therapy and deep venous thrombosis

Risk
Non-users
RR for DVT
1.0
RR for PE
1.0
Absolute for DVT
913/100 000
Absolute for PE
< 1/100 000
RR, relative risk; PE, pulmonary embolism
Users
2.13.6
2.1
2635/100 000
23/100 000
procedure and commonly used devices are Pipelle and Vabra. Its limitations are
that it is a blind procedure, samples between 4 and 40% (Vabra) of the
endometrial surface, may miss a polyp and can cause discomfort or pain.
Sometimes the procedure is not possible to perform because of pain or tight
cervical sclerosis, or does not provide an adequate sample. In those cases,
hysteroscopy and dilatation and curettage (D&C) should be considered. For
women on sequential therapy, the ultrasound should be performed immediately
after the withdrawal bleeding because the endometrial thickness depends on the
phase of the therapy. If the ultrasound scan shows an endometrial thickness < 4
mm, further assessment may not be necessary. If the endometrial thickness is > 4
mm, an endometrial biopsy should be performed. Ultrasound is a very good
technique for assessing women on continuous combined HRT. Endometrial
biopsy in such patients may not yield any sample.
Thromboembolism
The effects of HRT on hemostasis are complex, and recent observational and
randomized controlled studies have shown a two- to three-fold increase in risk of
venous thromboembolism (VTE) in current users of HRT (Table 6.17). Deep
venous thrombosis (DVT) is the commonest form of VTE and in 10% of cases it
may lead to pulmonary embolism (PE). The mortality of PE is 12%.
A substantial proportion of thromboembolic episodes occur in women with
disorders of coagulation, for example deficiency of antithrombin, protein C or
protein S, APC resistance/Factor V Leiden, or G20210A prothrombin gene
mutation. These conditions tend to run in families and are known as familial
thrombophilias. The prevalence of thrombophilia in healthy individuals and in
those with VTE is summarized in Table 6.18.
Table 6.18 Prevalence of thrombophilia in healthy individuals and those with venous
Thrombophilia
factor
Prevalence in
healthy population
(%)
Prevalence in
patients with VTE
(%)
RR of thrombosis if
thrombophilia
factor present
Factor V Leiden
Prothrombin G
20210A gene
mutation
Protein S deficiency
Protein C deficiency
Antithrombin
deficiency
5
3
40
616
5
25
2
0.3
0.02
4
35
1
2
>10
2550
Table 6.19 Features suggestive of familial thrombophilia

Family history of VTE
First episode at an early age (< 45 years)
Recurrent VTE
Unusual site of thrombosis, e.g., cerebral, mesenteric
Thrombosis during pregnancy or puerperium or use of COC or HRT
Spontaneous venous thrombosis without environmental or acquired risk factor
Recurrent superficial thrombophlebitis
Pulmonary embolism
Unexplained stillbirth
Unexplained spontaneous abortions ( 3)
VTE, venous thromboembolism; COC, combined oral contraceptive; HRT, hormone
replacement therapy
If there are historic features suggestive of thrombophilias (Table 6.19), a

coagulation screen should be performed before prescribing HRT. In women with
thrombophilia, HRT is contraindicated. In cases where long immobilization is
expected, such as fracture or peri-operatively, HRT needs to be terminated. In
cases of long distance travel the standard advice is to keep well hydrated, move
around or exercise the legs frequently and wear compressive hosiery.
Hormone replacement therapy and endometriosis
Women with a history of endometriosis often require extensive counseling
regarding the risk of recurrence with HRT. They may be reassured that such a
risk is mainly theoretical and rather remote. Indeed, the current accepted medical
treatment for endometriosis is LHRH analogs with add-back HRT.
Hormone replacement therapy and fibroids
There is a theoretical possibility that HRT may lead to enlargement of fibroids,
because they are hormone- and, especially, estrogen-dependent. Evidence for
this fact is that fibroids commonly enlarge during pregnancy and that treatment of
fibroids with LHRH analogs is effective and is often practiced before surgical
intervention. However, we have not found this to be a problem and in our clinic
we reassure women that HRT is unlikely to lead to recurrence or enlargement of
fibroids. We recommend that fibroids are monitored by USS, twice in the first
year of HRT and then yearly.
PRESCRIBING HORMONE REPLACEMENT

THERAPY
Compliance
Prescribing HRT is complicated by the difficulties in persuading an apparently
healthy population of women to take a treatment for a considerable period of
time with the aim of preventing potential illnesses later in life. Compliance with
HRT, although often good in the short term, is usually poor in the longer term.
This is due to a combination of factors including adverse side-effects, fears over
breast cancer and poor understanding of long-term HRT benefits from sustained
use. Almost 40% of women advised to start HRT for bone density preservation
had discontinued treatment within eight months of starting in one study, mainly
because of adverse side-effects (see Table 6.20).
Table 6.20 Common side-effects of hormone replacement therapy
Estrogenic
Progestogenic
Breast tenderness/enlargement
Edema/bloating
Headache
Nausea
Leg cramps
Vaginal discharge
Eye irritation
Breakthrough bleeding
Breast tenderness
Bloating
Headache
Acne/seborrhea
PMS symptoms
Depression
Dysmenorrhea
Libido changes
Insomnia
Lethargy
Scalp hair loss
Hirsutism
PMS, premenstrual syndrome
Choice of therapies
Changing the dosage or route of treatment can attenuate certain of the adverse
effects of HRT. Beneficial metabolic effects of HRT have been demonstrated for
the oral and transdermal routes of administration, and both routes have been
shown to be effective in relieving postmenopausal symptoms, as well as
beneficial in preventing postmenopausal bone loss. It is important to emphasize
this to women about to embark on long-term treatment, since better compliance
will usually follow if the patient is allowed free choice of her therapy or is
encouraged to try alternatives if the first dosage or route of treatment is
unacceptable. HRT can be given via various routes (Table 6.21), which should
allow individualization of therapy.
The basic hormonal substances used in HRT preparations are only few, but
various routes of administration and dose permutations have led to more than 50
systemic and topical preparations currently being licenced for use in the UK.
Commonly used estrogens are estradiol, CEE, estrone and estriol. Commonly
used progestogens are dydrogesterone, levonorgestrel, medroxyprogesterone and
norethisterone.
Traditionally, oral routes of administration have been most widely used for
HRT. Long-term compliance with oral regimens has been poor, but with the
advent of better and
Table 6.21 Routes of administration of hormone replacement therapy
Route
Preparation
Oral
Transdermal
Tablets
Patches
Gels
Creams/gels
Rings
Pessaries
Implants
Injection
Spray
Vaginal
Subcutaneous
Intramuscular
Intranasal
less irritant patches, both the oral and the transdermal routes are becoming
increasingly popular and might be expected to encourage compliance, especially
with the introduction of seven-day patches. In a recent study approximately 90%
of women did not miss a single application of a matrix-type seven-day patch
(FemSeven) over a period of 18 months. In addition, the newer matrix patches
seem to represent an improved option over reservoir patches in terms of skin
reactions and improved adhesion.
Knowledge of the pharmacokinetics of oral and transdermal estrogen is useful
in predicting the possible effects of treatment via these two routes. Oral
estrogens are subject to extensive first-pass metabolism before metabolically
active compounds can act systemically. Thus, larger doses are required than with
transdermal delivery systems, which avoid this firstpass effect. Oral estrogen
administration is associated with alterations in bile composition which leads to a
greater degree of gastrointestinal disturbance and increased risk of gallstone
disease. The transdermal route is preferred in cases of chronic liver disease, liver
transplant or history of gallstones. Oral estrogens are known to exert a beneficial
effect on serum lipoprotein levels via their extensive hepatic metabolism, but
recent studies have also shown that transdermal estrogens exert beneficial effect,
albeit to a lesser extent, on cholesterol but to a greater extent on triglyceride

values. Transdermal delivery systems tend to lead to a more stable serum
Table 6.22 Mean estradiol blood levels with various hormone replacement therapy
preparations
Preparation
Dose
Level (pmol/1)
CEE
Oral estradiol
1.25 mg
1.0 mg
2.0 mg
50 g/24 h
100 g/24 h
1.5 mg
3.0 mg
1.0 mg
50 g/24 h
110125
110130
200225
125150
250350
225250
350400
300400
150
Estradiol patches
Estrodiol gel (Oestrogel)
Estradiol gel (Sandrena)
Vaginal ring (Menoring)
CEE, conjugared equine estrogens
estradiol level than with orally administered estrogen, and may be more
appropriate, for example, in women using enzyme-inducing drugs or who
smoke. Cigarette smoking is thought to reduce estradiol bioavailability via its
effect on hepatic metabolism, but since transdermal estradiol avoids first-pass liver
metabolism, it may be less affected than oral estrogen by the effects of cigarette
use. There may be a theoretically lower risk of VTE with transdermally
administered estrogen replacement. Although firm evidence is lacking, it is
possible that patients suffering from conditions such as hypertriglyceridemia,
fibrocystic breast disease or migraine may be better suited to transdermal therapy.
In addition, transdermal therapy is a good alternative for women who prefer not
to take daily oral medication or who absorb medications poorly because of
gastrointestinal malabsorption syndromes (e.g., post-surgery, Crohns disease,
etc.). Often, women ask for a blood estrogen level estimation. Generally, if the
symptoms are controlled, the blood level is likely to be adequate and no estrogen
blood level is necessary. Estradiol blood level measurement is sometimes
indicated in anxious patients, if there are difficulties in symptom control or when
monitoring estrogen treatment for osteoporosis. An estradiol level in excess of
200 pmol/1 is considered satisfactory. Typical plasma estradiol levels reported in
pharmacokinetic studies are given in Table 6.22.
Oral estrogens, including CEE, give wise to plasma estrone levels. Estrone is
310 times less potent than estradiol and is not measured by most laboratories. In
pharmacokinetic studies, usually only estradiol is studied and there are limited
data on estrone. Estrone measurement is unnecessary when prescribing estradiol.
Patient profiling
Patients understanding of the menopause and the benefits of HRT use on their
future health could be improved with dedicated well women clinics, leaflets and
posters in the surgery. The initial assessment should include age of menopause
and type (i.e., natural or surgical), presence of menopausal symptoms and their
severity, risk factors for future heart disease, osteoporosis or other diseases
potentially modified by HRT, and contraindications to HRT. Selection of the
most appropriate dose and route of administration can then be made using the
initial assessment according to the womans individual needs or co-morbid
illness. This should improve patients satisfaction with care, allowing early
intervention and tailoring of therapy, and should improve the take-up and
continued use of HRT. Review of patients should occur at least every six months
to ensure compliance, and more frequent follow-up visits may be necessary if
unacceptable side-effects occur. Treatment can be altered as necessary if there
are significant side-effects, or lack of symptom control. Early and easy access to
a specialized menopause clinic should be offered to any patient with resistant
symptoms or side-effects, or preexistent medical problems that may complicate
postmenopausal hormone therapy. Breast and pelvic examinations should be
performed if clinically indicated and routine mammography (every three years)
should continue while HRT is being used.
Women about to undergo hysterectomy with or without oophorectomy should
be counseled regarding the benefits and risks of HRT by the gynecologist prior to
surgery. A decision regarding the use of HRT should be possible well in advance
of the operation. Good communication between the surgeon and the general
practitioner should avoid delays or interruptions in treatment. Counseling about
Table 6.23 Causes for premature ovarian failure
Idiopathic
Turners syndrome
Autoimmune
Chemotherapy
Familial
Pelvic surgery
Pelvic irradiation
Galactosemia
46XY gonadal dysgenesis
the benefits and possible risks of HRT is particularly important in young women
with surgically induced menopause, since these women are at especially high
risk of future problems, as discussed above.
PREMATURE OVARIAN FAILURE

Premature ovarian failure (POF) is the cessation of normal reproductive function
before the age of 40 and is seen in about 1% of women. Patients may present
clinically with either primary or secondary amenorrhea, or with menstrual
irregularity or with hot flashes, sweats, fatigue, irritability or depression. The
diagnosis is confirmed by the finding of elevated gonadotropin levels, measured
on three separate occasions, one to two months apart. The causes of POF are
numerous (Table 6.23), but they all converge in a common pathway of
accelerated follicular loss. Most cases are idiopathic (about 5560%), the second
in prevalence being Turners syndrome (2025%).
Investigations beyond those confirming POF need not be extensive.
Chromosomal analysis is necessary for women with primary amenorrhea if there
are features suggestive of a chromosomal abnormality. The presence of the Y
chromosome increases the risk of a germ cell tumor. The connection between
POF and autoimmune disease should be considered and periodic screening for
subclinical thyroid disease, adrenal insufficiency, pernicious anemia and
antinuclear antibodies is often practiced. Ovarian biopsy does not add
information which leads to change of management and is not recommended.
The young woman who is found to have POF requires a great deal of
emotional support. Because POF is currently untreatable, it puts the patient at
greatly increased risk of CVD and osteoporosis, and the diagnosis has major
implication for sexual relationships, sex, sexuality and fertility. It is of
paramount importance that patients understand the nature and prognosis of their
condition, not least because it helps their acceptance of long-term hormone
replacement. HRT will minimize the risk of CVD and osteoporosis, will alleviate
menopausal symptoms if present, will bring sexual maturation and development
of secondary sexual characteristics in infantile women and will restore and
enhance sexuality. Often higher than usual doses of estrogen are necessary in
these unfortunate patients. Androgen replacement should be offered to women
who, in spite of adequate estrogen replacement, continue of complain of
persistent fatigue, loss of determination and general well-being, and low sex
drive. Androgen is best administered via subcutaneous implants, 50100 mg
every four to six months. In about a quarter of cases with POF (especially in
idiopathic cases or after chemotherapy) there is spontaneous reversal of the
condition and patients may start menstruating again or even become pregnant. It
may be useful to monitor such patients by stopping HRT every one to two years
for three months and measuring their gonadotropins. However, the fertility
prognosis is generally poor and those patients desiring a family should be
encouraged to think in terms of adoption or egg donation. Provisions for longterm follow-up should be in place to provide continuous support and health
surveillance, and to monitor HRT.
SELECTIVE ESTROGEN RECEPTOR MODULATORS

The search for an even safer alternative to HRT has led to the evaluation of
several compounds, previously referred to as antiestrogens. Initially, these
compounds were used for the treatment of hormonally responsive cancers, such
as breast cancer. Therefore, they were termed antiestrogens. One such
compound is tamoxifen. However, after the realization that postmenopausal
women with breast cancer treated with tamoxifen had lower cholesterol and
increased spinal bone density compared with untreated controls, it became
evident that the term antiestrogen did not fully describe these compounds. The
term selective estrogen receptor modulators (SERMs) has been suggested in
order to define more precisely these substances, which are capable of binding to
and activating ERs, but which have effects on target tissues that are different
from those of estradiol. Newer SERMs are raloxifene, droloxifene and
toremifene. The estrogen agonist/antagonist properties of SERMs are not fully
understood and are difficult to explain. One major mechanism appears to be a
change in the conformation of the ER; another mechanism lies in differences in
recruitment of co-activators and co-repressors; and a third mechanism is by
activation/deactivation of different classes of ERs. For example, raloxifene
seems to activate predominantly ER and only to a lesser extend ER which
accounts for the lack of stimulation of the breast or uterus. For a more detailed
discussion of ERs the reader is referred to Chapter 2. The fundamental concept
behind SERMs is to try and maintain the beneficial effects of HRT while
avoiding its drawbacks, especially with regard to endometrial stimulation, breast
cancer and prothrombotic changes.
The one SERM that has been particularly well studied in radomized clinical
trials in menopausal women and that is licensed for use is raloxifene. It, like
estrogen, reduces bone remodeling in estrogen-deficient early postmenopausal
women and induces a positive calcium balance shift. At 60 mg/day, raloxifene
leads to an increase of bone mineral density in the spine and the hip and a
reduction in vertebral fracture rates. Raloxifene decreases LDL, Lp(a) and
fibrinogen, increases HDL-2, but not total HDL, and has no effect on
triglycerides or PAI-1. During a median of 40 months of treating
postmenopausal women for osteoporosis, there was a 76% reduction in newly
diagnosed invasive breast cancers. Raloxifene does not cause endometrial
stimulation or breast tenderness, but does cause DVT at a rate similar to that of
HRT. The effects of raloxifene on CHD and stroke was studied in the Multiple
Outcomes of Raloxifene Evaluation (MORE) trial, a randomized controlled trial
of menopausal women with osteoporosis. It recruited 7705 patients who were
followed for 4 years. There was no difference in the rates of coronary events or
stroke between the treatment and placebo groups. A subgroup analysis found
that women with a high risk of CHD or stroke may even benefit from the
treatment. Reassuringly, raloxifene does not seem to affect cognitive function.
Overall raloxifene is well tolerated with discontinuation rates in clinical studies
similar to placebo, but it may slightly worsen hot flashes and it can cause leg
cramps in a small percentage of women. It is very likely that in future new
SERMs will be developed and their indications will broaden to include relief of
estrogen deficiency symptoms, prevention of breast cancer, treatment for
fibroids, endometriosis, uterine cancer, etc.
NON-HORMONAL STRATEGIES FOR
IMPROVEMENT OF WOMENS HEALTH IN THE
MENOPAUSE
Bisphosphonates
Bisphosphonates are chemical analogs of pyrophosphate which bind strongly to
bone to exert anti-resorptive effects which lead to improved bone density. They
become incorporated at the site of bone resorption (pits) where they: (1) change
physico-chemical characteristics of the bone and reduce the rate of its
dissolution; (2) reduce the rate of formation of new pits; and (3) exert cytotoxic
effects on osteoclasts. Bisphosphonates are poorly absorbed orally and have to be
taken on an empty stomach. Three types of bisphosphonates are widely used
etidronate, alendronate and risedronate. All three increase the bone mineral
density at clinically relevant site (radius, spine, neck of femur) and decrease the
incidence of fractures. When taken for two years positive changes in bone
density of 38% have been reported. Alendronate is available as a once a week
dose (70 mg) which makes administration even simpler. For many women with
osteoporosis, bisphosphonates may be the treatment of first choice.
Phytoestrogens
Phytoestrogens have a structure resembling estrogen and are found in plants.
They have mixed estrogenic/antiestrogenic properties, the estrogenic effect being
5001000 times less than that of estradiol. There are several different classes of
phytoestrogen, but most prominent in the human diet are phenolic ones
flavones, isoflavones, lignans, coumestans. Isoflavones are the most common
form of phytoestrogens and are found in a variety of fruits and vegetables but are
particularly abundant in leguminous plants and especially soy. The
phytoestrogens found in foods are precursors because they undergo complex
transformation in the gut, being metabolized by the bacteria, and then in the
body. The end result is appearance in the blood of the active constituents:
daidzein, genistein and equol. The daily consumption of isoflavones in Japan and
other Asian communities has been estimated at 2545 mg/day, but it is much less
in the typical Western diet. Observational studies and laboratory experiments
have linked high consumption of phytoestrogens with low incidence of CVD,
osteoporosis and cancer of the breast, colon, prostate and uterus. Those
observational data have various epidemiologic deficiencies and cannot prove a

cause and effect relationship.
The only rigorously tested association is between intake of phytoestrogen and
hot flashes. Randomized controlled trials have shown that phytoestrogens (in the
form of soy flour) have modest activity in curtailing the severity of hot flashes. It
seems, therefore, sensible that menopausal women should be encouraged to
increase their intake of phytoestrogens, which not only may relieve their hot
flashes, but may also have wider health benefits. Daily intake of 2060 g of soy
protein or soy flour has been most widely used in clinical studies, but this may
not be easily achievable in day-to-day life. Phytoestrogen tablets and isolates are
less effective. According to two studies ipriflavone (synthetic isoflavone)
prevents bone loss in postmenopausal women with low bone mass. Other studies
investigating the effects of phytoestrogens on lipid metabolism and the
cardiovascular system demonstrated a decrease in cholesterol and improved
vascular function. No good data is available on phytoestrogens and cancer.
Herbs
Medicinal herbs are crude drugs of plant origin used for treatment of diseases,
often of a chronic nature, or to promote good health. Herbs for treatment of
menopausal symptoms have been available long before the discovery of HRT. A
number of such herbs are currently widely advertised by the health food
industry, which claims improvements in hot flashes, mood and general wellbeing. Some examples are ginkgo (Ginkgo biloba), gingseng (Panax gingseng),
St Johns wort (Hypericum perforatum) and valerian (Valeriana officinalis). Of
these, only St Johns wort has been properly researched and has been shown to
be effective in mild to moderate depression. Its side-effects include
gastrointestinal symptoms, allergic reactions, dizziness, confusion, tiredness/
sedation and a dry mouth. St Johns wort interacts with many medications in a
way which may reduce or potentiate their efficacy and/or plasma concentration,
because it reduces the cytochrome P450 enzyme system. Medications the activity
of which is diminished by St Johns wort are warfarin, cyclosporin, oral
contraceptives, anticonvulsants and digoxin. The effect of triptans (i.e.,
sumatriptan) and selective serotonin reuptake inhibitors (i.e., fluoxetine) is
increased, which leads to increased incidence of adverse reactions. Doctors
should always ask about self-medication, including the use of herbal products.
Natural progesterone creams
Table 6.24 Risk factors for cardiovascular disease (CVD)
Age
Male sex
High low-density lipoprotein cholesterol
Reduced high-density lipoprotein cholesterol
Raised blood pressure

Smoking
Diabetes
Family history of CVD
Obesity
Sedentary life-style
Homocystinemia
are not efficacious in prevention or treatment of osteoporosis. Their role in

abating hot flashes is still under investigation. Indeed, the Medicines Control
Agency issued advice that women using oral contraceptives should not use St
Johns wort because the latter might result in unwanted pregnancy.
Diet, exercise, smoking and weight control
As mentioned earlier in the chapter, coronary artery disease is the leading cause
of death and cerebrovascular disease and stroke is the third most common cause
of death in most developed countries. Women tend to present with less severe
symptoms, but suffer higher mortality and are under-investigated in comparison
with men. Many dozens of putative risk factors have been put under scrutiny
over the years, but the number of proven ones is relatively small (Table 6.24).
Stopping smoking, weight reduction, taking up exercise and proper diet are far
more important interventions on population levels than is treatment with HRT to
decrease the incidence of CHD. During the last two decades the incidence of
CHD has declined, smoking has declined and the diet of many people has
improved. Sadly, the level of physical activity has declined and that of obesity
has vastly increased. Women that do not smoke, have a healthy, varied diet,
exercise and maintain a normal BMI are 8090% less likely to develop CHD
than the general population. So primary prevention of CHD should revolve
around this premise. All women should be given comprehensive dietary advice,
educated to have a diet rich in fruits and vegetables and low in saturated fat, and
should be encouraged to try and maintain a cholesterol level appropriate for their
age. Evidence from cohort studies suggests that eating more fruit and vegetables
reduces the risk of heart attack and stroke. Eating fish, especially oily ones, is
also beneficial. Dietary modifications in older age are often difficult to achieve
and sustain even in patients with significant obesity and hypercholesterolemia.
Therefore education about diet should start early in life. A diet rich in calcium
and vitamin D helps with sketetal integrity after the menopause. This is more
important for citizens of northern countries such as the UK, where the cutaneous
synthesis of vitamin D is suboptimal because of insufficient exposure to
sunlight. An additional 1.0 g of elementary calcium has been recommended after
the menopause but the value of such supplementation is questionable with a wellbalanced diet. The recommended daily intake of vitamin D is 400 IU (10 mg), but
700 IU of vitamin D may be advisable for citizens of northern countries who

have little sunlight exposure. Sources of vitamin D are oily fish, egg yolk, liver,
butter, fortified milk and margarine. Sources of calcium are listed in Table 6.25.
Physical activity (moderate level of activity daily for 30 min) leads to 3050%
reduction in relative risk of CVD compared with people who are sedentary, after
adjusting for other risk factors. The bone protection benefit of weight-bearing
exercise is well established in the hip and it should be encouraged in
postmenopausal women. Physical activity may bring a number of other health
benefits (Table 6.26), and should be encouraged. The link between obesity and
cancer mortality can be considered well established. Recent data suggest that
obesity is responsible for 20% of all cancer deaths in the USA.
Smoking is strongly related to overall mortality and especially increases the
risk of CHD and stroke. The risk of CHD and stroke
Table 6.25 Calcium content of some foods*
Food
Calcium
Cheddar cheese
Milk
Yogurt
Cottage cheese
Butter
Canned sardines in oil
Haddock
Bread
Spinach
Broccoli
Green beans
Baked beans
Carrots
Peas
Orange
Almonds
*All entries expressed as mg per 100 g portion
674
120
180
60
24
550
55
75
93
100
86
45
37
26
51
234
Table 6.26 Some conditions for which exercise is beneficial

Cardiovascular disease
Diabetes
Fracture risk
Poor postural balance
Colorectal cancer
Breast cancer
declines rapidly in both men and women two to four years after stopping
smoking. Hypertension is undoubtedly a major risk factor for CHD and stroke. In
people with essential hypertension, some modest reduction of the blood pressure
and the risk of complications can be achieved with non-pharmacologic measures
such as exercise, a low fat/high fruit and vegetable diet, reduced alcohol
consumption, salt restriction and weight loss. There is no good evidence about
the effect of magnesium supplements. The role of antioxidants has not been well
defined. One systemic review of epidemiologic studies found a consistent
association between increased dietary or supplementary intake of vitamin E and
lower cardiovascular risk and a less consistent association for -carotene and
vitamin C. A randomized controlled trial using 500 mg of vitamin C and 400 IU
of vitamin E (n=108) or placebo (n=105) did not find any effect on coronary
artery stenosis after a mean of 2.8 years of follow-up. The Heart Protection
Study, a double-blind placebo-controlled trial of 20 536 subjects aged between
40 and 80 years, randomized patients to 600 mg vitamin E, 250 mg vitamin C
and 20 mg -carotene daily or placebo. After a follow-up of 5 years no
differences were noted between the groups with regard to fatal and non-fatal MI,
stroke, cancer or overall mortality. Both these studies were published in 2002.
This is in concordance with earlier studies, some of them big (n > 29 000) and
long (follow-up > 12 years), not showing beneficial effects of supplements. The
fact that HRT and vitamins and antioxidants are not as effective as previously
thought does not leave our patients short of options. As mentioned earlier
lifestyle interventions are excellent for both primary and secondary prevention of
CVD. For secondary prevention of CHD and stroke, treatment of hypertension,
diabetes, high cholesterol and other risk factors with diuretics, -blockers, ACE
inhibitors, calcium-channel blockers, statins, antiplatelet agents, etc. is safe, well
established and proven intervention that decrease both morbidity and mortality.
SUMMARY
The physiologic changes in women around and after the menopause are complex
and not completely understood. Some of these changes are due to the aging
process and some undoubtedly have a hormonal basis. The normal menopause
occurs because of aging (not the other way around) and for some time it was
widely thought that the clock can be turned back by use of HRT. This belief may
have been over-optimistic, but it was not frivolousthere was a mountain of
experimental and observational data to support it. Estrogen was thought to
prevent CHD, improve mood, cognition, sexuality and well-being, delay the
onset or change the severity of Alzheimers disease and improve stress
incontinence. This was on top of the well known effects on the bone, vasomotor
symptoms and urogenital atrophy. The
Table 6.27 Absolute differences in the rates of major, potentially fatal diseases per 10 000
postmenopausal women per year from western countries using HRT based on results from
randomized trials
Disease
Differences in events
Coronary heart disease

8
Stroke
8
Pulmonary embolism
8
Invasive breast cancer
8
Hip fracture
5
Colorectal cancer
6
Total mortality
No difference
HRT, n=10872; placebo, n=10 437; of those on HRT 91% were on 0.625 mg of CEE and
2.5 mg of MPA and the rest on estradiol
pharmaceutical industry responded with developing numerous estrogenic agents,

regimens and routes of administration. Hormonal preparations were widely
prescribed and poor compliance lamented by doctors and policy makers. With
the results of a number of randomized controlled trials being published the
current state of affairs is changing. The main conclusions are that: (1) the results
are not immediately generalizable to all women and for all HRT preparations; (2)
for many women the risks overweight the benefits; (3) women with established
CHD or stroke should not take certain continuous combined HRT preparations;
(4) the absolute risks of HRT are small; (5) some suspected benefits are now
established, e.g., on incidence of hip fracture and bowel cancer; (6) women
should not start HRT with the sole aim of preventing CHD; (7) in normal women
with mild or no vasomotor symptoms continuous combined HRT (0.625 mg of
CEE and 2.5 mg of MPA per day) does not improve quality of life in terms of
sleep, sexual or cognitive function or body pains; (8) hot flashes are not deadly,
but can be very disabling and short-term use (23 years) of HRT in healthy
women is safe and effective treatment to relief this symptom. Table 6.27 gives a
summary of risks and benefits of HRT based on most published controlled trials.
REFERENCES
(1) Herrington DM, Reboussin DM, Brosnihan KB, et al. Effects of estrogen replacement
on the progression of coronary artery atherosclerosis. N Engl J Med 2000;343:5229
(2) Waters DD, Alderman EL, Hsia J, et al. Effects of hormone replacement therapy and
antioxidant vitamin supplements on coronary atherosclerosis in postmenopausal
women. J Am Med Assoc 2002;288:243240
(3) Clarke SC, Kelleher J, Lloyd-Jones H, et al. A study of hormone replacemtn therapy
in postmenopausal women with ischemic heart disease: the Papworth HRT
Atherosclerosis Study. Br J Obstet Gynecol 2002; 109: 105662
(4) Hulley S, Grady D, Bush T, et al. Randomized trial of estrogen plus progestin for
secondary prevention of coronary heart disease in postmenopausal women. J Am
Med Assoc 1998; 280:60513
(5) Grady D, Herrington D, Brittner V, et al. Cardiovascular disease outcomes during 6.8
years of hormonal therapy. Heart and Estrogen/Progestin Replacement Therapy
Follow-up (HERSII). J Am Med Assoc 2002;208: 4957
(6) The ESPRIT team. Oestrogen therapy for prevention of reinfarction in
postmenopausal women: a randomised placebo controlled trial. Lancet 2002;360:
20018
(7) Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus
progestin in healthy postmenopausal women: principal results from the Womens
Health Initiative randomized controlled trial. J Am Med Assoc 2002; 288:32133
(8) Viscoli CM, Brass LM, Kerman WN, et al. A clinical trial of estrogen replacement
therapy after ischemic stroke. N Engl J Med 2001; 345: 12439
(9) Wassertheil-Smoller S, Hendrix S, Limacher M, et al. Effect of estrogen plus
progestin on stroke in postmenopausal women. The womens Health Initiative: a
randomized trial. J Am Med Assoc 2003;289:267384
7
Sexually transmitted infections and common
genital tract infections
Alison Stirland, Chris Wilkinson and Nikolai
Manassiev
INTRODUCTION
Sexually transmitted infections (STIs) and their sequelae such as infertility and
chronic pelvic pain cause significant physical and psychologic morbidity. The
diagnosis of an STI affects well-being, self-confidence and personal
relationships.
Many of those infected are unaware that they have an STI, as symptoms are often
absent or non-specific. STIs are frequently multiple, so the presence of, say,
warts or gonorrhea should lead the practitioner to consider other infections, such
as chlamydia. Many factors can lead to the individual to delay or avoid seeking
treatment, including embarrassment, fears of stigma, concerns about
confidentiality, lack of awareness of STIs and ignorance or denial of the risk of
infection. Prompt diagnosis and treatment of STIs is, however, important for
both personal and public health as it reduces that chance of the individual
developing complications and transmitting the infection(s) to others. The
presence of some STIs (gonorrhea, herpes, syphilis, chancroid) leads to
disruption of the surface barriers of the body (skin, mucosa) and facilitates HIV
transmission. Thus, detecting and treating STIs also reduces the incidence of
HIV.
The transmission of STIs can be lowered by changes in sexual behavior
(abstinence, mutual monogamy and safer sex practices) and infection control
programs (screening, early diagnosis, treatment of those infected, contact tracing
and immunisation).
The burden of STIs is notoriously difficult to estimate. It varies according to
the population studied, i.e., sex, age, race, occupation, education, rural, urban or
inner city area are all important factors. The rates seen at genitourinary medicine
(GUM) clinics are higher than those seen at general practice. Many infection
episodes are asymptomatic so any reported rate is likely to underestimate the real
situation. Some recent epidemiologic data are depicted in Table 7.1.
SEXUALLY TRANSMITTED INFECTIONS 177
Table 7.1 New cases of STIs seen at genitourinary medicine clinics (England 2001) and new
sexually acquired HIV infections (UK 2001)
Cases (n)
Sexually
transmitted
infection
Male
Rate per 100 000 individuals aged

1544 per year
Female
Male
Female
Uncomplicated 15 476
6642
153
65
gonorrhea
Uncomplicated 29 166
38 248
288
373
chlamydia
Herpes simplex 6492
10 558
64
103
(first attack)
Genital warts
32 636
29 568
323
288
(first attack)
Infectious HIV 598
98
6
0.95
Data derived from New Cases seen at Genitourinary Medicine Clinics: England 2001.
Public Health Laboratory Service (PHLS) Communicable Disease Report,
2001 and the Population Estimates Unit, Office of National Statistics, UK. HIV,
human immunodeficiency disease
GENERAL CONSIDERATIONS
Managing sexually transmitted infections in primary care
In the UK, GUM clinics have the best facilities for diagnosing and managing
STIs. Attending a specialist clinic, however, may not always be practical or
acceptable. Basic management of common STIs and other genital infections lends
itself to protocols and so readily falls within the scope of appropriately trained
doctors and nurses working in general practice and family planning. The ability
to manage STIs in primary care is rapidly increasing with recent advances in
diagnosis and single-dose therapy. Nucleic acid amplification techniques
(NAATs), polymerase chain reaction (PCR) and ligase chain reaction (LCR) are
increasingly available. They are more sensitive than many antigen and culture
tests and are less dependent on rapid transport to the laboratory than cultures.
Effective single-dose antibiotic therapy is now available for some STIs
(gonorrhea and chlamydia) and for other non-sexually transmitted genital
infections (candidiasis and bacterial vaginosis (BV)).
The diagnosis of an STI can have a major impact on the personal life and
health of a patient. While making a positive diagnosis is important, so is reliably
excluding STIs. It is therefore vital that quality standards are applied to the
whole process of managing STIs (Table 7.2). To ensure that their patients can
access the full range of services, it is important that individual practices have
links with local GUM clinics and microbiology laboratories.
When to refer to genitourinary medicine services

Patients should be referred to a GUM clinic when a specialist service or an
expert opinion is required. On-site microscopy at GUM clinics enables
presumptive diagnoses of gonorrhea and syphilis and definitive diagnoses of
candidiasis, trichomonas and BV to be made at the first visit. These clinics have
facilities
Table 7.2 Management of sexually transmitted infections
History and examination
Sexual history
Gynecologic history
Genital, pelvic and abdominal examination
General physical examination including mouth and skin, if indicated
Investigations/diagnosis
Decide
which diagnostic test should be taken and when?
which site(s) to sample
Optimize quality of specimens
good sampling
appropriate transport media
correct storage and rapid transport of specimens to laboratory
Treatment
Ensure correct treatment is given, taking into account local antibiotic resistance
patterns and possibility of pregnancy
Consider epidemiologic treatment
Partner notification (contact tracing)
Counseling (emotional and sexual difficulties)
Patient information (verbal and written)
Confidentiality of service
Limitations of testswhich diseases have been tested for
Sequelae of infection
Effect of disease and its treatment on pregnancy and contraception
Transmission to partners (safer sex, asymptomatic shedding of herpes and wart virus)
Advise abstinence until partner(s) fully treated
Health promotion (strategies to reduce the risk of re-infection)
Follow-up
Carry out test of cure if indicated
Enquire about patient compliance (medication and abstinence)
Ascertain if partner(s) treated
Administration
Practice confidentiality policy

Liaison with local laboratory and genitourinary medicine service
Regular review of practice and audit
to inoculate culture media for gonorrhea, herpes and trichomonas directly,

optimizing sensitivity. Therefore referral to a GUM clinic is recommended for
patients with genital ulceration, suspected gonorrhea and recurrent vaginal
discharge. Patients with conditions
Table 7.3 Establishing the sexual history of a patient
Question
Relevance
Number of partners
Regular partner(s)
Non-regular partner(s) in the last 3 months
For each partner
Partners gender and the nature of the
sexual contact (i.e., receptive or insertive;
vaginal, oral or anal intercourse)
Length of relationship/date of last sexual
contact
Condom use
Establishes the risk of STIs and facilitates

partner notification (if an STI is detected)
Establishes the risk and nature of a

potential STI and indicates which site to
test
Together with incubation periods,
provides a guide when to perform tests
Establishes the risk of STIs and provides
an education and counseling opportunity
Partners symptoms or diagnosis
Risk of STI, choice of test*
Overseas contact
Consider tropical diseases and resistance
to gonorrhea therapy
*For example, if partner has symptoms suggesting gonorrhea, practitioner should
consider testing multiple sites, repeating negative tests or offering
epidemiologic treatment. STI, sexually transmitted infection
requiring specialist tests or treatment such as tropical diseases and syphilis

should also be referred. Patients with warts should be offered referral to a GUM
clinic for treatment, especially if they are pregnant or do not wish to use
podophylotoxin at home.
Referral to or liaison with the health advisor at the GUM clinic should be
considered for partner notification (contact tracing). Health advisors also provide
counseling and health education. Finally, patients may prefer the relative
anonymity and confidentiality of a GUM clinic if they feel uncomfortable
consulting their usual practitioner about an STI or sexual difficulty.
Sexual history
Patients are unlikely to object to questions about their sexual relationships and
previous STIs if they appreciate their relevance, especially if they perceive
themselves to be at risk of infection. Seeking permission to ask personal

questions, reassuring about confidentiality and only seeking information that will
affect management, increases the acceptability of taking a sexual history
(Table 7.3).
The use of gender-neutral terms such as partner is helpful, as the women
may be lesbian or bisexual. Some infections such as trichomonas can be spread
between women, especially if sex toys are used, and some lesbians may be at risk
of STIs from heterosexual contact in the past. Lesbians do not require
contraception and so are less likely to attend family planning and well-women
sessions. They should be offered STI testing and cervical cytology examination
as appropriate. It is recognized that the comfort level and skills to talk about sex
may vary between practitioners and their relationships with patients.
Women who report sexual assault should be offered referral for both forensic
(if they have not already reported the incident to the police) and clinical
examination. If the woman chooses to have a forensic examination, it should be
performed before the clinical examination. Assessment centers, known as rape
suites, exist in some areas and are usually located in hospitals or police stations.
They specialize in the forensic assessment of both male and female victims of
sexual assault. According to the womans history, knowledge of the assailant and
nature of the
Table 7.4 Testing for sexually transmitted infections (STIs): indications
On demand
Identified risk
Clinical features of STI
Under 25 years of age
New partner in previous 6 months
More than one partner in previous 12 months
High-risk partner (e.g., symptomatic or has an STI or multiple partners)
Recent history of an STI (consider re-infection)
Before clinical procedures
termination of pregnancy
IUD insertion
other intrauterine procedures
(laparoscopy and dye injection, hysteroscopy, hysterosalpingogram, endometrial
biopsy, dilation and curettage)
IUD, intrauterine device
assault, clinicians should offer emergency contraception, hepatitis B vaccination

and testing or prophylactic treatment for STIs and HIV. Counseling and referral
to support organizations should also be offered.
Who to test for sexually transmitted infections

Symptoms and signs of genital infection are not specific and may be absent.
Therefore women should be tested on request, if at risk (Table 7.4), or if they
have clinical features of STIs (Table 7.5). Recommendations on screening await
the outcome of pilot studies conducted by the Department of Health in the UK.
A woman may request STI testing for many reasons. She may be concerned
about being infected by a specific partner, planning a pregnancy or seeking a
check-up before starting a new relationship or discontinuing condoms.
Awareness of the incubation periods of diseases is important in timing tests for
STIs and in interpreting results. If a patient presents for testing during the likely
incubation period, infection cannot be excluded. In these circumstances, it may
be advisable to defer or repeat testing according to the risk of infection
Table 7.5 Clinical features of genital infections including sexually transmitted infections*
Vaginal or urethral discharge
Vulval or pubic pruritis
Genital malodor
Vulval or peri-anal pain
Lesions (ulcers or lumps)
Dysuria
internal (urethral or bladder pain)
external (urine in contact with inflamed vulva)
Dyspareunia (superficial or deep)
Abdominal or pelvic pain and tenderness
Abnormal bleeding
intermenstrual
postcoital
contact bleeding from cervix
Inflammation of vulva, vagina, cervix, peri-anal area and anal canal
Signs of pelvic inflammatory disease
Cardinal
cervical excitation
uterine or adnexal tenderness (usually bilateral)
Additional signs (may be present but are not essential for diagnosis)
pyrexia (oral temperature > 38.3C/> 101F)
adnexal mass
lower abdominal tenderness
peritonism
cervical or vaginal mucopurulent discharge
*Note: the absence of symptoms or signs does not exclude a sexually transmitted
infection
and the likelihood of her returning for follow-up. For example, if a woman
presents a week after having unprotected intercourse with a new partner it may
be possible to detect gonorrhea but too soon for a chlamydia test to be reliable.
However, it may still be useful to test for chlamydia as she may have a preexisting infection, and, if negative, to repeat the test after the incubation period.
It is important to explain to the patient which diseases are (and which are not)
being tested for. Although a clinical diagnosis can be made from the lesions of
warts or herpes, it is impossible to say, with routine tests, that a patient is not
carrying herpes simplex or wart virus. The patient should also be informed of the
limitations of testing, as both false-positive and false-negative results can occur.
An awareness of the positive and negative predictive values of tests, such as
chlamydia antigen detection, can be useful in interpreting the results as the
predictive values depend on the population prevalence. The local laboratory can
provide information on the accuracy of their diagnostic tests.
MAKING A DIAGNOSIS
Examination and testing of the genital area
Specimens for STI tests are taken during examination of the genital tract. In
order to optimize the quality of the samples, it is suggested that the tests are
taken according to the manufacturers instructions and in the sequence set out
below.
Inspect the vulval, pubic and peri-anal areas first, then pass a speculum into
the vagina. If there are lesions at the introitus that would make this painful, such
as herpetic ulcers, consideration should be given to deferring further examination.
A high vaginal swab for Trichomonas vaginalis, candidiasis and BV is taken
from the vaginal walls and posterior fornix and used to test for pH and sent for
microscopy, culture and sensitivity (MC&S) analysis. If indicated, a cervical
smear should be taken for cytology at this stage. The ectocervix should then be
wiped to remove any vaginal discharge. An endocervical swab, to be sent for
MC&S analysis, is then taken for gonorrhea testing. An endocervical or urinary
chlamydia test should also be taken, depending on which test is offered by the
local laboratory. If a cervical test is to be taken for chlamydia it is important to
sample endocervical cells (as chlamydia is an intracellular organism) by rotating
the swab against the wall of the endocervix (Table 7.6). The diagnosis of
chlamydia and gonorrhea can be improved if urethral swabs are taken in addition
to cervical samples. Urethral tests require samples to be taken with a narrow
swab or loop and can be uncomfortable and are unacceptable to many women.
Testing the rectum and pharynx for gonorrhea should be considered if the partner
has urethral gonorrhea and anal or oral (fellatio) intercourse has
Table 7.6 Basic testing for sexually transmitted infections (triple swabs)
Organism/condition tested for
Test performed
High vaginal swab

Candida and trichomonas
BV
Endocervical swab
Gonorrhea
Endocervical swab or urine*
Chlamydia
Microscopy, culture and sensitivity

Microscopy as above
Microscopy, culture and sensitivity
Use most sensitive test available locally,
these may include: EIA, LCR, PCR, DIF,
culture
Vaginal discharge
BV and trichomonas
pH, using narrow range pH paper
BV
Amine test
*Depends on test used; EIA, enzyme immunoassay; LCR, ligase chain reaction; PCR,
polymerase chain reaction; DIF, direct immunofluorescence; BV, bacterial
vaginosis
occurred. A bimanual pelvic examination should be performed to detect signs

of pelvic inflammatory disease (PID), uterine or ovarian pathology. This is
especially important if gonorrhea or chlamydia is suspected or there is a history
of pelvic or low abdominal pain or dyspareunia. A general physical examination
including the mouth and skin may reveal signs of parasitic infection, syphilis,
HIV and complications of STIs. Testing for other sexually transmissible
infections such as syphilis, HIV, hepatitis B and C should be considered.
pH and amine testing
In community settings a preliminary assessment of vaginal discharge may be
made by noting the character of the discharge, the presence of inflammation and
by testing the pH; some also advocate amine testing (Table 7.7). Vaginal
discharge may not be typical and these tests are not sufficiently specific to
Table 7.7 Features helpful in the preliminary assessment of vaginal discharge
Organism/ condition Classic description of Inflammation of
discharge
vagina
pH
Amine test
Bacterial vaginosis
Absent
> 4.5
Positive
Present
> 4.5
Positive
Present
< 4.5
Negative
Trichomonas
vaginalis
Candida Spp.
Grey, thin,
homogenous
Yellow/green, thin,
frothy
White, curdy
provide a definitive diagnosis but may be useful especially where microscopy is

not available. A sample of vaginal secretion should be placed on pH paper such
as Whatmans narrow range pH paper. Care should be taken to avoid sampling
cervical mucus or lubricant placed on the speculum, which would artificially
raise the pH. pH testing is also unreliable in the presence of semen, menstrual fluid,
vaginal treatments such as spermicides, douches and some systemic drugs. The
pH is normal (< 4.5) in candidiasis but > 4.5 in BV and trichomoniasis.
The amine test is performed by adding a drop of 10% potassium hydroxide to
a sample of vaginal discharge on a glass slide. Amines are released which can be
detected by their characteristic odor. The amine test is positive in BV or
trichomoniasis (because of the accompanying overgrowth of anaerobes) and
weakly positive with menstrual blood or semen. Potassium hydroxide is
corrosive and should be handled and stored with care.
Transport and storage of specimens
If specimens cannot be plated for culture at the time of collection, appropriate
transport media should be used. A charcoal-based medium, for example, is often
recommended for gonorrhea culture. High vaginal and endocervical swabs for
bacterial culture should be kept at room temperature. Urine specimens for
bacterial culture and swabs for viral and chlamydia culture usually require
refrigeration and the temperature needs to be maintained until the specimen
reaches the laboratory. Individual practices should check the manufacturers
instructions and seek advice from their local laboratory. If a significant delay in
the transport of cultures to the laboratory is likely for a patient with suspected
gonorrhea, immediate referral to a GUM clinic should be considered.
TREATMENT OF SEXUALLY TRANSMITTED
INFECTIONS
Suitable treatment should be given after considering patient compliance and the
possibility of allergy, drug interaction, method of contraception, pregnancy,
lactation and antimicrobial resistance. Antimicrobial treatment may be given
when an STI is suspected from the patients history, after a tentative diagnosis
has been made or after it has been confirmed. Decisions on the timing of therapy
should be made according to the risk of infection, the availability of diagnostic
testing and the likelihood of the patient returning for results and abstaining from
sexual inter-course. Treatment on epidemiologic grounds can be given to a
patient whose partner is known to be infected. For example, a woman who has
been having unprotected intercourse with a man with gonorrhea may be offered
treatment before a diagnosis has been made. Investigations to confirm or exclude
the diagnosis and exclude other STIs should still be performed, but treatment is
given without waiting for the results.
All patients should be advised to abstain from sexual intercourse until they and
their partner(s) have completed the treatment and tested negative (if a test of cure
has been performed). Information should be offered about the disease and its
treatment and how to reduce the risk of further infection and transmission. A
follow-up visit is recommended to ascertain if the condition has resolved, check
patient compliance and find out whether partner(s) have been notified. It is also
an opportunity to provide further information and counseling for emotional and
sexual difficulties. At follow-up, a test of cure should be performed for
gonorrhea and trichomonas infection in all women and for chlamydia in women
treated with erythromycin. As even intelligent patients may find it difficult to
absorb all the information due to embarrassment and anxiety, written information
should be offered.
Partner notification (contact tracing)
Partner notification involves informing sexual contacts that they have been
exposed to STIs. The purpose is to prevent treated patients from being reinfected, detect their partner(s) undiagnosed infection(s) and to reduce STIs in
the community. The rationale is that every patient has caught an STI from one or
more partners and may subsequently infect others. Infected partners (contacts)
may not appreciate their risk of infection and/or be asymptomatic.
The benefits of partner notification are greatest for the bacterial STIs because
they can be cured and the risk of sequelae can be reduced by prompt treatment.
Partners with incurable viral STIs, such as genital herpes and HIV, can be given
information about the infection and advice on strategies to reduce the risk of
transmission. All can be offered testing for other STIs including HIV and advice
about safer sex.
The patient is usually advised to ask her/his partner to attend a clinic for
testing and treatment. It is useful to provide a contact slip or note with the
diagnosis for the contact to give to their healthcare worker. In order to maintain
confidentiality, no information about the patient or contact(s) should be given to
anyone else without their permission. In practice, it is preferable to seek
permission to disclose the name of the infection(s) that the patient acquired so
that an adequate explanation of the disease, tests and any necessary treatment can
be given to the contact. Naming the infection prevents the partner assuming that
it is HIV A patient may be reluctant to inform her partner(s) that they have an STI
but be willing to provide information to enable a health professional, such as a
GUM clinic health advisor, to do so. It is common practice to contact all partners
with whom the patient had sexual contact in the 3 months prior to diagnosis.
BACTERIAL CERVICITIS AND PELVIC

INFLAMMATORY DISEASE
Gonorrhea
Gonorrhea is an STI caused by the bacterium Neisseria gonorrhoeae, a Gramnegative intracellular diplococcus. Although gonorrhea is not common in many
parts of the UK, sporadic outbreaks occur and the infection is endemic in many
inner cities. In 2001 the rate of gonorrhea in female GUM clinic attendees in
England was 65/100 000. There is wide regional variation with rates being
highest in Greater London (over 165/100 000). There has been a recent increase
in infection rates, especially amongst women under 20 years of age.
The incubation period of N. gonorrhoeae is 3 to 5 days. The common sites
affected are the endocervix, urethra, pharynx and rectum, which may be infected
by anal intercourse or contamination with vaginal discharge. Gonococcal
conjunctivitis can also occur. Gonorrhea is asymptomatic in up to 50% of women
with genital infection and in up to 90% of those with pharyngeal infection.
Knowledge of local gonorrhea rates and a high index of suspicion are required to
optimize opportunities for testing.
When present, symptoms include abnormal vaginal discharge, dysuria and
symptoms of upper genital tract infection such as low abdominal pain, dyspareunia
and intermenstrual bleeding. Gonorrhea can also present as a Bartholin's abscess.
There may be no abnormal clinical signs, but there may be mucopurulent
endocervical discharge, contact bleeding and signs of PID. Coexistent urethral
infection is common but discharge is rarely apparent in women.
The main complication is PID; disseminated infection causing arthritis and
skin lesions is rare. Very occasionally pericarditis, endocarditis, hepatitis and
meningitis are seen. Vertical transmission can lead to opthalmia neonatorum,
which is a notifiable disease.
Diagnosis
If gonorrhea is suspected, specimens should be taken from the urethra and rectum
in addition to the endocervix. The oropharynx should also be tested if fellatio has
occurred.
Microscopy demonstrates the typical appearance of Gram-negative
intracellular diplococci within polymorphonucleocytes. Microscopy of an
endocervical sample gives a presumptive diagnosis in 20-50% of women but
should not be used for pharyngeal specimens. Culture provides definitive
diagnosis and antibiotic sensitivities. If gonorrhea is strongly suspected but the
test results are negative, some advocate re-testing prior to treatment.
Treatment
Treatment for gonorrhea should be guided by local antibiotic resistance patterns,
which are monitored by microbiology laboratories or GUM clinics. Resistance to
penicillins, tetracyclines and quinolones occurs, especially in cases imported
from locations overseas such as South East Asia. Penicillins should only be used
as a first-line treatment if the incidence of resistance is known to be low.
Pharyngeal gonorrhea responds poorly to penicillins (Table 7.8). As many
women with gonorrhea are also infected with chlamydia, it is common practice
to treat with a combination of antibiotics effective against both organisms. After
treatment further cultures should be performed to detect treatment failure or reinfection.
Table 7.8 Single-dose treatment regimens for gonorrhea
a) Women who are not pregnant or lactating
Drug (dose)
Uncomplicated genital gonorrhea
Oral
Ampicillin (2 g) with probenecid (1 g)
Ciprofloxacin (500 mg)
Ofloxacin (400 mg)
Levofloxacin (250 mg)
Alternative regimen for uncomplicated genital gonorrhea imported from South East
Asia
IM
Ceftriaxone (250 mg)
Cefotaxime (500 mg)
Spectinomycin (2 g)
Pharyngeal gonorrhea
Oral
Ciprofloxacin (500 mg)
Ofloxacin (400 mg)
IM
b) Pregnant and lactating women*
Drug (dose)
Uncomplicated genital gonorrhea
Oral
Ampicillin (2 g) with probenecid (1 g)
IM
Cefotaxime (500 mg)
Spectinomycin (2 g)
*Quinolones and tetracyclines are contraindicated in pregnant and lactating women; IM,
intramuscular
Chlamydia trachomatis
Chlamydia trachomatis serotypes D to K are obligate intracellular bacteria that
cause a genital infection with a similar clinical presentation to gonococcal
infection. Chlamydia is much more prevalent than gonorrhea and is less confined
to inner city areas. Longstanding asymptomatic genital infection is not
uncommon: up to 75% of infected people have no symptoms. Establishing a
sexual history is therefore important to identify women who are at risk of
chlamydial infection.
The rate of chlamydia is highest in sexually active teenagers. High
prevalences have also been reported in women seeking termination of pregnancy
(Table 7.9) and following intrauterine device (IUD) insertion for emergency
contraception. In 2001 the reported rate of chlamydia in England was 373/100
000, with higher rates being observed
Table 7.9 Prevalence of chlamydial infection in women (1944 years) reported from
various clinical settings in the UK, 19972001
Population
Median prevalence (%)
Range (%)
General population
1.5
12
General practice
4.5
112
Gynecology clinics
4.8
36
Family planning clinics
5.1
37
Women seeking abortions
8.0
712
GUM clinics
16.4
729
GUM, genitourinary medicine. Data derived from Chlamydia Trachomatis. Summary
and Conclusions of CMO Expert Advisory Group. London: Department of
Health
in Greater London and considerably lower ones in East Anglia and the South West
of England.
The incubation period of Chlamydia trachomatis is approximately 2 weeks.
The main sites of infection are the urethra and cervix, although the pharynx and
rectum may also be involved. When present, symptoms include vaginal
discharge, mild dysuria, intermenstrual and postcoital bleeding and lower
abdominal pain with dyspareunia. Contact bleeding from the cervix may be
noted on examination. Pharyngeal and rectal infections are usually asymptomatic,
although rectal pain and anal discharge may be reported. Rarely, Chlamydia
causes adult conjunctivitis, perihepatitis and sexually acquired reactive arthritis
(SARA). When transmitted vertically, the neonate may develop opthalmia or
pneumonia. Chlamydia is responsible for the majority of cases of PID.
Chlamydia causing only minimal symptoms and signs of PID can cause chronic
pelvic pain, tubal damage and subfertility. However, the risk of infertility should
not be overemphasized, so that the woman does not discontinue her method of
contraception. Chlamydial infection has also been estimated to account for 40%
of ectopic pregnancies.
Diagnosis
A number of speciments can be used to test for chlamydia. Trained medical
professionals can take swabs from the cervix and urethra. The cervix needs to be
cleaned of excess mucus or discharge before swabbing. The cervical swab should
be inserted 12 cm into the cervix past the squamocolumnar junction and turned
several times in order to exfoliate columnar cells. A second swab is taken from
the urethra. The urethral swab is inserted 1 cm into the urethra and rotated 12
times. Both swabs are usually transported together.
First voided morning urine is an excellent specimen for nucleic acid
amplification assay. The first 1020 ml of the morning urine contain epithelial
cells from the urethra and may contain chlamydia. Urine specimens have the
advantage of being simple and non-invasive, but specimens need to be
maintained at low temperatures during transportation to the laboratory. Vaginal
swabs obtained by the patients themselves have also been shown to be good
specimens for chlamydia testing.
NAATs such as LCR and PCR are more sensitive than culture tests or enzyme
immunoassays (EIA or enzyme-linked immunosorbent assay (ELISA)) and, if
available, are the diagnostic methods of choice. LCR and PCR may be useful as
screening tests as they can often be carried out on urine specimens, avoiding the
need for a vaginal examination. The full potential of these tests is still being
evaluated. Direct immunofluorescence (DIF) and culture tests are expensive and
unsuitable for analyzing a larger number of specimens. Culture tests are required
in forensic cases, such as rape, in view of their high specificity.
Treatment
Uncomplicated chlamydial infection in non-pregnant women should be treated
with doxycycline 100 mg orally twice daily for 7 days or azithromycin 1 g orally
as a single dose. Women who are pregnant, lactating or who do not tolerate these
drugs may be treated with erythromycin stearate 500 mg orally twice daily
Table 7.10 Findings supporting a diagnosis of pelvic inflammatory disease
Oral temperature > 38.3C (> 101F)
Cervical and/or vaginal mucopurulent discharge
Presence of WBC on microscopy of vaginal secretions
Elevated ESR
Elevated CRP
Laboratory diagnosis of N. gonorrhoeae or C. trachomatis
WBC, white blood cells; ESR, erythrocyte sedimentation rate; CRP, C-reactive protein
for 14 days. Erythromycin leads to a slightly lower cure rate than doxycyline, so
patients treated in this way should be re-tested three weeks after completing
therapy.
Screening
In the UK, there is no routine screening for chlamydia. Patients are tested for
chlamydia only when it is clinically indicated or to perform opportunistic
screening in high-risk groups. Table 7.4 lists indications when testing for STIs
(including chlamydia) should be instituted.
PID is an ascending pelvic infection, which may produce a combination of
endometritis, salpingitis, oophoritis and parametritis. It may be complicated by
tubo-ovarian abscess, pelvic peritonitis and peri-hepatitis. It is usually related to
cervical infection with N. gonorrhoeae or C. trachomatis. The latter is
responsible for most cases, although the bacteria may coexist. Anaerobic bacteria
associated with BV (bacteroides, anaerobic cocci) may also be involved in the
pathophysiology of PID. Other microorganisms found in patients with PID
include E. coli, Mycoplasma hominis and ureaplasma.
PID is more common in women under 35 years old and in those with multiple
partners or an STI. It is rare in pregnancy, before menarche or after menopause.
Hormonal and barrier (condoms, diaphragm) methods of contraception appear to
be protective. PID is not always due to an STI and can occur after a gynecologic
procedure in the absence of either chlamydia or gonorrhea. The risk of PID after
termination of pregnancy is approximately 515% and less than 1% following
IUD insertion. These rates are highest if there is a pre-existing cervical STI. The
risk of pelvic infection with an IUD in situ is only raised above the background
risk for 20 days after insertion. It has been demonstrated that the rate of
postabortal PID can be approximately halved when prophylactic antibiotics are
used at the time of termination of pregnancy. The Royal College of Obstetricians
and Gynaecologists Guidelines recommend that selected women are tested for
STIs and/or given prophylaxis before an intrauterine procedure (see page 59 for
reducing the risk of PID in women having an IUD fitted).
Diagnosis
Women may be asymptomatic, but it is more common that PID presents with
lower abdominal pain, deep dyspareunia, vaginal discharge and intermenstrual
bleeding. The diagnosis of PID is usually made on clinical findings, as the gold
standard, laparoscopy, is rarely used. The only findings on examination required
to make a diagnosis of PID are cervical, uterine or adnexal excitation (cervical
motion tenderness) and adnexal tenderness. In addition, the patient may also be
pyrexial and/or have abdominal tenderness, signs of peritonism or a pelvic mass.

Right upper abdominal pain suggests the presence of peri-hepatitis, a rare
condition associated with both chlamydial and gonococcal PID, known as the
Fitz-Hugh-Curtis syndrome. Other complications of PID are tubo-ovarian
abscess, pyosalpinx and hydrosalpinx. A raised white blood cell count, Creactive protein or erythrocyte sedimentation rate supports the clinical diagnosis
of PID, retrospectively. Because of the need to carry out effective contact tracing,
testing for STIs is important. A pregnancy test may be required to exclude
ectopic pregnancy. Other differential diagnoses to consider include acute
appendicitis, torted or ruptured ovarian cyst and endometriosis. Additional
criteria supporting a diagnosis of PID are listed in Table 7.10.
Treatment
Early treatment of PID reduces the risk of developing long-term sequelae such as
ectopic pregnancy, infertility, chronic pelvic pain and dyspareunia. The risk of
developing subfertility is approximately 9% after one episode of PID and
approximately doubles with each subsequent episode. The risk of ectopic
pregnancy for women with a history of PID is 10%. Therefore, there should be a
low threshold for treatment. As PID is polymicrobial, combination antibiotic
therapy is required to cover gonorrhea, chlamydia and anaerobic infection.
Treatment depends upon local patterns of antibiotic resistance but usually
consists of oral doxycycline 100 mg twice daily for 14 days plus oral
metronidazole 400 mg twice daily for 14 days and ciprofloxacin 500 mg stat.
Hospital admission and parenteral treatment is indicated for more severe clinical
disease, particularly in the presence of HIV infection (Table 7.11). One inpatient regimen is cefoxitin 2.0 g IV every 6 h plus doxycycline 100 mg orally or
IV every 12 h. Analgesia may be required. When PID is diagnosed in a patient with
an IUD, it is advised to leave the device in place unless the condition has not
improved 48 h after starting treatment.
Patients should be advised to avoid inter-course until they, and their partner
(s), have completed treatment and follow-up. Clear verbal and written
information should be provided. Pelvic examination should be performed at
follow-up visits, 2 days and 2 weeks after commencing treatment.
VAGINAL INFECTIONS
Vaginal discharge is a common complaint in sexually active women. Normal
discharge in premenopausal women is non-irritant,
Table 7.11 Indications for hospital admission
Diagnostic uncertainty
Clinical failure with oral therapy
Presence of a tubo-ovarian abscess

Inability to tolerate oral therapy
Immunodeficiency
non-offensive, not blood-stained and has a pH of 3.54.5. Normal vaginal flora

includes Corinebacterium, Bacteroides, Peptostreptococcus, Mobiluincus,
Gardnerella, Mycoplasma and Candida spp. The acidic pH, which serves a
protective function, is maintained by lactobacilli, which produce lactic acid.
There are no glands in the vagina. Vaginal discharge originates predominantly
from vaginal desquamation, bacteria and secretions from the cervix and upper
genital tract. It may be, therefore, a presentation of upper genital tract disease
including infection and, rarely, malignancy.
The important symptoms in women with abnormal vaginal discharge are
pruritis, odor, intermenstrual bleeding (including postcoital bleeding) and
abdominal pain. On examination, in addition to the color and nature of the
discharge itself, the presence of vulvitis, vaginitis and cervicitis should be noted.
Whilst the commonest causes of vaginal discharge, BV and candidiasis, are not
sexually transmitted, the same symptoms can be caused by other conditions and
the possibility of an STI should be considered. Foreign bodies like retained
tampons usually result in vaginal discharge. Atrophic vaginitis and allergic
reactions to bubble baths, douches and other cleansing or perfumed agents can
cause soreness and itching.
If an STI is suspected, appropriate tests should be performed or the patient
referred to a GUM clinic. It is common practice to treat empirically if an STI is
not suspected and many patients self-medicate with, e.g., antifungal therapy.
However, it is important that women should be examined and investigated if
symptoms persist.
Table 7.12 Treatment of bacterial vaginosis
Regimen
Non-pregnant women
Metronidazole orally
400 mg twice daily for 7 days
2 g as a single dose
Clindamycin 2% vaginal cream*
One applicator full each night for 7 days
Pregnant women (or suspected pregnancy)
400 mg twice daily for 7 days
*Clindamycin cream may and cervical caps and is weaken latex condoms, diaphragms
contraindicated in pregnancy
Bacterial vaginosis
BV, also referred to as anaerobic vaginosis, is a cause of vaginal discharge but is
non-sexually transmitted. It is common with a prevalence of up to 20%. BV is
characterized by an altered vaginal bacterial flora with a preponderance of
anaerobic bacteria, such as Mobiluncus spp., Gardnerella vaginalis, Bacteroides
spp. and Mycoplasma spp., and an absence of lactobacilli. The etiology of BV is
poorly understood. Although it is related to sexual activity, a sexually transmitted
pathogen has not been identified and BV can occur in women who are not
sexually active. There is an association with vaginal douching and the use of
IUDs.
BV may predispose women to postoperative pelvic infection, endometritis
after birth or termination of pregnancy, chorioamnionitis, second trimester loss,
premature birth and rupture of membranes. It is also believed to play a role in the
pathogenesis of PID.
Vaginal discharge and fishy odor may occur but approximately half of all
women with BV have no symptoms. As BV does not cause inflammation of the
vagina and vulva, a complaint of soreness or pruritis should lead to consideration
of coexistent conditions. The clinical findings are malodor and thin, grey,
homogenous vaginal discharge.
Diagnosis
The diagnosis of BV is made if three of the following four criteria are present: (1)
thin white/grey discharge; (2) vaginal pH > 4.5; (3) positive amine test; and (4)
clue cells detected on microscopy of a wet mount or gram stain. Clue cells are
vaginal epithelial cells coated in Gram-variable bacilli that have a characteristic
appearance on microscopy. Where immediate microscopy is not available, the
history, clinical findings and a raised vaginal pH suffice for a presumptive
diagnosis. Setting up a culture for Gardnerella vaginalis is not helpful in the
diagnosis of BV.
Treatment
Women with a diagnosis of BV should be offered treatment (Table 7.12), even if
they do not report symptoms as some may not regard their discharge as abnormal
or are too embarrassed to mention symptoms such as odor. Treatment is advised
for women with BV who are pregnant, especially if they have symptoms, a
history of late miscarriage or premature labor. The value of routinely screening
asymptomatic women in pregnancy has not yet been demonstrated.
BV may resolve spontaneously but recurrences are common and frequently
noticed after menstruation or intercourse. Treating the male partner(s) does not
prevent recurrence. Follow-up tests are not performed if the patient is no longer
symptomatic, except in pregnant women with a history of late miscarriage or

premature labor who should be re-tested after 1 month.
Vulvo-vaginal candidiasis
Candidiasis is caused by the yeast Candida. Over 90% of cases are due to the C.
albicans species, most of the remainder being due to C. glabrata. About 6070%
of women experience at least one episode of candidiasis in their lifetime. Such
factors as reduced immunity, steroid therapy and undiagnosed diabetes are
occasionally involved in recurrent infection. It is not sexually transmitted,
although some male partners develop mild, pruritic balanitis soon after
intercourse, which usually resolves within 24 h.
Table 7.13 Treatment of vaginal candidiasis
Regimen
Notes
Effect on latex
contraceptives is unknown
Fluconazole (oral tablet)
500 mg single dose noct

or
200 mg noct for three
nights
or 100 mg noct for six
nights
150 mg single dose
Second-line therapy
Miconazole (vaginal ovule)
1.2 g single dose noct
Damages latex
contraceptives
Damages latex
contraceptives
First-line therapy
Clotrimazole (vaginal
pessary)
Econazole (vaginal
pessary)
Nystatin (vaginal cream or

pessary)
150 mg single dose noct

or
150 mg noct for three
nights
100 000 units noct for 14
nights
Contraindicated in
pregnancy
Cream, but not the pessary,

damages latex
contraceptives
Diagnosis
The most notable symptoms are vulval pruritis and a white vaginal discharge.
Soreness and superficial dysuria and dyspareunia may also be present due to
inflammation and fissuring of the vulva. The clinical findings may vary from
very mild to severe vulvo-vaginitis with a typical white curdy discharge. Vulval
erythema usually has a marked edge and adjacent satellite lesions may be
present.
In GUM clinics, the diagnosis of vulvovaginal candidiasis is made by

detecting yeast and pseudohyphae on microscopy of vaginal discharge on a gram
stain or wet slide prepared with 10% potassium hydroxide. The pH of vaginal
discharge is usually less than 4.5 unless BV and/or trichomonas is also present.
In community settings a presumptive diagnosis can be made by clinical findings
and a normal pH. Culture confirms the diagnosis and the causative species.
Treatment
Ten to twenty per cent of women of child-bearing age and 3040% of pregnant
women may have Candidiasis asymptomatically and do not require treatment.
The mainstay of treatment of candidiasis is with azoles, many being available
without prescription (Table 7.13). Topical therapy such as clotrimazole 1% cream
is useful for vulvitis but should not be used alone to treat vaginal candidiasis.
After treatment no specific follow-up is required. Male partners do not require
treatment. Balanitis usually resolves if unprotected vaginal intercourse is avoided
until the vaginal infection is treated.
Patients with recurrent infection should be examined and tested to confirm the
diagnosis of candidiasis and exclude other infections. Diabetes and
immunodeficiency caused by conditions such as HIV infection and corticosteroid
therapy should be considered when candidiasis recurs frequently, although these
are uncommon causes of candidiasis in the general population. Patients can be
advised to avoid products such as bubble baths and vaginal deodorants and tight
underwear made of synthetic fabric, if these appear to exacerbate the condition.
Prophylactic drug regimens for recurrent infection are empirical and
include clotrimazole 500 mg pessaries one every 1 or 2 weeks. Women who
notice symptoms of candidiasis occurring premenstrually can be treated 2 days
prior to the anticipated onset of symptoms. Women prone to candidiasis during
antibiotic therapy can also be offered prophylaxis. In women with a history of
recurrent candidiasis, treatment of the male partner should be considered.
Trichomoniasis
The flagellated protozoan Trichomonas vaginalis (commonly known as TV)
causes trichomoniasis, which is almost always sexually transmitted. It is
uncommon, compared with BV and candidiasis, and is asymptomatic in up to
half of cases. The incubation period of T. vaginalis is 1 to 3 weeks. It affects the
vagina and urethra and has no long-term complications. It is a cause of nonspecific urethritis (NSU) in men. The diagnosis of trichomoniasis should alert the
clinician to test for presence of other STIs.
Diagnosis
Clinical features range from no symptoms or signs to a severe vulvo-vaginitis
with profuse vaginal discharge and abdominal discomfort, There is usually
marked erythema of the vaginal epithelium and the classic strawberry cervix is
occasionally seen. The discharge may be malodorous, blood-stained and frothy
and yellow/green in color.
The diagnosis, suspected by clinical features and a vaginal pH above 4.5, is
made by culture or microscopy analysis of a wet mount from a high vaginal
swab. As it has a low specificity, trichomoniasis suspected on cervical cytology
should be confirmed by culture or microscopy analysis. Both trichomoniasis and
BV cause a raised vaginal pH, but the former can usually be distinguished from
the latter by the presence of vaginal inflammation.
Treatment
Oral metronidazole is recommended as either 2 g in a single dose or 400 mg
twice a day for
Table 7.14 Causes of genital ulceration
Herpes simplex
Syphilis
Chancroid
Lymphogranuloma venereum
Granuloma inguinale
Trauma
Malignancy
Anogenital amoebiasis
Behcets syndrome
Crohns disease
5 days. The single high-dose regimen should be avoided in pregnancy. Male

partners should be examined and tested for trichomoniasis and other STIs. As
culture or microscopy analysis for trichomoniasis is insensitive in men, partners
should be treated for it, even if the organism is not detected.
A test of cure should be performed in women. Successful treatment is
dependent upon patient compliance and the simultaneous treatment of her partner
(s). If resistance occurs and re-infection has been excluded, advice on further
treatment should be obtained from a microbiologist or GUM physician.
GENITAL ULCERS
Genital ulceration is common. Whilst the vast majority of cases are due to the
herpes simplex virus, it is important to differentiate between those that are due to
trauma, infection or cancer (Table 7.14). Traumatic ulcers are usually due to
chronic rubbing or localized scratching. Ulcers caused by infectious diseases
usually clear without treatment. Malignant ulcers, which may appear similar,
should be suspected by their failure to heal. A diagnosis should be sought in all
cases of genital ulceration.
Genital herpes simplex virus
Genital herpes, a common STI, is usually caused by herpes simplex virus (HSV)type 2 but an increasing proportion of new cases are due to type 1 (HSV-1). In
1998 the estimated rate of first-time genital herpes nationally was 103/100 000
women aged 1644 (Table 7.1). In London the rate was considerably higher at
almost double this number. A UK study published in 2000 found that the
prevalence of HSV-1 antibodies was 24.5% in a random sample of children under
15 years of age (almost certainly representing oro-labial HSV infection) and 54%
in women aged 2530 years of age. HSV-2 antibodies were detected in the sera
of 3.3% of men and 5.1% of women over the age of 16 years. Higher
prevalences of 10.4% and 12.4% were reported in London from antenatal
patients and blood donors, respectively. A representative national sample of noninstitutionalized US population aged > 12 found HSV-2 prevalence of 26% and
18% in females and males, respectively. Prevalence in African-Americans was
more than double that of the Caucasian sample. Higher prevalence for HSV-2 is
found in homosexual men, GUM clinic patients, HIV sero-positive persons and
commercial sex workers. Symptoms of genital herpes due to HSV-1 tend to be
milder and recurrences are less frequent. HSV is transmitted during genital and orogenital (including oro-anal) contact. Both types, most commonly HSV-1, can
also cause oro-labial and ocular herpes. Important factors in the spread of herpes
are under-diagnosis due to absent or atypical symptoms and asymptomatic
shedding. The incubation period is approximately 3 to 10 days.
Terminology
Primary genital infection is the term used when initial infection with HSV-1 or -2
occurs. This is usually associated with a clinical episode. Common sites of viral
entry are the vulva, peri-anal area, vagina and cervix. There is cross-reactivity
between antibodies to HSV-1 and -2, so primary infection with HSV-2 tends to
be mild or asymptomatic in individuals with previous exposure to HSV-1 and
vice versa.
The first episode is the first recognizable clinical episode of genital herpes.
This can occur a long time after the primary genital infection. Thus, it is not
possible to be dogmatic about when the actual infection was acquired.
Recurrent episodes and asymptomatic shedding
HSV exhibits latency in the sensory root ganglion of the site of entry.
Reactivation can give rise to both recurrent symptomatic episodes and
asymptomatic shedding. A person with herpes can infect others when the virus
reactivates as they shed the virus from the genital area or mouth. It is not
possible clinically to detect when a person is shedding virus. The majority (about
70%) of cases of genital herpes are transmitted by viral shedding when the
patient is asymptomatic because people with herpes tend to avoid intercourse
when they are aware that they have a recurrence. Discordant couples who avoid
intercourse during identified recurrences have an estimated transmission rate of
10% per annum.
Clinical features
Primary genital herpes The features of primary genital herpes vary widely and
unrecognized infection is common. Primary herpes may be asymptomatic or
cause local symptoms at the site of viral entry and/or systemic illness. The typical
description of primary genital herpes is of a flu-like syndrome with fever,
malaise and myalgia. Associated autonomic neuropathy may lead to urinary
retention, constipation and aseptic meningitis. Rarer complications are skin,
joint, liver or lung involvement. Three to four days after the onset of the systemic
illness, multiple vesicles develop at the site of infection. The blisters can become
small, sometimes pinpoint ulcers, or coalesce to form a large lesion resembling a
syphilitic chancre. The lesions are very painful and cause severe dysuria and
vaginal, urethral or rectal discharge according to their location. There is
associated bilateral tender inguinal lymphadenopathy and edema. Complete
healing can take 23 weeks.
Recurrent genital herpes Individuals with recurrent genital herpes may
experience a prodrome, typically neuralgic type pain, tingling, itching and
hyperasthesia at a localized site where a lesion is to develop. The lesions are few
in number and tend to recur at the same site with each outbreak. Recurrences are
said to be precipitated by ultraviolet light, febrile illness, menstruation and
stress, although the role of these factors is debated. Recurrences are common in
the first year, especially in men and those with a prolonged first episode, but
become less severe and less frequent with time.
Pregnancy and genital herpes

In comparison to genital herpes, neonatal herpes is very rare but the morbidity
and mortality are high. Neonatal herpes occurs in approximately 1 in 50 000
neonates and the majority of affected babies are born to women with no history
of genital herpes.
Neonatal herpes is transmitted during delivery and post-natally when babies
are kissed by people with oro-labial infection or handled by those with herpetic
whitlow. The risk of neonatal herpes is highest if the woman has primary herpes
during her pregnancy, especially at the time of delivery. Pregnant women with
partners who have a history of herpes should be advised how to avoid acquiring
the infection during pregnancy. Pregnant women with primary herpes should be
referred for specialist advice for consideration of aciclovir and, if late in
pregnancy, of prophylactic aciclovir and Cesarean section.
The risk of neonatal herpes in an infant whose mother has a history of
recurrent genital herpes is very low. Routine testing for viral shedding during
pregnancy or delivery has not been demonstrated to be of value. If genital lesions
are present at the time of labor, delivery by Cesarean section should be
considered.
Herpes and immunocompromised patients
In the presence of HIV infection, herpes tends to be chronic and severe and
worsens as the HIV infection progresses. Lesions are often large, their
appearance is atypical and secondary infection is common. Intravenous therapy
may be required and prophylaxis often given to prevent pain and systemic
infection. Advice should be sought from a specialist in HIV medicine.
Diagnosis
The diagnosis of HIV infection may have considerable psychologic, sexual and
social implications. Therefore, if suspected from clinical examination, the
diagnosis should be confirmed by isolating the virus in tissue culture. Viral
culture is best performed on vesicular fluid taken from the base of a fresh ulcer.
Culture becomes less reliable when there is crusting or the lesion is dry. In one
study the positive rate for culture in comparison to PCR was vesicle/pustule 90%,
ulcer 70%, and crust 27%. Referral to a GUM clinic or liaison with a virology
laboratory is necessary as the specimen must be taken with appropriate swabs
and placed in viral transport or culture media kept at 4C. Diagnosis is likely to
improve when NAATs such as PCR become commercially available.
The interpretation of HSV serology is complex. Genital herpes can be caused
by HSV-1 or -2 and serology may take up to 3 months to become positive after
primary infection, the antibodies persist indefinately. Positive serology does not
indicate when the infection occurred and therefore does not distinguish between
HSV from a childhood cold sore and genital herpes in adulthood. Type-specific
HSV serology is likely to become available in the UK soon, but its quality and role
in clinical management and screening are yet to be established. The psychosocial
impact of a diagnosis of asymptomatic HSV infection should also be considered.
Type-specific serology may be useful in advising patients with their first episode
of genital herpes, counseling asymptomatic partners of patients with genital
herpes and in the diagnosis of recurrent genital ulceration.
Management
A patient presenting with genital herpes, in pain and unwell from a flu-like
illness, needs good symptom relief, clear factual information and time for
discussion. Follow-up visits and counseling are important, as psychologic or
psychosexual complications are common. Issues that may arise include deciding
how and when to tell new partners about herpes, feeling unclean and loss of sexual
confidence and libido.
Treatment of primary episodes with oral antiviral agents reduces the severity of
the illness and accelerates healing (Table 7.15). Therapy should be commenced
in the first 5 days of an episode or when lesions are still appearing. Warm baths
and oral analgesia provide symptomatic relief. Topical anesthetic agents such as
lignocaine ointment are also helpful. Increasing fluid intake and urinating into
the bath or shower can reduce external dysuria. If urinary retention occurs, it
should be managed by suprapubic catheterization.
Recurrences are usually managed with symptomatic treatment alone, although
episodic and suppressive therapy should be considered according to the
frequency and severity of the episodes and the impact they have on the patients
life.
Episodic therapy is a 5-day course of antiviral medication given early in a
recurrence to shorten its duration. Suppressive therapy or prophylaxis, taken on a
daily basis, reduces the frequency of recurrences and viral shedding. A common
regime is to start with oral aciclovir 400 mg twice daily and titrate the dose
according to the number of recurrences. Supportive therapy reduces the
frequencies of recurrences by 7080% in those with 6 recurrences per year.
Prophylaxis is usually given for a year initially. Patients should be advised how
to recognize recurrences so that they can avoid sexual contact at the earliest stage
of an episode until the lesions have
Table 7.15 Five-day courses of oral antiviral therapy for herpetic episodes
Drug
Primary herpetic infection
Recurrent herpetic infection
Aciclovir
Valaciclovir
Famciclovir
200 mg five times daily

500 mg twice daily
250 mg three times daily
200 mg five times daily

500 mg twice daily
125 mg twice daily
healed. If they are not sure whether their symptoms are due to a recurrence they
should seek further advice. Condoms may reduce the risk of transmission from
asymptomatic viral shedding at other times, although the degree of protection is
uncertain. Asymptomatic shedding is more frequent in the first 12 months of
acquiring HSV-2.
The diagnosis should be confirmed before commencing suppressive or
episodic treatment. A GUM clinic, which may have a herpes or special problems
session, can provide testing, counseling and specialist advice.
Syphilis
Syphilis is a rare but important STI that may be evident on genital examination
in the early, primary and secondary stages. Syphilis is included in the differential
diagnosis of many conditions as its presentation is frequently not classical. It
may go unrecognized unless detected by routine testing in settings such as GUM
and antenatal clinics. Syphilis is caused by the spirochete Treponema pallidum
which has an incubation period of 990 days, typically 21 days. In acquired
syphilis T.pallidum enters through the mucous membranes or skin and rapidly
disseminates throughout the body. The classic presentation of primary syphilis is
painless local lymphadenopathy and a single papule, which erodes to form a
painless indurated ulcer or chancre. The chancre heals in 48 weeks in untreated
patients. The secondary stage, which often develops 28 weeks after the
appearance of the chancre, is characterized by systemic symptoms such as fever
and weight loss, rashes,
Table 7.16 Tropical causes of genital ulceration
Infection
Organism
Features
Chancroid
Hemophilus ducreyi
Lymphogranuloma
venereum
Chlamydia trachomatis
Granuloma inguinale
Calymmatobacterium
granulomatis
Painful ulcers and

suppuration of the inguinal
lymph nodes
Vesides and ulcers which
may be painless, followed
by suppurative
lymphadenopathy with
skin sinuses and discharge;
constitutional symptoms
Painless beefy-red nodules
and ulcers; secondary
infection common; leads to
gross soft-tissue
destruction; no regional
lymphadenopathy
generalized painless lymphadenopathy and multi-system involvement including

hepatosplenomegaly. Hypertrophic papules called condyloma lata occur in moist
areas and are extremely infectious. Snail track ulcers may be observed in the
mouth.
Early syphilis (up to 2 years, including primary, secondary and early latent1) is
highly infectious after which infectivity gradually declines. Late syphilis (late
latent2, tertiary and quaternary) has serious long-term neurologic, skeletal and
cardiologic consequences in 30% of those who are not treated. Sequelae include
dementia, sensory deficit, skeletal deformity and aortitis, which can lead to aortic
regurgitation and aneurysm. Congenital syphilis is now very rare, but is
preventable with effective screening and treatment.
The diagnosis is made by fluorescent techniques or dark-ground microscopy
of serum from a lesion, or more commonly by serology. Serological results
should be interpreted by an experienced clinician who can exclude the possibility
of previous treated infection, false positives and disease caused by other
treponemes such as yaws. Early disease is easily treated providing compliance is
good but serology often remains positive for life. Cases of suspected syphilis
should be referred to GUM clinics for diagnosis, treatment and partner
notification.
Tropical diseases
Chancroid, granuloma inguinale (Donovanosis) and lymphogranuloma venereum
cause genital ulceration with associated lymphatic involvement. Basic
information about them is shown in Table 7.16. They are common in many parts
of the tropics and are occasionally seen in the UK in patients returning from
overseas. If suspected, referral to a department of tropical medicine or GUM
clinic for diagnosis and management is recommended.
VIRAL INFECTIONS AND INFESTATIONS OF THE
SKIN
Genital warts and human papillomavirus infection
Genital warts are tumors caused by the human papillomavirus (HPV). There are
over 90 subtypes of HPV, about half of these cause diseases in man. Genital HPV
is usually sexually transmitted and is the commonest of these infections with
over 30 HPV subtypes implicated, notably type 6 and 11. Genital HPV has a
prevalence rate of 2046% depending on the clinical setting and country.
Incidence figures for England are given in Table 7.1. Vertical transmission
during delivery occurs, but complications of this are rare. Young women usually
become infected with HPV within a few years of becoming sexually active.
1Early latent disease is asymptomatic disease without evidence of tertiary or quaternary
disease where the time from the original infection is known to be less than 2 years.
Multiple concurrent and sequential infections with various (including oncogenic)

types of HPV are common. Most such infections are with the low-risk subtypes
(6 and 11) that are cleared, and by 12 months 70% of these women are no longer
infected. Persistent infection is present in about 10% of women after 5 years, and
half of these women will progress to develop precancerous lesions or cervical
cancer if screening is not performed routinely.
The incubation period for genital warts is typically 3 weeks to 6 months,
although longer periods do occur. Subclinical infection is very common and the
factors determining which HPV-infected individuals develop warts are poorly
understood. Genital warts are more common in pregnancy and in association
with HIV infection.
The sites most commonly infected are the vulva and peri-anal areas. Warts can
also occur in the cervix, vagina, anal canal, urethral meatus and mouth. There is
a wide range of clinical findings, from lesions only visible on colposcopy to
confluent exophytic genital warts. Warts can be single or multiple, flat or
pedunculated, and, according to their location, are firm and keratinized or soft.
Symptoms may be absent or include itching, bleeding and discomfort. Emotional
and psychosexual difficulties may also occur.
HPV subtypes 16, 18, 31, 33 and 35, which may not lead to clinical wart
infection, are implicated in the etiology of high-grade cervical intraepithelial
neoplasia and squamous cell cervical cancer. Virtually all squamous cell cervical
cancers contain DNA from one of the 18 high-risk HPV subtypes known to be
associated with cervical cancer. They are also associated with vaginal and vulval
intraepithelial neoplasia. However, cervical cytology should not be performed
more frequently than usual in women with warts unless indicated for another
reason.
Diagnosis
Genital warts are diagnosed by a careful and thorough clinical examination.
Biopsy and colposcopy are performed if the diagnosis is uncertain, to exclude
malignancy and pre-cancer. Biopsy is also indicated for cervical lesions.
Treatment
It is increasingly recognized that the purpose of treatment for genital warts is to
improve the cosmetic appearance and reduce psychologic morbidity. Treatment
does not eradicate subclinical infection and its effect on the degree and duration
of infectiousness is unknown. Treatment may also fail or new warts may appear
during or after treatment. Warts may also regress spontaneously without
2Late
latent is asymptomatic disease without evidence of tertiary or quaternary disease

where the time from the original infection is greater than 2 years.
treatment. In view of these factors and as many treatments are uncomfortable and
inconvenient, the therapeutic options should be discussed with the patient. Some
will opt to remain untreated. Patients who are distressed may benefit from
counseling.
GUM clinics provide a range of treatment options and wart treatment may be
available at convenient hours without an appointment. This is important, as
multiple attendances are often required. Ablative methods such as cryotherapy
and electrocautery are useful for keratinized lesions whilst cytotoxic methods
such as podophyllin and podophylotoxin are used on soft lesions. Electrocautery,
scissor excision, laser or surgical removal, trichloroacetic acid and intralesional
interferon are occasionally used in specialist centers. Podophylotoxin and
imiquimod (an immune-response modifier) are available for self-application and
can be useful for patients with external warts if they are confident in identifying
lesions, follow instructions carefully and are not at risk of pregnancy.
Progress should be assessed weekly until the warts have been eradicated.
Improvement should be seen within 3 weeks and resolution is usually achieved
in 6. Specialist management should be sought for patients who are
immunocompromised or who have warts affecting the vagina, cervix, urethral
meatus and anal canal. Sexual partners may already be infected with HPV by the
time warts
Table 7.17 Recommended treatments for external genital warts
Treatment
Applied by patient
Podophillotoxin 0.5% solution
Imiquimod 5% cream
Administered by healthworker
Cryotherapy
Podophyllin resin 15% in compound
benzoin tincture
Trichloracetic acid 8090%
Surgical treatment
Electrosurgery
Curettage
Shave and scissor excision
Application
Apply twice daily for 3 days, followed by
4 days of no therapy. Treatment can be
repeated up to four cycles
Apply once at night three times a week for
up to 16 weeks. Wash area after 610 h
Apply with liquid or cryoprobe. Repeat
every 12 weeks
Apply to each wart and allow to dry; repeat
weekly as necessary
Apply to each wart and allow to dry; repeat
weekly as necessary
become apparent. Condoms are usually recommended for 1 month after

resolution. Recommended treatments for genital warts are summarized in
Table 7.17.
Pregnancy and genital warts
In pregnancy genital warts may enlarge or increase in number due to altered
immunity. Treatment may be offered to reduce the size and number of lesions in
an attempt to reduce neonatal exposure and lower the risk of very large lesions
obstructing labor. However, it may be decided to wait and see until after the
delivery, as many treatments for warts are contraindicated in pregnancy, lesions
tend to regress post-natally and the complications (neonatal laryngeal papillomas
and obstruction of labor) are rare.
A new development in the preparation of HPV infection is a vaccine against
HPV type 16. Approximately 20% of all HPV infections are of this subtype, and
it is present in 50% of cervical cancers and high-grade cervical intraepithelial
neoplasia. The vaccine consists of empty viral capsids; it is well tolerated and
generates high levels of antibodies against HPV type 16. In one controlled
clinical trial of over 2300 women, none of the vaccinated patients developed a
HPV type 16 infection after a median of 17.4 months of follow-up. In the
placebo group, 3.8% of women developed an infection. Immunising HPV type
16-negative women may reduce their risk of cervical cancer. Vaccines against
other types of HPV are being evaluated and may help to reduce the incidence of
genital warts.
Molluscum contagiosum
Molluscum contagiosum is caused by a pox virus of the same name. It is spread
by skin-to-skin contact. In adults, it is usually sexually transmitted, especially
when it affects the groin, genital area or lower abdomen. Mollusca commonly
occur in children where they affect the face, trunk and upper limbs and are not
indicative of sexual activity. Lesions appear about 13 months after infection.
They regress spontaneously after several months but can last for up to 2 years.
The lesions are usually asymptomatic or associated with mild pruritis. The
clinical appearance is of papules with shiny umbilicated domes 23 mm across.
In HIV-positive individuals the lesions may be multiple, large, prone to
secondary infection and often located on the face. The diagnosis is made on
clinical grounds but, if required, can be confirmed by electron microscopy of
material from the core of the lesion. As an alternative to waiting for spontaneous
regression, the lesions may be treated by cryotherapy, curettage, expression of
the core or piercing with an orange stick dipped in phenol.
Infestations
Scabies and pubic lice are frequently spread by sexual contact so testing for STIs
should be considered in infested patients. As the incubation period is
approximately 4 weeks for scabies and 14 weeks for pubic lice, sexual partners
should be treated irrespective of symptoms. Permethrin should be used with
caution in women who are pregnant or breastfeeding.
Scabies
Scabies is caused by the mite Sarcoptes scabiei that is transmitted by skin-toskin contact. It has an incubation period of approximately 4 weeks. Clinical
features include pruritis, a rash and signs of excoriation; burrows, frequently seen
on the wrists, elbows and web spaces; and nodules or papules, especially on the
genital area. Secondary infection can occur especially in those with HIV who
may develop highly infectious, extensive, crusted lesions. If the diagnosis is
unclear, mites can be observed on microscopy of material from the burrows.
Individuals and their sexual and household contacts should be treated, whether
or not they have symptoms, with permethrin 5% cream or malathion 0.5%
aqueous liquid. The treatment should be applied to the whole body from the neck
downwards, including the hands, and left on overnight for 12 h. If it is correctly
applied, a single treatment should be sufficient in the immunocompetent. Further
application may cause sensitization and thus worsen symptoms. Permethrin is the
preferred treatment for patients with HIV.
Crotamiton cream and antihistamines are useful for pruritis, which may persist
for several weeks after treatment, especially at the site of nodules. Bedding and
clothing should be washed in hot water or left unused for 3 days, by which time
the mites will have died.
Phthirus pubis (pubic lice)
Phthirus pubis is spread by close bodily contact and can affect hair on the face
and body in addition to the pubic area. As the louse survives less than 24 h
without the human host, fomite transmission is uncommon. The disease may be
asymptomatic. Clinical features include itching, a macular rash and the presence
of lice (crabs) and eggs (nits).
Malathion 0.5% aqueous liquid is recommended for the treatment of pubic
lice. Alternatives include phenothrin 0.2% lotion and permethrin 1% cream rinse
but these are in an alcohol base, which should be avoided by asthmatics and may
irritate excoriated skin and genitalia. Treatment is applied to the whole body and
dry hair and left on overnight for 12 h. Treatment should be repeated after seven
days to kill any newly hatched lice. Casts of eggs remaining attached to hairs
after treatment can be removed with forceps or by combing, but eggs seen at the
base of hairs may signify re-infection or treatment failure. Lice affecting the
eyelashes can be treated with aqueous malathion (which is not licensed for this
use), removed with forceps or coated with petroleum jelly twice daily for a
week. Bedding and clothing used in the previous 24 h should be washed in hot
water or left unused for 24 h, by which time the mites will have died.
BLOOD-BORNE SEXUALLY TRANSMISSIBLE
VIRUSES
The blood-borne sexually transmissible viruses, hepatitis B and C and HIV, are
transmitted vertically, by sexual contact, intravenous drug use and by treatment
or accidental inoculation with blood and its products (Table 7.18).
Table 7.18 Risk factors for sexually transmissible bloodborne viruses
Sexual contact with an infected individual or with a person with risk factors whose
infection status is unknown
Sexual contact with a person from a geographical area where HIV is endemic
Vertical transmission*
Intravenous drug use
Men who have sex with men
Blood transfusion or use of blood products
*Vertical transmission is not proven for hepatitis C. In countries where there is a high
prevalence of hepatitis B in the heterosexual community this is a common
mode of transmission for hepatitis B and the diagnosis may not be made until
adulthood. HIV transmitted vertically usually becomes evident early in
childhood; the risk varies between countries, it is negligible in the UK
Human immunodeficiency virus

There are two types of human immunodeficiency virus, HIV-1 and HIV-2. The
majority of the estimated 49 500 cases of HIV in the UK are due to HIV-1 with
less than 100 cases due to HIV-2. In the UK, approximately 4400 people are
diagnosed as being HIV-positive in 2001 and 36% of new infections are
attributed to heterosexual intercourse. Many people who are HIV-positive
(including about 50% of those acquiring the infection through heterosexual
exposure) are unaware of their HIV status. Between 1986 and 2001 the number
of diagnoses of HIV infection attributed to heterosexual intercourse increased
from 80 to 2444 a year. The majority (over 70%) of these are acquired abroad,
predominantly in Africa. The rise in the number of infected women increases the
potential for vertical transmission. The majority of cases of vertical transmission
are preventable if maternal infection is diagnosed prenatally or in early
pregnancy with appropriate antenatal, intrapartum and neonatal care.
The major advance in the management of men and women with HIV is the
development of highly active antiretroviral therapy (HAART) which delays the
onset of AIDS and death in many of those treated; it is of note that deaths due to
AIDS fell by two-thirds
Table 7.19 Approximate risks of HIV transmission in various settings in Europe and the
USA
Female to male
Male to female
Receptive anal intercourse
Mucous membrane exposure
Needle stick injury
HIV-infected blood in blood transfusion
l:1000 to 1:10000
1:1000
1:30 to 1:125
1:1000
1:300
1:500 000 per unit transfused
between 1995 and 1999 and has remained at the same level since.
The risk of HIV transmission from a single act of unprotected vaginal
intercourse has been estimated to be approximately 1 in 1000 from a male to a
female and less for female to a male (Table 7.19). The risk is higher following
unprotected receptive anal inter-course. The risk of transmission from oral
intercourse is thought to be very low, but has been reported. The likelihood of
infection varies considerably according to the stage of disease, therapy taken by
the infected person and the presence of other conditions such as STIs. The risk is
increased if other STIs are present, if sexual intercourse takes place during
menstruation and in women with cervical ectopy. The risk for acquiring or
transmitting HIV infection is reduced in circumcised men. Condoms, when used
correctly, offer good protection against HIV transmission. Condoms or latex
barriers (also known as dental dams) are recommended for oral intercourse. The
value of prophylactic therapy after condom failure or unprotected intercourse
with an infected person is widely debated. Prophylactic therapy is not widely
available and each case should be considered individually. Prophylactic treatment
for needle-stick injury is more established and should be offered to those
affected. Without treatment, if the needle is contaminated with HIV, the risk of
infection is estimated to be approximately 3 per 1000.
Testing for the human immunodeficiency virus
Until routine antenatal screening was advised in the UK, women were less likely
to be tested for HIV than gay men and, if infected, were less likely to seek
medical care, take medication and to participate in clinical trials.
When HIV infection has been recognized, the patients immune state can be
monitored and, if appropriate, prophylaxis offered for the opportunistic
infections caused by Pneumocystis carinii and cytomegalovirus (CMV). Early
diagnosis in women gives the opportunity to screen more frequently for cervical
dysplasia and to provide appropriate counseling and medical management of
contraception, preconception and pregnancy. Cervical dysplasia is 10 times more
common in HIV-positive women and is related to immunosuppression rather

than HIV itself.
Women who are aware that they are infected with HIV may qualify for certain
social and welfare benefits and are able to make more informed decisions about
their lives. Early diagnosis means that they have longer to live with the
knowledge that they are infected and the associated psychologic and social
sequelae. For many women this is overridden by the benefits of an improved
prognosis, choices about pregnancy and the ability to reduce the risk of
transmission to others, including their children. In addition, those too frightened
to have a test may become depressed and engage in risk-laden behavior and so
need support.
It is important, therefore, to make HIV testing as routine and accessible as
possible. Testing should be performed only with the clients informed consent
with referral to specialist counselors reserved for those who are at high risk of
infection or are extremely anxious. Patients should understand the meaning of a
positive and negative test and the 3-month window period. The advantages and
disadvantages of testing include medical benefit, stigma, social and psychologic
effects, impact on relationships, work and insurance. Any service providing HIV
testing must have a protocol for managing people with positive results, who may
need immediate psychologic support and medical referral. This is particularly
important in areas of low prevalence where facilities and expertise may be
limited. Both negative and positive results should be given in person, preferably
at morning clinics, when help for those with positive results can be sought.
Clients who test negative may need to repeat the tests after the window period
and may require advice about how to remain uninfected.
Prevention of vertical transmission of the human
immunodeficiency virus
The prevalence of HIV among women giving birth in London has risen five-fold
since 1988 and in 2001 it was 0.35% in London and 0.04% in the rest of the UK.
In London, the prevalence of HIV in women having a termination of pregnancy
is approximately two times that of women continuing with their pregnancy.
Unless maternal HIV infection is diagnosed before or in pregnancy the risk of
vertical transmission is approximately 20%, and possibly as high as 30% in the
developing world. Additional 1214% are infected if the mother breastfeeds the
infant into the second year. In the US Center for Disease Control study ACTG
076, vertical transmission of HIV was reduced from 25.5% to 8.3% by giving
zidovudine to mothers during pregnancy and labor and to the neonate. Other
interventions to reduce vertical transmission are elective Cesarean section and
abstaining from breast-feeding. The combined intervention of antiretroviral
drugs, elective Cesarean section at 38 weeks and no breastfeeding reduces the
risk of HIV transmission to less than 2%. The options of drug therapy, Cesarean
section and alternatives to breastfeeding may not be available in the developing
world. A child born with HIV despite these measures can benefit from early
intervention such as prophylaxis for P. carinii infection. Due to the
transplacental passage of maternal antibodies to HIV, the status of the neonate
cannot be determined until the child is approximately 18 months old; until this
time the HIV status of the child is referred to as being indeterminate.
Human immunodeficiency virus infection and infertility
treatment
HIV infection is not in itself a contraindication to infertility treatment and each
case should be considered on its merits by the general practitioner, gynecologist
and patient. Patients considering a pregnancy should see a specialist, particularly
if the couple are discordant. Women with HIV require information on reducing
the risk of transmission to their partner and fetus. Where the male partner is HIVpositive, recent work to reduce HIV transmission by washing semen samples
prior to insemination is encouraging.
Hepatitis A, B and C
All patients seeking consultation for STIs should be advised about hepatitis A,
B, and C. Although uncommon, some patients may present with symptoms, signs
or laboratory findings of viral hepatitis. This brief section is a reminder to the
healthcare provider not to forget that hepatitis A, B and C can be sexually
transmitted.
Hepatitis A
Hepatitis A is caused by the hepatitis A virus (HAV), which is transmitted via a
fecal-oral route. HAV has an incubation period of about 4 weeks (range 1550
days). It replicates in the liver and is shed in the feces. Over 80% of infected
people have symptomatic infections, but in some the infection is inapparent. Like
any enteric infection, hepatitis A can be sexually transmitted. Outbreaks of
hepatitis A among men who have sex with men have been reported.
In a recent survey of sexual behavior in Britain, 11% of women and 12% of
men reported anal sex in the past year. Inapparent fecal contamination may be
present during heterosexual intercourse. Many sexual practices and inadequate
personal hygiene also facilitate the fecal-oral transmission of HAV. Condoms do
not prevent the transmission. Vaccination is recommended for people at risk of
sexual transmission of the virus and for drug users.
Hepatitis B and C
Hepatitis B is caused by infection with the Hepatitis B virus (HBV). HBV
replicates in the liver and is found in a high concentration in the blood and in
lower concentrations in other body fluids: semen, vaginal secretion, and wound
exudates. A person with a chronic HBV infection is potentially infective for life.
Transmission of HBV can occur in heterosexual partners and in men who have
sex with men.
Other risk factors for hepatitis B are essentially the same as for HIV
(Table 7.16), whereas hepatitis C is much less likely to have been acquired
through sexual intercourse. People identified as having HIV or hepatitis C
infection or who are carriers of hepatitis B should be referred for specialist care.
Those at risk of hepatitis B who are non-immune should be offered vaccination.
Hepatitis B is a notifiable disease. The incubation period for hepatitis B is
approximately 40160 days while hepatitis C serology is usually positive after 3
months.
8
Benign breast conditions and screening for
breast cancer
Nikolai Manassiev
INTRODUCTION
Breast disorders account for a large number of consultations. It is estimated that
30 per 1000 women consult their general practitioner about a breast problem
every year. In general surgical units, breast problems can occupy some 25% of
the workload. Breast disease presents as a painless lump in 35% of women, a
painful lump in 33% and as diffuse or generalized pain in the breast in 18%.
Nipple discharge is the presenting symptom in about 5% of patients and a
smaller percentage present as breast or nipple distortion, inflammation or eczema
or change in appearance in the breast or the nipple. The bedrock of diagnosis is
the so-called triple assessment or a combination of (1) breast examination; (2)
imaging (mammography, ultrasound); and (3) biopsy or cyst aspiration. It is
important to reach a diagnosis as soon as possible because women with breast
symptoms are commonly afraid that they have breast cancer. It has to be
emphasized that the majority of women who present with breast symptoms do not
have breast cancer. About half of all women who attend breast clinics are found
to have no abnormality on examination and investigation, and a further 40%
have benign disease.
CLINICAL APPROACH TO BREAST DISEASE
Nomenclature of breast disease is confusing. The simplest classification is to
describe what is felt when the patient is examined, i.e., a lumpy breast or a discrete
lump. By separating a discrete solitary lump from the lumpy breast, women are
separated into those who will need further investigation and those who require
only explanation and reassurance. The discrete solitary lump can be a
fibroadenoma, a cyst or a carcinoma. Other discrete solitary lumps are rare and a
detailed discussion of them is beyond the scope of this review.
A lump in the breast needs to be at least 1 cm in diameter to be detected
clinically. About 30% of women have lumpy breasts. The preferred term to
describe lumpy breast(s) is benign breast change. Terms like chronic mastitis
or fibrocystic disease are meaningless and suggest that a histologic diagnosis can
BREAST CONDITIONS FOR BREAST CANCER 213
be established at the time of the clinical examination when it cannot. The lumpy
breast may or may not be accompanied by cyclical pain associated with
menstruation. Women with no discrete lumps but with lumpiness should be
reassured. They should not be let to believe that they have a disease. Similarly,
young women who get cyclical pain for about a week before their mensessocalled cyclical mastalgiashould also be reassured. Brownish nipple discharge,
particularly from several ducts, is usually caused by duct ectasia and is a
common condition but not sinister. All other cases, particularly discrete lumps at
any age, should be referred to a breast specialist (Table 8.1). Difficult cases,
where it is not certain whether it is a lump or lumpiness, should also be referred.
Many women consult their doctors not because of symptoms but simply because
of a family history of breast cancer. It is important to explain to these women
that breast cancer is a common disease that makes it likely that in some families
there will be a case of breast cancer. One such
Table 8.1 Patients for whom referral to a breast specialist is recommended
Discrete mass
Persistent asymmetric nodularity
Nipple discharge, especially if blood-stained, profuse or in a woman above 50 years of
age
Nipple retraction or distortion
Severe mastalgia
Changes in the breast skin, i.e., dimpling, tethering, etc.
Relevant family history
case in a patients family history does not necessarily point to hereditary breast
cancer but that the individual may run a higher than average risk. There are
special cases where an individual is strongly predisposed to breast cancer and
these should be recognized and referred to a specialist unit.
BENIGN BREAST CONDITIONS
Fibroadenoma
Fibroadenoma is the most common benign breast neoplasm and accounts for
about 12% of all palpable breast lumps. They are particularly frequent in women
aged 1530 years. Fibroadenomas commonly present as a painless breast lump
and some 20% are multiple. Clinical breast examination reveals a firm, mobile,
smooth or lobulated non-tender mass. The impression of a benign tumor is
confirmed by imaging and fine-needle cytology. The natural history of a
fibroadenoma is that approximately 5% grow progressively, the majority remain
the same size and about 20% regress. In women under 40 years of age, small
(less than 2 cm) fibroadenomas do not need to be removed. If the lump starts to
grow, however, removal is indicated. Many surgeons recommend excision of any
lump in women over 40 years of age.
Breast cyst(s)
Benign breast cysts are common and most frequent in the 4050 year age group.
In one study of 725 patients who died from causes other than breast cancer,
microcysts (< 1 mm) were found in 37% of women and larger cysts were
detected in 21%. Breast cysts are frequently multiple, often asymptomatic and
are often discovered by chance by the patient. A solitary cyst is smooth and
spherical. In consistency it can vary from soft to firm to hard. Usually it is not
possible to demonstrate fluctuation, fluid thrill or transillumination. The clinical
diagnostic feature is its smooth round shape. When subjected to triple evaluation,
they exhibit specific X-ray features and fine-needle aspiration usually obtains
green to bluish-black fluid. Provided that no residual lump remains after
aspiration and the fluid is not blood-stained, cytology is not necessary. If there is
a residual lump, it needs to be subjected to biopsy, unless cytology suggests
otherwise. Recurrence of cysts is infrequent, but if the patient is known to have
recurrent cysts and presents with another lump, it is generally safe to perform
aspiration without a new triple evaluation. Figure 8.1 depicts an algorithm for the
management of breast lumps.
Breast pain
Breast pain is the third commonest presenting symptom of breast disease. Breast
pain is either cyclical, non-cyclical or does not originate from the breast. A
careful history and clinical examination usually can help distinguish between
these categories. Sometimes it is helpful to ask the patient to keep a pain diary so
that the nature and cyclicity of the pain can be established. Cyclical pain can
become continuous as it becomes more severe. If the pain is clearly cyclical and
the breast examination does not reveal a discrete lump, no further investigation is
needed. If the pain is of recent onset, non-cyclical and located in one breast only,
investigation with imaging is necessary. If the results of the examination and the
imaging are negative, the patient has to be reassured. If the imaging gives cause
for concern, a biopsy is indicated.
Non-cyclical breast pain has inflammation as the underlying pathology. It is
difficult to treat, but stopping smoking and a trial of non-steroidal antiinflammatory drug may help. If the pain is localized to a single tender spot
within the breast, infiltration with local anesthetic and a corticosteroid may help.
Gamolenic acid is taken by many women, but it is not usually effective.
Figure 8.1 Management of breast lumps
Cyclical mastalgia
This is a condition which presents with pain lasting typically for about a week in
the second half of the luteal phase. The pain is due to the effect of cyclical
hormonal changes in the breast, which may increase some 1015% in size
premenstrually. Common strategies to help women with cyclical mastalgia are:
properly fitting brassieres, danazol, tamoxifen and prolactin treatments, normally
tried in that order. Treatment of 812 weeks is recommended before assessing
the result and deciding to change. Diuretic therapy and supplementation with
vitamins B, B6 and E have not been proven to be effective. Dietary
manipulations (excluding coffee, tea and chocolate) can also be tried. Figure 8.2
represents a common treatment algorithm for breast pain. Until recently,
gamolenic acid was commonly prescribed for breast pain. However, because of
lack of effectiveness it is no longer available on the UK National Health Service
(NHS).
Figure 8.2 Management of breast pain. tds, three times a day; bd, twice a day; od, once a
day
Nipple discharge
Nipple discharge occurs in over 10% of women with benign breast disease and in
23% of women with cancer. In 5% of women consulting their physician for a
breast problem, spontaneous nipple discharge is the primary complaint. The
discharge can be clear, milky, bloody or of green/dark color. Bilateral nipple
discharge, clear or milky, in the absence of breast lump(s), excludes breast
cancer and indicates systemic cause, such as a prolactinoma or medication.
Unilateral clear or bloody discharge is commonly caused by duct papilloma or
duct ectasia. Pressing with one finger around the periphery of the areola will
reveal the culprit duct. Excision of a single duct is the recommended treatment,
so intraduct carcinoma can be excluded. Some practitioners evaluate clear
discharge with mammography and cytology, reserving duct excision for patients
with bloody discharge. Multiduct discharge due to duct ectasia does not require
treatment except for symptomatic relief. The patient should be advised to wear a
properly fitting brassiere and be discouraged from aspirating the discharge or
manipulating her breasts.
BREAST CANCER
Cancer is the second most common cause of death in the UK. Two in five people
in Britain will have a cancer diagnosed at some time during their life and one in
four will eventually die from the disease. Some recent cancer statistics are
outlined in Table 8.2. Many forms of cancer are eminently treatable when
discovered early but the prognosis worsens the later the cancer is diagnosed.
Therefore establishing a screening program for the early detection of cancer,
preferably in the preclinical stage, makes sense.
Breast cancer is the most frequently diagnosed cancer after skin cancer. In
1998 it was the most frequent cause of cancer death among British women but
was overtaken by lung cancer the following year. Estimated lifetime risk of
breast cancer in British women is approximately one in 11, or 9%. Because it is a
cumulative risk estimate the one-in-eleven statistic, although accurate, is the most
Table 8.2 Cancer statistics for women (excluding non-melanoma)
IncidenceUK 1999
DeathsUK 2001
Cancer
n (%)
Cancer
n (%)
Total
malignant
Breast
136 160
Total
malignant
Breast
79 422
Five-years survival for

selected cancers (%)*
Total
43
malignant
40 989 (30)
12 994
Malignant
82
melanoma
Colorectal
16 811 (12) Lung
13 038
Breast
74
Lung
14 737 (11) Colorectal
7 630
Uterus
65
Ovary
6 800 (5)
Ovary
4 657
Cervix
61
Uterus
5 612 (4)
Pancreas
2 527
Colorectal
39
Cervix
3 202 (2.4)
3 543 (5)
Ovary
28
*From registration 1986-1990; data derived from Cancer Research UK May 2003
(www.cancerresearchuk.org/aboutcancer/statistics/)
Table 8.3 Risk factors for breast cancer
Factors influencing risk
Estimated relative risk
Age
Residency in Western Europe or North
America vs. Asia
Residency in urban area
Higher educational status or family income
One first-degree relative with breast cancer
Two first-degree relatives with breast cancer
Premenopausal breast cancer in mother or
sister
Nulliparity or late age at first
birth (> 30 vs. < 20 years) No breastfeeding
for > 6 months
Early menarche (< 12 vs. > 15 years)
Incidence strongly influenced by age

4-5
1.5
1.5
2-3
4-6
3.0
2.0
1.5
1.5
Factors influencing risk
Estimated relative risk
Late menopause ( 55 vs. 40-45 years)

1.5
Biopsy-confirmed proliferative breast disease 2.0
Obesity (postmenopausal only) ( 200 vs. <
2.0
125 lb)
History of breast cancer in one breast
4-5
History of primary ovarian or endometrial
1.5
cancer
HRT use (for 5 years after the menopause)*
1.35
Oral contraceptive use*
1.2
High alcohol intake (approx. 2 units/day)
1.4
The risk disappears after 5 years of stopping the therapy; HRT, hormone replacement
therapy
Table 8.4 Protective factors for breast cancer
Early first-term pregnancy
Lactation ( 6 months)
Physical activity
Low alcohol consumption
Diet high in fresh fruits and vegetables
Early menopause: before 45 years
Age of menarche: 20% decrease for each year that menarche is delayed after the age of
16 years
dramatic way of describing the risk. It is important to emphasize that only

25-35% of women developing breast cancer actually die from the disease - an
important fact for concerned women. The estimated lifetime risk of dying from
breast cancer is about 1:30-35 women. There are approximately 33 000 new cases
of breast cancer a year in the UK, and the total mortality from this disease is
about 13 000 a year. Rates vary, with the Far East having a much lower
incidence than Western Europe and North America. Some risk factors for breast
cancer are given in Table 8.3, while some protective factors are listed in
Table 8.4. It should be noted that the numbers in Table 8.3 are not absolute. They
tend to change as new data become available and they vary between studies.
According to life tables, the potential years of life lost because of breast cancer
for 1000 women is 463 as compared to 460 potential years of life lost from lung
Table 8.5 Risk of developing breast cancer in the USA stratified by age
Age interval (years)
Risk of developing breast cancer (%)
095
3040
12.64
0.4
Age interval (years)
Risk of developing breast cancer (%)
4050
1.65
5060
1.95
6070
3.6
7080
4.1
6585
5.48
Data derived from (1) Garber JE, Smith BL. Management of the high-risk and the
concerned patient. In Harris JR, et al., eds. Diseases of the Breast. Philadelphia,
PA: Lippincott, 1996:324; and (2) Feuer EJ, Wun LM. The lifetime risk of
developing breast cancer.J Natl Cancer Inst 1993;85:8927
cancer and 1535 years lost from cardiovascular disease. These calculations show
that, although breast cancer is an important cause of premature death, the number
of deaths it causes is approximately equivalent to that of lung cancer (a
predominantly preventable disease) and vastly smaller than that of
cardiovascular disease.
The background risk for breast cancer (Table 8.5) is different in different age
groups. For counseling purposes, one might consider providing breast cancer risk
figures for various time intervals, such as the next year, the next 10 years or a
lifetime.
Appreciating the magnitude of breast cancer risk is not possible unless a
comparison is made. To put this risk into context, it is necessary to give the risk
of other life events. Examples are given in Table 8.6.
High-risk groups and family history
Inherited mutations in the breast cancer BRCAl and BRCA2 genes predispose
women to both breast and ovarian cancers, often at younger ages. BRCAl/2induced cancer accounts for 57.5% of all breast cancer, the rest being sporadic.
The pattern of inheritance in families that are carriers of BRCAl/2 mutations is
autosomal-dominant, with 50% of the offspring inheriting the mutations. For
Table 8.6 Risk of death from various life events per annum
Life events
Relative risk
All natural cause, age 40 years

Influenza
Road traffic accident
Leukemia
Maternal mortality
Playing football
Accident at home
Accident on railway
1:850
1:5000
1:8000
1:12 500
1:16 700
1:25 000
1:26 000
1:500 000
Life events
Relative risk
From one unit of blood transfused

Hit by lightning
1:5 000 000

1:10 000 000
young women with high-penetrance mutation(s), the lifetime risk of developing

primary breast cancer may be as high as 90%, the risk of breast cancer in the
unaffected breast about 65%, and the risk of ovarian cancer may exceed 40%.
Therefore, women at risk may consider preventive strategies such as tamoxifen,
prophylactic mastectomy and/or prophylactic oophorectomy. Screening for
BRCAl and BRCA2 genes is performed in regional genetic centers, which should
be able to provide referral guidelines on request.
Proper risk estimation and family tree reconstruction is possible only if at least
some of the affected relatives are still alive and blood samples can be taken for
genetic screening. It has been recommended that for families with very high risk,
annual mammography and breast examination should start at an age 10 years
younger than the youngest affected relative. For women with high risk because
of the family history or simply at increased risk because of non-familial causes,
annual mammography and breast examination should start 5 years before the age
of the youngest affected relative, but no later than 3540 years of age. There is
no agreed definition what constitutes high risk or very high risk, but examples
are: (1) Very high risk: two or more first-degree relatives with breast or ovarian
cancer, one or more first-degree relatives with breast cancer before the age of 40
years
Table 8.7 British Association of Surgical Oncology guidelines for familial breast cancer
management
High risk (refer to regional genetic center for testing)
Breast/ovarian cancer families with four or more relatives on same side affected at any
age
Breast cancer in three affected relatives with average age at diagnosis under 40 years
Breast/ovarian cancer families with three affected relatives with average age at
diagnosis under 60 years
Family with one relative with both breast and ovarian cancer
Moderate risk (annual mammography age 3549;
mammography every 18 months for patients above 50 years
One first-degree relative with breast cancer diagnosed at under 40 years
Two first- or second-degree relatives with breast cancer diagnosed at under 60 years
Three first- or second-degree relatives with breast cancer diagnosed at any age
Two first- or second-degree relatives with ovarian cancer diagnosed at any age
One first-degree relative with bilateral breast cancer diagnosed at under 60 years
One first-degree male relative with breast cancer at any age
Reproduced from Emery J, Murphy M, Lucassen A.Hereditary cancerthe evidence for

current recommended management. Lancet Oncol 2000; 1:916, with
permission from Elsevier
or any first-degree relative with bilateral premenopausal breast cancer; and (2)
High risk: any one first-degree relative, three or more second-degree relatives or
any second-degree relative with breast cancer before the age of 40 years. An
example of recently published guidelines from the British Association of Surgical
Oncology is presented in Table 8.7. The reader should bear in mind that
guidelines vary between countries and even within the same country, and do
change. Guidelines should be used to justify referral pattern at all times.
Clinical breast cancer
About 8590% of clinically discovered breast cancers present with a lump in the
breast; most of the remaining 1015% present with pain, skin or nipple retraction
(5%) and discharge from the nipple (2%); pain or swelling in the axilla is also
occasionally noted. Signs include a mass, tethering of the skin and reduced
mobility, dimpling of the skin and nipple inversion. Skin infiltration or erosion,
the classic peau dorange and axillary or supraclavicular lymph node enlargement
are signs of advanced disease. An eczematous nipple may be a sign of an
underlying intraductal cancer. Occasionally, the patient may present with
symptoms from secondary deposits, for example in the spine or brain. About 90%
of all breast cancers originate from the epithelium lining the lactiferous ducts and
ductules and are therefore typical ductal adenocarcinomas. The rest originate
from the alveoli and are lobular adenocarcinomas. Intraductal carcinomas of the
breast (ductal carcinoma in situ) without true invasion are early lesions, often
multifocal and are increasingly discovered during mammographic screening.
Breast cancer spreads lymphatically, both locally and to distant sites.
Hematogenous spread occurs particularly to bone, liver, lung, skin and the central
nervous system and can happen early during the course of the disease.
The diagnosis for a breast lump is established by clinical examination,
mammography and/or ultrasound scan, and fine-needle aspiration biopsy or
histology. Aspiration of cysts is easy and the finding of cysts with typical
greenish fluid and disappearance of the lump after aspiration make the diagnosis
of cancer extremely unlikely. Fine-needle aspiration cytology from solid lesions
is established as a useful and accurate technique. If there is diagnostic
uncertainty, a much larger piece of tissue can be obtained by core biopsy with a
wide bore percutaneous biopsy needle, which usually yields an adequate core of
tissue. Ultrasound-guided core needle biopsy, stereotactic biopsy and magnetic
resonance imaging (MRI)-directed biopsy are important diagnostic tools,
especially for women with suspicious but non-palpable breast masses. If a
diagnosis cannot be reached after these investigations then excisional biopsy is
necessary. Treatment options for breast cancer are surgery, radiotherapy,

chemotherapy and hormonal manipulation.
Table 8.8 Risk stratification and survival rates for breast cancer
Group
Five-year survival
(%)
Example
Treatment
Minimal risk (stage

1)
> 90
Local
Low risk (stage 2)
7090
High risk (stage 2)
5070
Locally advanced
(stage 3)
Metastatic (stage 4)
3050
Screen-detected < 1
cm or ductal
carcinoma in situ
Node negative,
histologic grades I
and II
Node positive or
histologic grade III
Large tumor or skin
fixation/ulceration
Skin, bone, lung,
liver brain
1218
Loco-regional
Loco-regional and
systemic
Primary systemic
Primary systemic
Prognosis depends on the stage, histologic grade and estrogen receptor (ER)
status. Prognosis is best when there is no lymph node involvement and worse
when four or more lymph nodes are affected. Treatment modalities and survival
rates are outlined in Table 8.8. Breast cancer can recur many years after the
initial diagnosis and treatment. Overall survival rates from all stages combined
are 65% at 5, 35% at 10 and 30% at 15 years.
Hormone receptors in breast cancer
Normal breast cells have both estrogen and progesterone (PR) receptors. The
breast estradiol receptor content is 510% of that in the endometrium. ERs are
present in 65% of cancers in postmenopausal women, but only in 30% of cancers
in premenopausal women. ER and PR positivity denotes that the tumor cells are
better differentiated and have retained some of the features of the healthy cells.
ER-positive breast cancers are more likely to respond to hormonal manipulation,
thus oophorectomy can be avoided in patients who have ER-negative tumors. At
most 57% of ER-negative tumors will respond to hormonal manipulation.
Conversely, 3040% of either ER- or PR-positive tumors will respond; when
both receptors are present the rate is 7090%. Tamoxifen reduces the risk of
relapse and mortality by 25% and 17% at five years, respectively. Adjuvant
tamoxifen taken for up to five years reduces the risks of recurrence and death in
postmenopausal women independent of the ER status of the tumor,
independently of nodal involvement or chemotherapy. The same is true for
premenopausal women but only for those with ER-positive tumors. There is no
additional benefit from extending treatment beyond five years and there is an
increased risk of cancer of the endometrium and venous thromboembolism

associated with tamoxifen treatment. For premenopausal women, ovarian
ablation either by surgery or radiotherapy significantly improves survival,
independent of lymph note status. If tamoxifen fails, aromatase inhibitors are
used as second-line and progestins as third-line treatment. In hormone-resistant
disease, chemotherapy is recommended.
Prevention of breast cancer
Tamoxifen and raloxifen substantially decrease the risk of breast cancer. This
was shown in a recent major controlled trial with over 7000 participants
demonstrating that in high risk women 20 mg/day tamoxifen for 4 years
decreases the risk of breast cancer by a third. However, the routine prescription of
these drugs for prevention has not yet become established clinical practice.
Hemoprevention should be considered for individuals at high risk for breast
cancer. Other preventative measures are: (1) decreasing alcohol and dietary fat
intake; (2) increasing exercise; and (3) breastfeeding.
Screening for breast cancer
To screen or not to screenthat is the dilemma. The problem is not simply
medical but also a matter of economics. To screen the entire adult female
population on a regular basis is expensive. In healthcare systems, such as the NHS,
it can only be justified if screening together with effective treatment of
asymptomatic disease can be shown to reduce the mortality rates in a costeffective manner.
Ideal criteria for establishing a screening program are set out in Table 8.9.
Sadly, so far, there is no screening program which fulfills all these criteria.
The purpose of breast cancer screening is to distinguish women who are
clearly normal from those with abnormality. The goal of breast cancer screening
is to reduce morbidity and mortality caused by breast cancer. This is to be achieved
by intervening in the disease process after biological onset but before symptoms
develop. There are three methods for breast cancer screening that are currently
practiced: X-ray mammography, clinical breast examination and breast selfexamination.
Mammography
Breast cancer screening by mammography is the only screening procedure which
has been evaluated by means of randomized controlled trials. Nevertheless,
screening mammography has been more controversial than perhaps any other
medical intervention. Provided that the intervention does not cause significant
harm, we subscribe to the view that a treatment is effective until proven
ineffective, in parallel with the well-established concept of innocent until proven

guilty.
The most definitive measure of efficacy of a breast cancer screening program
and the least subject to bias is the breast cancer mortality rate as determined by
comparing screened and unscreened groups in randomized clinical
Table 8.9 Ideal criteria for establishing a screening program
Important health problem
Acceptable treatment available
Natural history understood
Recognizable latent phase
Suitable test available:
simple
acceptable
accurate
repeatable
high sensitivity and specificity
Early treatment improves prognosis
Agreed policy on whom to treat
Effective diagnosis and treatment available
Case finding is a continuous, not one-off process
Cost of treating early disease substantially lower than cost of treating advanced disease
trials. Survival, in itself, does not establish that the natural history of the disease
has been altered or that mortality has been reduced. Screening aims to detect
breast cancer at a very early stage when cure is more likely. Mammography can
detect cancers as small as 1 mm, which compares very favorably with clinical
examination. Mammography does not have 100% accuracy and negative
mammography does not mean that there is no cancer present. However,
mammography detects over 90% of all breast cancers. Mammography and
clinical examination are complementary and if there is strong suspicion of a
palpable lesion, biopsy should be attempted even if the mammography is
negative.
Single-view mammography uses a 1.2 mSv radiation exposure to the breast.
The lifetime risk of induction of a cancer from one such examination in this age
group is about 1:100 000. For women aged 4049 this risk is approximately
doubled. The risk of developing breast cancer naturally in any one year is about
120150 per 100000 women. The small carcinogenic risk of mammography is
justified on the basis that mammographically detected cancers carry a greatly
improved prognosis. Radiation exposures from widely
Table 8.10 Radiation exposure from various widely used diagnostic procedures
Diagnostic procedure
Typical radiation dose

(mSv)
Approx. equiv. period of

radiation from a natural
background source
Chest (single postero0.02

3 days
anterior film)
Hip
0.3
7 weeks
Abdomen
1.0
7 months
Mammography
1.2
8 months
Lung ventilation/perfusion 1.3
8 months
scan
Computed tomography
2.3
1 year
head scan
Barium enema
7
3.2 years
mSv, milli Sievent (unit of dose of ionizing radiation which delivers one joule of energy
per kg recipient mass)
used diagnostic procedures are outlined in Table 8.10.

Screening in the UK is performed by inviting all women aged between 50 and
64 years to undergo a mammography every three years. The first screen consists
of a two-view mammography, and subsequent mammograms are performed by a
single-view (in a two-view mammography the projections are cranioaural and
mediolateral, whereas in a single-view mammography there is only an oblique
mediolateral view). Practices vary between countries. For example, in the USA,
mammography is recommended every year after the age of 40 years, while in
Sweden every 1824 months is the standard recommendation. In both countries
two-view mammography is the norm. The optimum age group to be screened and
frequency of mammography remain uncertain but it is thought that screening
decreases mortality by 2025% 1, 2, 3.
When a screening program begins, about 1020 prevalent cases are detected
per 1000 women. At follow-up, the new incident case rate is about 26 per 1000
women per year. Of all mammographically detected cancers, 20% are in situ
disease and 40% are less than 1 cm in diameter. Overall around 65% are less
than 2 cm in diameter. This compares very favorably with clinically detected
cancers, where barely one-quarter are 2 cm or less. Cancers less then 2 cm in
diameter which have no lymph node involvement carry the best prognosis. When
there is an invasive lesion as opposed to in situ, there is always a possibility of
metastasis. Once the tumor is over 5 cm in diameter, a cure is unlikely. Currently,
90% of women who are referred for further investigation upon screening do not
have cancer, and this point should be stressed to minimize anxiety. The
effectiveness of mammographic screening depends, amongst other things, on the
total number of women attending regularly for screening. Currently the uptake
for screening is between 55 and 90%, depending on education, social class, age
and area of the country. A downside of breast cancer screening is that it

generates additional work for staff and anxiety in some women. In addition,
some of the in situ cancers may not become clinically significant in the lifetime
of the woman.
Breast self-examination
More than 80% of clinically diagnosed breast cancers are discovered as a lump
by the patient. Intuitively it follows that regular breast self-examination may help
discover some cancers at an earlier stage, when the prognosis is more favorable.
However, less research has been devoted to clinical breast examination and/or
breast self-examination than to mammography. Breast self-examination should
probably start after the age of 35 years. Women should be taught by a welltrained practitioner. The stages of examination are as follows:
(1) The woman should undress to the waist and stand in front of a mirror, carefully
looking at all parts of both breasts, first with her arms relaxed, then stretched
over her head. Then she should put her hands on her hips and watch the breasts
when she presses her hands into her hips and relaxes.
(2) The woman should be looking for any difference in shape between the
breasts. Size is not important because often one breast is bigger than the
other. She should be looking for changes with arm movements and when her
hands are pressed against her hips. With early cancer, there can be slight
depression, flattening, rippling or dimpling of the skin in one part of one
breast. The nipple may become deviated or become depressed or retracted.
These changes can occur in very early cancers when there is no lump to feel.
Tethering or peau dorange are signs associated with both early and
advanced disease and can be seen in any position.
(3) Palpation of all areas of both breasts, including the axillary tail, should be
covered and any new differences between the two sides should be reported.
Cancers under 2 cm are not usually the cherry stones that most women
expect. They could be just a bit of thickening with a slight depression when
the pectoral muscles are contracted. However, tumors usually feel harder
than they are, due to involvement of the surrounding tissue.
(4) Any new symptoms should be reported. A blood-stained nipple discharge is
very worrying to the woman, but the majority are benign and are due to
either duct papillomas or duct ectasias. One-sided and particularly serous
discharges from one duct of one nipple should be reported to the doctor, as
should the development of localized discomfort or an odd, strange feeling
which is often localized and difficult to describe but which does not
resemble premenstrual tenderness.
(5) Monthly self-examination, after menstruation, is ideal.
There are now several epidemiologic studies indicating that survival is increased
in women practicing breast self-examination and that cancers detected by breast
self-examination tend to be smaller. However, as discussed earlier, an increase in
survival does not necessarily translate into reduction in the mortality rates.
Although these results are promising, firm evidence that the mortality rate is
reduced is lacking and more data are needed.
Clinical breast examination
Clinical breast examination (CBE) has not been adequately tested against an
unexamined control group, and there is no experimental evidence that the benefit
of annual breast examination exceeds the possible harm resulting from falsenegative and falsepositive examination. Not surprisingly, recommendations
regarding CBE vary. In the UK, the Department of Health (the governments
advisory committee on breast cancer screening) has advised that breast palpation
should not be included as part of routine health screening. However, the
Canadian Task Force on periodic health examination, the US Preventive Services
Task Force and the American College of Physicians all recommend yearly CBE
starting from the age of 40 years. It is a well known fact that the mortality from
breast cancer in the US is lower than that in the UK. To what extent, if any, CBE
is contributing to the lower mortality is still matter of debate.
When performed by carefully trained medical personnel, CBE is quoted to
have a sen sitivity of 80% and specificity of 8896% at the first examination4.
These figures may look overoptimistic and non-attainable in everyday clinical
practice; however, on the other hand, they clearly show the potential of CBE.
ACKNOWLEDGEMENTS
This chapter was extensively reviewed by Dr J.Steel, Consultant, Breast
Screening Service, and Dr L.Chapman, Department of Surgery, both at Derifford
Hospital, Plymouth, UK.
References
1.
2.
3.
Nystrm L, Andersson I, Bjurstam N, et al. Long-term effects of mammography

screening: updated overview of the Swedish randomised trials. Lancet 2002;359:
90919
Tabar L, Yen MF, Vitak B, et al. Mammography service screening and mortality in
breast cancer patients; 20-year follow-up before and after introduction of
screening. Lancet 2003 361: 140510
Otto SJ, Fracheboud J, Looman CW, et al. Initiation of population-based
mammography screening in Dutch municipalities and effect on breast cancer
mortality: a systematic review. Lancet 2003;361:14117
4.
Rimer BK. Breast cancer screening. In Harris JR, et al., ed. Diseases of the Breast.
Philadelphia, PA: Lippincott 1996:318
9
Sexual function and dysfunction
Nikolai Manassiev
INTRODUCTION
Sexuality is an important component of physical, intellectual, psychologic and
social well-being. This central role of sexuality in a persons life is affected by
health or illness and by many psychologic factors. Physicians have the
opportunity to assess the sexual function in the course of routine history taking;
however, this is rarely done. Additionally, many doctors are uncomfortable with
the patients questions about sexuality and feel uneasy about broaching the
subject themselves. In some cases, they feel that such questions are an intrusion
on the patients privacy, even though they realize that bowel and drug habits,
cigarette and alcohol use and reproductive status are also private matters. In
other cases, they believe that the patients sexual concerns are not of medical
significance or that their own ability to treat such concerns is limited. In this way,
they ignore or dismiss the patients concerns.
Patients may expect their physician to be an authority on sexual matters but
frequently are unable to express their concerns for fear of being criticized or
misunderstood. Surveys of clinical practices show that only 10% of patients will
initiate a discussion of sexual problems if the physician does not, but over 50%
will describe a sexual concern if the doctor provides an opportunity for
discussion. Thus, the onus of breaking the vicious circle of avoiding talking about
sexual matters seems to fall on the physician. Such enquiry may lead to a
diagnostic clue in an otherwise elusive diagnosis.
Concerns about sexual matters and sexual dysfunctions affect all ages. It is
important to remember that the demographics of the Western societies are
changing. There is an increase in longevity, which leads to two separate
phenomena. On the one hand, there is a large population of middle and retirement
age people who are spared the ravages of harsh physical labor, and who age in
good general health with a secure income. On the other hand, many patients with
previously untreatable chronic diseases, such as cancer, hypertension, angina,
diabetes, depression, rheumatoid arthritis and osteoarthritis, live much longer
with an improved prognosis. In both groups, the presence of a sexual dysfunction
may completely spoil the enjoyment of better health. Therefore, it is necessary
that health professionals nowadays should have a basic understanding of human

sexuality and sexual dysfunctions.
HUMAN SEXUAL RESPONSE
Procreation through sexual activity is an adaptive evolutional response, which
gives the species a high potential for survival. Sexual behaviora much wider
subjectis, however, a learned behavior. In mammals and non-human primates,
it is controlled by instincts with timing dependent on the estrus cycle of the
female. By contrast human sexual behavior is influenced by the family,
sociologic factors (mass media, community institutions and social milieu),
individual experience and choice.
Even though sexual behavior and attitudes toward sex vary greatly among
individuals, the desire for sexual pleasure is thought to be strong in most men
and women. It should be noted that sex for satisfying sexual hunger is only one
reason for sexual experience. Other reasons for having sex with a partner, and
particularly important for women, are: (1) to enhance emotional closeness,
bonding, commitment, sharing and tolerance; (2) to show love and affection; or
(3) to let the partner see that he/she has been missed (emotionally and/or
physically). There is no consensus regarding terminology for the force that
makes us initiate or respond to sexual behavior, but commonly used terms for it
are libido, sex drive and sexual desire. Another definition of libido is: the force
by which sexual instinct is represented in the mind. Libido is a word of Latin
origin and means pleasure, lust, desire.
Some researchers make a distinction between sex drive and sexual desire. For
them sex drive is an omnipotent force that can lead to all forms of sexual outlet:
sexual fantasies, masturbation, intercourse. Sexual desire is defined as the sexual
drive toward a particular sexual outlet, i.e., intercourse with husband in
preference to masturbation. This divide may be quite unnecessary and most
people (professionals or lay) use libido, sex drive and sexual desire
interchangeably. The frequency and intensity of sexual desire and sexual activity
and the degree of sexual satisfaction vary throughout ones life. Nevertheless, the
phases of the sexual response cycle remain the same and do not change.
Meaningful discussion about sexual dysfunction is impossible without being
thoroughly familiar with the phases of the sexual response.
Phases of the sexual response cycle
The phases of human sexual response are sexual desire, arousal (excitement),
orgasm and resolution (Table 9.1).
SEXUAL FUNCTION AND DYSFUNCTION 231
Desire
This phase is characterized by sexual fantasies and the desire to have sexual
activity. It is distinct from other phases because it is psychological and reflects
motivations, drives and personality.
Arousal (excitement)
The physiologic purpose of sexual arousal is two-fold: (1) to facilitate the
painless penetration of the vagina by the penis and to reduce the risk of discomfort
and trauma during sexual intercourse; and (2) to induce a pleasure response
which will motivate an individual to seek sexual activity on another occasion.
Sexual arousal is dependent on sexual stimuli, of which there are two types:
those dependent on the brain (psychic), such as sight (visual), sound (auditory),
smell (olfactory) and sexual fantasies, and those dependent on touch (reflexive).
The latter can be effective independent of the brain, e.g., following spinal cord
transection. The most powerful of these stimuli is touch, especially of the
erogenous areas of the body. There is a wide variability between persons and
within the same person in sensitivity to sexual stimuli, which may be under
biochemical, hormonal, circadian or social influence.
Sexual stimulation leads to central and peripheral arousal and genital
response. Central arousal is the state of alertness that focuses the attention on
sexual stimulation. Peripheral arousal is increased sensitivity to touch. In the
female, genital responses include local vasocongestion, vaginal lubrication,
clitoral erection, uterine elevation and increased muscle tone. Local
vasocongestion leads to eversion of labia majora and minora, thereby facilitating
penile penetration. As a result of increased tone of the pubococcygeal muscle,
the lower third of the vagina narrows and the upper third widens and elongates.
The uterus occupies a higher position in the pelvis and the moisture of the
secretions facilitates penile entry and thrusting. The neural pathways controlling
these changes are via the parasympathetic sacral outflow of S2-S4 via the nervi
erigentes. In addition, there is involvement in the sympathetic nervous system
leading to increased alertness, rise of pulse and blood pressure.
Orgasm and resolution
It is difficult to define orgasm but two such attempts described it as an explosive
discharge of neuromuscular tension or simply as piercing sexual pleasure. In
the female, a few seconds after the start of orgasm, there is a
Table 9.1 Female sexual response cycle
Parameter
Excitement phase
Orgasmic phase
Resolution phase
Time interval
Several minutes to
several hours
325 s
1015 min if
orgasm; if no
Parameter
Excitement phase
Orgasmic phase
Skin
Inconsistent sexual
flush:
maculopapular rash
may appear on
abdomen, anterior
chest, neck, face
Nipple erection in
two-thirds of
women; areola
enlargement. Breast
size increases by
25%
Enlargement in
diameter of glans
and shaft
Well-developed
flush
Breasts
Clitoris
Labia majora
Congestion and
edema. Eversion
Labia minora
Congestion, size
increases 23 times.
Eversion. Color
change to deep red
Bartholins glands Secretion
Vagina
Color: dark purple.
Lubrication,
ballooning of upper
third, constriction of
lower third prior to
orgasm.
Uterus
Elevation in the
pelvis
Rectum
Others
Myotonia
Resolution phase
orgasm 0.5 h to 1
day
Flush disappears.
Inconsistent
perspiration on
palms and soles
Breasts may become

tremulous
Return to normal
size within an hour
No changes
Detumescence in 5
30 min; if no
orgasm, several
hours
Return to normal
size in 115 min
Return to normal
within 5 min
No change
Contraction of
proximal labia
minora
315 contractions of
the lower third
Congestion
disappears in
seconds. If no
orgasm, in 2030
min
Contractions
throughout orgasm
Rhythmic
contractions of anal
sphincter
Loss of voluntary
muscle control
Return to normal
position
Return to baseline
spasm of the muscles surrounding the lower third of the vagina, known as the
orgasmic platform, followed by between five and eight rhythmic contractions. In
some women, anal and uterine contractions are also observed. Orgasm is a
sympathetic reflex, and during orgasm there is a rise in pulse rate (up to 160
beats per minute), blood pressure (both systolic and diastolic: by 2040 mmHg),
respiration rate and pupillary dilation. Orgasm lasts between 3 and 25 s and may
be associated with a slight clouding of consciousness. After the orgasm, a period
Figure 9.1 Diagram of the sexual response cycle
of calm follows which is termed resolution. Various surveys suggest that 3050%
of women experience orgasm from coitus, a larger number from clitoral
stimulation, and 1020% do not experience orgasm in spite of being highly
aroused sexually. It appears that orgasm in women is not a purely reflexive event
as in men but is more of a learned ability. The number of women able to
experience orgasm increases with age. In adolescence only 50% of women
experience orgasm; this increases to 95% by age 35. In women, the refractory
period is not very well defined and some even question its existence. Kinsey
reports that 14% of women are capable of experiencing multiple orgasms. The
time course of sexual responses in the female is longer than in the male. A summary
of the body changes during the sexual response cycle is provided in Table 9.1.
Figure 9.1 represents the phases of the sexual response cycle.
The sexual response is a unique blend of psychologic and physiologic
experiences. Psychosexual development, attitudes toward sexuality and the
sexual partner are directly involved with, and affect, the nature of human sexual
response (Table 9.2).
Stress is a pervasive cause of sexual problems. Difficulties at work,
unemployment, money concerns, worries over children and interpersonal
conflicts all contribute to sexual problems. The presence of relationship
problems is one of the most damaging types of stress as the source of the stress
and the sexual partner are the same person. An example of relationship problems
is excessive politeness and consideration, presenting with a low level of sexual
activity, vaginismus or impotence. Another example is when the couple has
different sexual attitudes or different sexual desires. In some couples, there is a
protective realtionship problem. It happens when one of the partners who does
not enjoy sex at the best of times is protecting the sicker partner from the stresses
of sex on spurious medical grounds. We should not forget extramarital affairs,
which may lead to a lack of desire in the partner who feels betrayed.
Most psychiatric conditions can lead to sexual problems. It is amply

documented that depression leads to decreased motivation and sex drive. In
anxiety states sexual problems are common. In schizophrenia the libido may be
preserved, but interpersonal relationship problems inhibit sexual activity.
Poor general health, notably peripheral vascular disease and diabetes, through
decreased vascular response and sensitivity, may lead to an insufficient sexual
response. For some, the rigor of sex may be too much a demand for the rest of
the body, even if there is a desire and genital response.
Excess alcohol may cause (1) low levels of testosterone; (2) neuropathy and
decreased genital sensitivity; (3) hypertension; (4) depression; and (5) jealousy
and partnership problems. In addition, the intoxicated partner may be clumsy,
smelly or demanding. In drug addiction, the sphere of interest can be so narrow
as to exclude everything else but drugs. Aversion to sex is well documented in
people who have experienced sexual abuse in childhood or rape.
An excessively rigid and cold upbringing can be particularly destructive for a
persons sex life. On the one hand, it may lead to promiscuity, where the person
seeks substitutes for love and affection and reassurance; on the other hand, it
may lead to decreased desire and arousal and the view that sex is dirty.
Aging and the sexual response
The speed and intensity of the vasocongestive response decreases with aging.
There is a reduction in the elasticity of the vaginal wall and the size of the vagina
itself. Vaginal lubrication is slower and less marked and breast changes are less
noticeable. Orgasm in older women is associated with fewer contractions and
occasionally may be painful. The
Table 9.2 Some factors affecting sexual response
Stress
Age
Relationship with partner
Physical and mental health
Sexual knowledge/education
Self-image and confidence
Sexual experiences
Sexual attitudes/values
Parental influence/attitude
Sexual novelty/boredom
Drug/alcohol addiction
resolution phase is more rapid in older women. These changes become

increasingly prominent after the menopause and some are related to estrogen and/
or testosterone deficiency. There is an increased latency to excitement and greater

need for longer tactile stimulation and an increased refractory period (Table 9.3).
Longitudinal data show that, for healthy women, aging is not associated with
decreased sexual desire or decreased orgasmic capacity. Aging may be
associated with quantitative but not qualitative changes in sexual activity.
Epidemiologic observations
Large-scale observations of human sexuality were started by Alfred Kinsey and
co-workers in the United States in 1941. Their work was expanded in 1947 with
the founding of the Kinsey Institute. Kinsey was professor of zoology at Indiana
University, when, in 1938, he was asked to teach marriage preparation classes. It
was then that he realized how little truly scientific data existed on human sexual
behavior. More than 18 000 interviews were conducted and a tremendous
amount of data collected. Many original observations and publications on human
sexual response, function and dysfunction as well as sexual behavior were based
on these data. Many of these observations are still true today, but some are not
because (1) the methodology used was not
Table 9.3 Factors associated with aging that adversely affect sexual response
Physical deconditioning
Chronic disease(s)
Increased use of medication
Age-related emotional problems
Situational
widowhood
nursing home environment
Expectations
society
personal
Previously low sexual activity
appropriate; (2) sexual behavior is a biological, psychologic and social

phenomenonas the society changes so do some aspects of sexuality.
Kinsey noted that in men social class is an important determinant of sexual
behavior. Working-class men would experience sexual intercourse at an early
age and engage much less in petting and oral sex. Once married, they would
become involved in extramarital affairs early on in the marriage, but less so
when getting older. Upper-class men would be more likely to engage in petting
and oral sex. They tended to be faithful until middle age, when they might seek
extramarital opportunities.
For women, social class was found to have a smaller impact on sexual
behavior. Kinsey noted that some women could go through long periods of
sexual inactivity. He concluded that men are more responsive to psychologic
stimuli (fantasies and visual cues), while women require more tactile
stimulation, though they also respond to visual, sexually explicit material. Kinsey
reported that almost all men and 75% of women had masturbated at some stage
in their lives.
Research into the epidemiology of sexual function continues, and the results
of two cross-sectional studies of women in the UK and the United States are
presented in Table 9.4. The UK study found that sexual interest in women varies
across social classes. Impaired sexual interest was reported by 12%
Table 9.4 Results of two cross-sectional studies investigating sexual disorders in women
in the UK and the United States
Problem
Study 1 (%)*
Study 2 (%)**
Impaired sexual interest

17
30
Impaired arousal
17
21
Impaired orgasm
16
25
Dyspareunia
8
16
Any sexual dysfunction
33
43
Sex not pleasurable
19
Anxiety about performance
11
Help seeking
4
20
*Comprising 436 sexually active women aged between 35 and 59 years; **comprising
1749 sexually active women aged between 18 and 59 years
of classes I-II; 18% in class III; and 15% in classes IV-V. There was no
correlation of sexual dysfunction to menopausal symptoms. A history of
psychiatric problems was reported by 10% of those reporting sexual dysfunction.
Age, marital problems and neurotic predisposition were identified in 72% of
cases. Interestingly, even though 33% of participants were found to have some
form of sexual dysfunction, only 10% identified themselves as having sexual
problems, and this was not related to age. Even more remarkable, only 4% said
that they would commence treatment if available. The American study found
that single people were more likely to have an orgasmic disorder than married
ones. High educational attainment was found to be associated with fewer sexual
problems in both sexes. Risk factors for sexual problems were stress and a
deteriorating economic position (expressed as a decline in household income).
Arousal disorders were frequently found in women with adult-child sexual
contact or forced sexual contact. Sexual problems were more prevalent in
younger women and older men.
One American cross-sectional study of adults aged 6085 years found that
69% of men and 30% of women were sexually active, married ones more so than
unmarried ones. Among married couples 74% of men and 56% of women were
sexually active. The corresponding figure for single individuals was 31% for
men and 5% for women. Sexual activity correlated with incontinence, poor
mobility, heart problems and sedatives. Among married men, 3065% were
impotent, depending on age.
It is evident from many studies that the main sexual problem in women is lack
of desire, while in men it is erectile dysfunction.
SEXUAL HISTORY
In medicine, history and examination are the cornerstones on which diagnoses
and treatment strategies are made. In the field of sexual medicine, history is of
paramount importance.
Proper history taking requires a lot of time. Time is limited in outpatient
clinics and surgeries and that is why history taking has to be shortened and
concentrated on clarifying the presenting complaints and on the relevant
background features. The doctor should not be embarrassed, otherwise the patient
may retract or deviate from the topic. Openness, good communication skills and
tact encourage and promote frank discussion.
The presenting complaint should be explored in detail regarding its nature,
development and duration and the role of situational factors. Bearing in mind the
nature of the sexual response in women, questions should be asked regarding the
presence of sexual desire or aversion to sex, adequacy of lubrication, the
partners ability to penetrate, reaction to penetration, pain during or after sexual
intercourse and the ability to achieve orgasm. Questions should be asked about
the partners sexual desire, quality of erection, orgasm and ejaculation. Those
about sexual knowledge and expectations are very relevant: for example, the
patient may not be aware that coital frequency varies considerably and tends to
decrease with age and with the length of a relationship. Questions regarding the
quality and duration of the current relationship, previous relationships, separation
and infidelities should come next. Then comes sexual development, sexual
experiences
Table 9.5 Areas that should be covered by the sexual history
Nature and development of the sexual problem
Sexual knowledge and expectations
Relationship with partner
development
sexual relationship
general relationship
children and contraception
infidelity
commitment
Sexual experience (positive/negative/traumatic)

Medical history (e.g., diabetes, heart disease)
Surgical history (e.g., pelvic or genital operations)
Psychiatric history (e.g., depression)
Alcohol, drug and tobacco use
Appearance and mood
Attitude to problem and treatment
(positive/negative/traumatic) and masturbation. The important points in taking a

sexual history are summarized in Table 9.5.
Inquiries about general medical, psychiatric and drug history will help in
assessing the possibility of an organic, psychologic or druginduced condition(s).
It is essential to keep in mind the possibility of depression and to ask specific
questions about mood, appetite, sleeping pattern, etc. The doctor should attempt
to form some impression about the character and personality of the patient. At
the end of the consultation the doctor should ask about the degree by which the
problem causes personal distress or strain to the relationship. Genital
examination and general physical examination should be performed only if
clinically indicated and with caution if there is a history of sexual abuse. A
chaperone should always be present and the option of a male or female doctor
should be offered if possible. Women with vaginismus may be very reluctant to
be examined and only agree to this over time, once trust has been established and
they can remain in control.
COMMON SEXUAL PROBLEMS
The classification of sexual dysfunction follows the pattern of sexual response
and a simplified version is given in Table 9.6. It is of
Table 9.6 Common sexual dysfunctions
Sexual desire disorders
hypoactive sexual desire
sexual aversion/avoidance
Sexual arousal disorders
Orgasmic disorders
Sexual pain disorders
dyspareunia
vaginismus
paramount importance to note that for a disorder to be diagnosed the mere

presence of a condition is not enough; it must also cause personal distress. For
example, we cannot diagnose hypoactive sexual desire in a woman who reports
no sexual fantasies but is not troubled by it. Each of the diagnoses in Table 9.6 is
subclassified as (1) life-long versus acquired; (2) generalized versus situational;
and (3) etiologic/organic, psychogenic, mixed or unknown.
Problems of sexual response
Any part of the female sexual response can be affected. It is useful to have some
working definitions when attempting to evaluate and help women.
Sexual desire disorders
Low sexual desire If a woman can generate sexual fantasies and daydreams or if
she masturbates, then by definition her sexual desire is intact. If, however, there
is a lack of thoughts about sex or masturbation, or a lack of responsiveness to her
partners initiation, then sexual desire is said to be impaired. An estimated 17
30% (depending on the population studied) of women have a hypoactive sexual
desire disorder. Often, women presenting with low sexual desire disclose that their
partners desire is higher than their own. The presenting problem then is
discrepant sexual desire. However, sexual activity may still be present even if
sexual desire is low. For example, many women are sexually activebut only to
please their partner or to preserve the relationship. It has been reported that for
6% of women sex is an obligation rather than an enjoyable activity. Such women
are defined as having a low proactivity (not seeking sexual behavior) but an
intact receptivity (ability to respond to sexual advances). The presence of desire
depends on several factors: biological drive, good sexual experiences, the
availability of a partner and a good relationship in non-sexual areas. Damage to
any of these factors may result in decreased desire. Other factors that can
suppress sexual desire are depressants of the central nervous system, abstinence
from sex for a prolonged period of time, major illness or an affected body image
(mastectomy, ileostomy, colostomy, hysterectomy or vulvectomy).
Inhibition of desire may be a defensive way of protecting against unconscious
fear of sex or pregnancy. Loss of desire may also be an expression of hostility or
the sign of a deteriorating relationship. It is important to establish a baseline of
sexual interest before the disorder began because sexual activity varies among
people (one study found that 8% of couples have intercourse less than once a
month). The diagnosis should not be made unless the lack of desire is a source of
distress to the patient.
Sexual aversion disorders Sexual aversion disorders are defined as a persistent
or recurrent extreme aversion to, and avoidance of, all or almost all genital sexual
contact with a sexual partner. This condition goes beyond the simple avoidance
of sexual activity to include sexual panic states, sexual aversion and sexual
phobias. Some of these patients may have a normal sex drive and sexual
fantasies, and be able to enjoy autoerotic activity, but when confronted with a
sexual partner in a sexual situation, they may experience aversion to the partners
touch or to contact with the partners genitalia or semen.
Impaired sexual excitement (arousal)
Problems with sexual excitement present as either an inadequate physiologic
response to sexual stimulation (lubrication, swelling, etc.) or a lack of sense of
pleasurable feeling during sexual stimulation. It is thought to present in about
20% of patients. Women who have impaired sexual arousal often have orgasm
problems as well. Sexual arousal naturally fluctuates, with some women
reporting greatest sexual excitement immediately after a period and others at the
time of ovulation. Impairment with physiologic excitement can be recognized by
the lack of genital changes in response to effective sexual stimulation. It should
be noted that some women do not register that genital changes have occured
when in fact they have. Changes in testosterone, estrogen, prolactin and thyroxin
levels have been implicated in arousal disorders. The progestogenic effect of the
progestogen-only pill, antihistamine and anti-cholinergic medications can cause
a decrease in vaginal lubrication. An insufficient genital response may simply be
due to inadequate sexual stimulation. The lack of pleasurable feeling during
sexual stimulation is more likely to be psychologic, and numerous psychologic
factors are associated with sexual inhibition (Table 9.7). These conflicts may be
expressed through inhibition of excitement or orgasm and are discussed in the
section on Orgasmic disorders, below. However, decrease in sensitivity in
erogenous areas may occur with hormonal deficiencies (Table 9.8).
Orgasmic disorders (anorgasmia)
Anorgasmia is an inability to achieve orgasm by masturbation or coitus and this
accounts for approximately 5% of sexual disorders. A futher 1520% report
dissatisfaction with the quality of their orgasms. It can be an isolated problem
with sexual desire and arousal being intact. Often, however, excitement and
orgasmic disorders coexist and share the same etiology. Anorgasmia may be
situational, i.e., more commonly present with the partner and not with
masturbation (i.e., many women are orgasmic with manual stimulation but not
during coitus). Orgasm during coitus may be achieved by the combination of
manual clitoral stimulation and penile vaginal stimulation.
Table 9.7 Summary of psychologic causes of sexual dysfunction
Deteriorating relationshipanger/boredom/habituation
Depression
Lack of
trust between partners
communication with the partner about sex
sex for a prolonged period of time

knowledge about sex organs and their function
Aging
Fears of
pregnancy
intimacy/dependency/rejection
partners genitals/semen
loss of control
performance failure
painful sex
Physiologic changes: transition to motherhood
Loss of fertility (i.e., early menopause)
Inhibitory factors
guilt after pleasurable experience/masturbation
religious upbringing/cultural expectations/societal restriction
trauma: forceful sex/rape/incest
belief in sexual myths, e.g., nice girls dont initiate sex Bereavement/grief
Primary orgasmic dysfunction exists when the woman has never experienced
orgasm with any sort of stimulation. Secondary orgasmic dysfunction exists if
the woman has experienced at least one orgasm regardless of circumstances or
means of stimulation. According to Kinsey, the first orgasm occurs during
adolescence in about 50% of women, and this proportion increases as women get
older. Kinsey found that the proportion of married women over 35 years old who
had never achieved orgasm by any means was only 5%. Increased orgasmic
potential in women over 35 has been explained on the basis of less psychologic
inhibition or greater sexual experience, or both. Orgasmic dysfunction is a
common complaint. A number of psychologic, organic and iatrogenic factors
areassociated with inhibited female orgasms (Tables 9.7 and 9.8).
Sexual pain disorders
Vaginismus is an involuntary contraction of the pelvic floor muscles and outer
third of
Table 9.8 Summary of organic and iatrogenic causes of female sexual response disorders
a) Organic causes
Endocrine
Estrogen deficiency
Testosterone deficiency
Diabetes
Hyperprolactinemia
Hypothyroidism
Hypopituitarism
Addisons disease
Cushings disease
Neurologic
Spinal cord conditions (i.e., multiple sclerosis, trauma)
Epilepsy
Stroke
Lumbar canal stenosis
Head injury
Tumor
Substance abuse
Alcohol
Drugs
b) Iatrogenic
Surgical
Mastectomy and other disfiguring surgery, e.g., colostomy
Sympathectomy
Retroperitoneal lymphadenopathy/lymphadenectomy
Pelvic/vaginal surgery
Induced premature menopause
Surgery
Radiotherapy
Chemotherapy
Medications
Dopamine antagonists
Sedatives
Hypnotics
Antidepressants (fluoxetine, monoamine oxidase inhibitors, tricyclic antidepressants)
Anxiolytics
-Adrenoreceptor antagonists
Combined oral contraceptives Antiandrogens
the vagina, making penetration impossible or very painful. It is usually a

psychologic problem, being a phobia of vaginal penetration. For example, a
phobic response may be triggered by painful sex (especially forceful
Table 9.9 Common causes of painful intercourse
Superficial pain
Vulvovaginal atrophy
Episiotomy
Tight skin bridge or fissure at the fourchette
Infections
herpes
genital warts
candidiasis
trichomoniasis
bartholinitis
Dermatologic conditions
allergy/irritations
eczema
lichen sclerosus
psoriasis
Vulvovaginal surgery
Cystocele
Vestibulitis
Lack of lubrication
Deep pain
Constipation
Endometriosis
Postoperative adhesions
Fibroids
Inflammatory bowel disease
Ovarian cysts
Cystitis
Superficial and deep pain estrogen deficiency
sex), fear of pregnancy, or a strict religious upbringing.

Dyspareunia means genital pain during or after intercourse. The pain may be
superficial, involving the vulva, the introitus and the lower third of the vagina, or
deep, when it is felt near the cervix or the lower abdominal area. Vaginismus and
dyspareunia are closely linked as vaginismus may be a cause of superficial pain
and dyspareunia may result in protective vaginismus reflex. Common pathologic
causes of painful intercourse are listed in Table 9.9.
Vulvar vestibulitis is inflammation of the vestibular glands, which are mucoussecreting glands. These glands are arranged concentrically around the introitus
between the labia minora and the hymen. Should they become inflamed, they
lead to dyspareunia with penetration, pruritus and erythema. On inspection there
may be erythema at the area and the vestibular glands may be raised, giving a
rough (uneven) appearance. Probing with a cottonwool swab reveals an exquisite

tenderness (point tenderness).
DIAGNOSIS AND MANAGEMENT
Although approaches to treatment of sexual dysfunction vary, some general
principles are applicable. The careful taking of a history, an appropriate clinical
examination and investigations should help distinguish between organic and
psychogenic causes (Tables 9.7 and 9.8). Although there are no controlled
research studies of most sexual dysfunctions, it is estimated that 6080% are of
psychogenic origin, marital disharmony and depression being the commonest.
Once such a differentiation is made, appropriate treatment can be instituted. We
see the role of the non-specialist as three-fold. First, ruling out organic disease
and assessing a contributing physical illness (arthritis, radical mastectomy,
stroke, heart attack, etc). Second, identifying psychologic factors, either as a
primary cause for dysfunction or contributing to an organic cause. Third,
eliciting discussion and educating the patient. The clinician should assist the
patient in understanding the basis of the human sexual response and the intricate
interplay between the physiologic and psychologic components. Open discussion
about sexual matters can dispel many fears, anxieties or misinformation. Many
patients have never had an opportunity to discuss their sexual experiences with a
health professional. Breaking the barrier of silence, reducing anger and
improving communication between partners may be sufficient for some patients.
The doctor needs to assess the motivation of the patient/couple because
treatment often requires considerable investment of time and effort.
A detailed description of the treatments is beyond the scope of this book and
only selected treatments are going to be discussed. We believe that the patient
should be given practical advice and treatment where possible but if (1) the
diagnosis is in doubt; (2) the problem is too difficult; (3) there is poor rapport; or
(4) there is no response, prompt referral to a psychosexual clinic should be made.
Organic causes for sexual response disorders, painful penetration and painful sex
should be treated accordingly. Depression needs to be excluded. If the problem
persists in spite of accurate diagnosis and adequate treatment, it may be that the
pathology cannot be fully resolved or there are coexisting psychologic factors.
Strategies to cope with the problem, rather than a complete cure, may be more
realistic.
Disorders of desire are the most difficult to treat. As mentioned above,
educating the patient about a decline in desire with age, habituation, stress and
relationship difficulties is important. A common sense suggestion, also
applicable for arousal disorders, is setting time aside for relaxation; the need for
warmth and perhaps flowers, scents, music, lubricants and in some cases sex
aides.
Possible therapeutic avenues are pharmacologic doses of testosterone, HRT in

postmenopausal women, apomorphine, buproprion, yohimbine. Of those only the
first two have been shown to be effective.
Because a sexual arousal disorder almost invariably leads to an orgasmic
disorder, the treatment of both disorders is similar. Counseling is very important.
It should explore the relationship and its strengths, the domestic situation,
occupation (e.g., shift work) and stressful life situations, etc. (Table 9.7).
Possible pharmacologic treatments are sildenafil, apomorphine, topical
prostaglandins, testosterone and hormone replacement therapy (HRT) in
postmenopausal women. The first three are promising, but unproven; the latter
two are the effective ones.
The Masters and Johnson sensate focus exercises, in which the couple moves
stepwise from non-genital pleasuring to genital pleasuring to non-demanding
coitus, generally benefit women regardless of the level of sexual inhibition.
Education should be provided regarding the function of the genital organs,
sexual responses and the best methods of stimulating the clitoris and the vagina.
Kegels exercises strengthen voluntary control of the pelvic floor muscle. The
muscles are contracted 1015 times three times a day. Alternatively women are
advised to do their pelvic floor exercises each time they pass urineso it
becomes simple routine. In two to three months, perivaginal muscle tone
improves, as do the womans sense of control and the quality of the orgasm.
The standard treatment of vaginismus consists of self-exploration by looking at
and feeling the genitals, information about genital anatomy and the physiology
of arousal, learning relaxation techniques, pelvic floor exercises, discussing the
problem with the partner, stopping attempts at penetrative sex, and gradual vaginal
dilation until confidence is rebuilt. Dyspareunia may also be relieved by the use
of artificial lubricants, or by the changing of sexual position to one where
penetration is limited (side by side) or controlled (the woman on top).
PREGNANCY AND THE PUERPERIUM
There are two special situations which warrant further discussion: pregnancy and
puerperium and the menopause. Sexual activity during pregnancy decreases from
85% in the first trimester to 23% in the 36th week. Common reasons are physical
discomfort, loss of interest and fear of injuring the fetus. After delivery, sexual
activity resumes in three months for most couples. However, 50% of mothers
and 15% of fathers report lower sexual desire and 60% of couples have less
sexual activity at one year after delivery of the baby. The main reasons for this
decline in sexual activity are summarized in Table 9.10.
All these factors need to be addressed in a simple and practical manner before
extensive investigations are undertaken and before the couple is labeled as
suffering from sexual dysfunction.
MENOPAUSE
Specific features of sexuality in the perimenopause and the menopause are given
in Table 9.11.
Table 9.10 Causes for decline in sexual activity in the puerperium
Breastfeeding causing
raised prolactin and low estrogen
milk release on arousal
time-consuming
Pain
episiotomy
tear
Cesarean scar
Change of role to mother
Weight gain and poor body image
Fear of pregnancy
Exhaustion
Disturbed sleep pattern
The psychologic and sociocultural dimensions need to be addressed in their own

right. Adequate explanation about the process of aging and its effects on sexual
dysfunction goes a long way. Most middle-aged and older people would not
expect themselves to be as fit or to look as well as when they were young;
however, some retain these expectations with regard to sexuality.
Practical steps such as prolonging foreplay, using gels for lubrication and
topical estrogens may be of help when the problem resides in sexual response.
Systemic estrogen and testosterone have been shown to be effective. Estrogen
and testosterone act locally to increase the genital sensitivity, congestion and
lubrication and centrally to increase sexual fantasies and sexual desire. Although
there is anxiety about testosterone supplements in many women and some
medical practitioners, our own extensive experience with testosterone implants
shows that after adequate explanation most women with a sexual response
disorder will try an implantation at least once. The main points in counseling are
summarized in Table 9.12. Recently, testosterone patches have been developed.
In controlled studies a 300 g patch was shown to be safe and effective treatment
for sexual dysfunction in women over 48 years of age who had undergone a
hysterectomy or oophorectomy. Additional benefits of testosterone are increases
in lean body mass and bone density.
Table 9.11 Factors contributing to sexual dysfunction in the menopause
Aging and its effects: dry skin, brittle hair, dry mucosae, painful joints, muscles
Pendulous breasts with increased fat content
Redistribution of body fat, especially to the buttock and abdomen (middle-aged spread)
Vasomotor symptoms
Sex hormone deficiency affecting
sexual desire
arousal
lubrication
congestion
orgasm
Reaction to changed body image
Attitude to menopause
Marital relationship
Support network and coping with midlife crises
Society emphasis on youth and slimness
Table 9.12 Counseling women regarding testosterone implantation
50 mg implant over 6 months equals approximately 0.27 mg/day, which is similar to
the natural production rate of testosterone
Adverse side-effects include
oily skin
acne
altered lipid profile
hirsutism
alopecia
voice changes
Adverse side-effects are uncommon, but oily skin and acne are reported with
frequency. The incidence of hirsutism is less than 1% in our clinic. Alopecia,
voice change and clitoromegaly are rare, so it is not possible to give an accurate
estimate. Altered lipid profile does not represent a real problem. In our opinion,
testosterone supplementation is an under-utilized treatment option.
ACKNOWLEDGEMENT
The author would like to thank Dr Fran Reader, Consultant in Reproductive
Health Ipswich Hospital, UK who revised the manuscript and made helpful
suggestions.
Further reading
Bancroft J. Human Sexuality and its Problems. Edinburgh: Churchill Livingstone, 1989
Basson R, Berman J, Burnett A, et al. Report of the international consensus development

conference of female sexual dysfunction: definitions and classifications.J Sex
Marital Ther 2001;27:8394
Diokno A, Brown M, Herzog A. Sexual function in the elderly. Arch Intern Med 1990;
150:197200
Griffin M. The sexual health of women after the menopause. Sex Marital Ther 1995;10:
27791
Hawton K. Sex Therapy -A Practical Guide. Oxford: Oxford Medical Publications, 1985
Lauman E, Paik A, Rosen R. Sexual dysfunction in the United States. J Am Med Assoc
1999;281: 53744
Meston C, Frohlich P. The neurobiology of sexual function. Arch Gen Psychiatry 2000;
57:101230
Modelska K, Cummings S. Female sexual dysfunction in postmenopausal women:
systematic review of placebo-controlled trials. Am J Obstet Gynecol 2003; 188:
28693
Osborn M, Hawton K, Gath D. Sexual dysfunction among middle age men in the
community. Br Med J 1988;296:95962
Reader F. Female sexual problems. In Studd J, ed. The Year Book of the Royal College of
Obstetricians and Gynaecologists. London: Royal College of Obstetricians and
Gynaecologists Press, 1996: 22334
Reader F, ed. Minisymposiumpsychosexual disorders. The Diplomate 1997;4:26489
Shifren JL, Braunstein GD, Simon JA, et al. Transdermal testosterone treatment in
women with impaired sexual function after oophorectomy. N Engl J Med 2000;343:
6828
Wellings K, Field Y, Johnson A, Wadsworth J. Sexual Behaviour in Britain. London:
Penguin, 1994
Appendix I
Currently available combined oral
contraceptive pills in the UK
Hormone content
Second-generation
pills
Ethinylestradiol and
levonorgestrel
norethisterone
norethisterone
acetate
Mestranol and
norethisterone
Third-generation
pills
desogestrel
gestodene
norgestimate
Proprietary name
Estrogen dose (g) Progestogen dose

(g)
Microgynon 30/
Ovranette
Eugynon 30/Ovran
30
Ovran
Trinordiol/Logynon
Ovysmen/Brevinor
30
150
30
250
50
30/40/30
35
250
50/75/125
500
Norimin
Binovum
Trinovum
Synphase
Loestrin 20
35
35
35
35
20
1000
500/1000
500/750/1000
500/1000/500
1000
Loestrin 30
Norinyl-1
30
50
1500
1000
Mercilon
20
150
Marvelon
Femodene/Minulet
30
30
150
75
Tri-Minulet/
Triadene
Cilest
30/40/30
50/70/100
35
250
250
Hormone content
Proprietary name
Estrogen dose (g) Progestogen dose

(g)
Not yet classified

drospirenone
Yasmin
30
Appendix II
Prevention of pelvic inflammatory disease
at the time of IUD insertion
Treat the patient as an individual

(1) Consider all relevant methods of contraception.
(2) Explain the risks of PID to the patient. Tell her why you are going to ask
questions about her personal life.
(3) Assess her risk:
(a) Age;
(b) Recent change of partner (< six months);
(c) Genital symptoms or low abdominal/ pelvic pain (two or more sexual
partners in the last 12 months).
(4) If at risk of an STI consider other methods.
Intrauterine device insertions
(1) All women having an IUD inserted should be advised of the risk of pelvic
infection after this procedure, taking into account any risk factors for STIs
that they might have themselves, e.g., young age ( 25 years) or multiple
partners. The risks in the absence of an STI are low, being under 1% (as low
as 0.1% in low-risk women); however, should PID develop there is a 6%
risk of subfertility.
(2) Nulliparous women under 35 years: If an IUD is being considered for
women in this category, the standard management is to take tests for genital
infections (see below) and if they are negative to fit a device. Antibiotic
prophylaxis (see below) may also be offered.
(3) Nulliparous women over 35 years not at risk for sexually transmitted
infection: An antibiotic prophylaxis may be offered.
(4) Parous women over 35 years at risk of a sexually transmitted infection:
If an IUD is being considered for women in this group, the standard
252
management is to take tests for genital infections (see below) and if they are
negative to fit a device.
(5) Parous women over 35 years in long-term monogamous relationships:
There is no need to offer screening for STIs or antibiotic prophylaxis.
Antibiotic prophylaxis available in family planning clinics
Azithromycin 1 g stat and Metronidazole 400 mg bd. for five days.
What tests should be done?
When testing for STIs the following tests should always be done:
(1) High vaginal swab (charcoal transport medium) for microscopy, culture and
sensitivity (MC&S) analysis;
(2) Endocervical swab (charcoal transport medium) for MC&S analysis; and
(3) Endocervical and urethral chlamydia swabs for ligase chain reaction assays.
Index
A
abstinence (sexual),
sperm count, 84
STI treatment, 138
acne management, 48
acrosome reaction, 79
actinomycosis, 58
activins, 21
age,
androgen production, 2021
cardiovascular disease, 113
follicular decline, 31
infertility, 81
menarche, 2324
menstrual cycle changes, 30, 31
sexual response, 172173
alcohol and sexual response, 172
Allis forceps, 56
alveolar unit (breast), 11
Alzheimers disease, 118119
biochemical/pathological features, 118
estrogen, 118119
incidence/prevalence, 118
study, 118119
amine testing, 137138
anatomy and physiology, 112
androgens (female),
action, 17
infancy to puberty, 23
menopause, 31
physiological functions, 1921
potency, 17
production, 20
age, 2021
stimulation, 14
androgens (male), 78
androstenedione,
production, 20
secretion rates/concentration,
anorgasmia, 176177
primary, 177
secondary, 177
anovulation, 8890
classification, 89
normogonadotropic, 8990
PCOS, 91
anovulatory cycles, 30
antenatal routines, 88
anterior pituitary secretions, 13, 14
antibiotics, interactions, 53
antioxidants, 131
antrum follicle, 9
anxiety and sexual response, 172
arterial disease, 47
arthritis,
menopausal, 109
rheumatoid, 48
assisted reproductive technologies (ART),
94103
cancer link, 102103
complications, 102
low birth weight, 103
malformations, 103
medications, 100101
new developments, 103
safety, 102103
see also intrauterine insemination
(IUI);
in vitro fertilization (IVF)
atherosclerosis, 112
attachment phase, 80
axillary tail of Spence, 10
253
254 INDEX
B
bacterial cervicitis, 139142
bacterial vaginosis (BV),
diagnosis, 144
etiology, 144
follow-up, 144
testing, 137
treatment, 144
balanitis, 144
treatment, 145
Bartholins glands, 1
basal body temperature (BBT), fertility,
4142
benign breast change, 157
benign breast conditions, 157168
cyclical mastalgia, 159
cysts, 158
fibroadenoma, 158
lumpy breasts, 157
management, 159
nipple discharge, 157, 159160
pain, 157, 158159
management, 160
presentation, 157
referral, 158
bisphosphonates, 128129
blastocyst,
formation, 80
transfer, 97
bleeding,
Depo-Provera, management, 63
HRT see hormone replacement therapy
(HRT)
Implanon, pattern, 65
menopausal see menopause
menstrual see menstrual cycle
blood-borne infection,
hepatitis, 156
see also human immunodeficiency
virus (HIV)
blood supply,
breast, 10
vagina, 4
blood vessels, menopausal symptoms, 109
110
body fat,
distribution in cardiovascular disease,
111
menarche, 25
body temperature see basal body
temperature (BBT)
body weight, menopausal health
improvement, 130131
bone mass, 114
BRCAl/BRCAl, 162163
guidelines, 163
risks, 162163
breast,
benign disease see benign breast
conditions
blood supply, 10
clinical examination (CBE), 167168
communications, 11
configurations, 10
cross-section, 10
cyclic changes, 11
pain, 157, 158
cyst, 158
development, 11
disease
clinical approach, 157158
referral, 158
hormonal regulation, 10
lobes/lobules, 11
lump, solitary, 157
management, 159
lumpy, 157
pain, 158159
management, 160
pregnancy, 10
self-examination, 166167
procedure, 167
structure, 10
triple assessment, 157
weight, 10
breast cancer, 160166
clinical, 163164
COC, 47, 5152
incidence, 5152
death, 160
diagnosis, 163164
facts and figures, 160162
family history, 162163
hormone receptors, 164
HRT, 120121, 122, 132
mammography, 165166
INDEX 255
accuracy, 165
risks, 165166
mortality, 160
origins, 163
presentation, 163
prevention, 164165
prognosis, 164
protective factors, 160
risk, 162
factors, 160
high, 162163
lifetime, 160
stratification, 164
screening, 165166
economics, 165
ideal criteria, 165
UK program, 166
uptake, 166
spread, 163
survival, 164
treatment, 164
breast feeding see lactation
Brevinor, 44
C
calcium,
in fertilization, 7980
food content, 131
menopausal health improvement, 130
Canada, 32
cancer see specific cancers
candidiasis see balanitis;
vulvo-vaginal candidiasis
capacitation, 7879
cardiovascular disease,
age, 113
death, 113
estrogen deficiency, 113
estrogen replacement therapy, 113, 115
forms, 113
HRT, 113, 115
inflammation markers, 112113
prevalence, 113
risk factors, 47, 111, 130
cardiovascular system,
estrogen action, 20, 109
menopausal symptoms, 109114
blood vessels, 109110

body fat distribution, 111
coagulation/fibrinolysis, 111112
estrogen receptors, 109
glucose/insulin metabolism, 111
inflammation markers, 112113
lipid changes, 110111
risk factors, 111
cartilage, menopausal symptoms, 109
castration, surgical, 14
central nervous system (CNS),
estrogen effect, 117118
cervical cancer,
COC, 52
cervical cap see diaphragm/cervical cap
cervical dysplasia, 155
cervical ectropion, 5
cervical eversion, 5
cervicitis, bacterial, 139142
cervix, 4
canal, 45
connections, 4
epithelium, 5
estrogen response, 5
external os, 4
fertility, changes, 4041
frontal section, 4
internal os, 5
mucus, 5
cycle changes, 5
fertility, changes, 4041
pain transmission, 6
sperm entry, 78
squamous metaplasia, 56
steps, 5
transformation zone, 5
chancroid, 133, 150
chlamydial infections, 140142
diagnosis, 141
ectopic pregnancy, 141
incubation period, 141
infection sites, 141
PID, 141
prevalence, 140141
rate of infection, 140
screening, 142
symptoms, 141
256 INDEX
testing, 137
treatment, 141142
Chlamydia trachomatis, 140141
cholesterol,
steroids, 14
Cilest, 49
climacteric, 23
clitoris, 2
clomiphene,
fertility treatment, 9394
PCOS treatment, 91
risks, 91
side-effects, 91
coagulation,
study problems, 112
coitus interruptus, 35
colorectal cancer, 119120
cause, 120
HRT, 132
incidence, 119
combined contraceptive patch, 54
interactions, 130
combined oral contraceptives (COC), 42
54
adverse events, incidence, 53
benefits, 43, 50
breast cancer, 47, 5152
cervical cancer, 52
classification, 4345
complication risks, 4546
contraindications, 48, 49, 50
dose, 43
efficacy, 45
examination, 52
family history, 4547, 51
follow-up, 5354
generation, 4345
gynecological history, 48
history, 4243
indications, 48
interactions, 47, 53
mechanism, 45
medical history, 4547
metabolic effects, 45
missed pills, 53
non-contraceptive benefits, 48
patient information, 53
phasic pills, 45
prescribing, 53
risks, 43
in perspective, 4952
smoking, 48
social history, 48
stroke, 50
venous thromboembolism, 51
compliance bias, 113
conception, 7881
conceptus division, 80
condom, 3637
advice, 3637
failure rate, 36
female, 39
frequency, 35
health benefits, 36
historical use, 35
non-contraceptive benefits, 36, 37
STI protection, 36, 37, 154
congenital malformations, assisted
reproductive technologies (ART), 103
connective tissue, menopausal symptoms,
109
Conova, 43
contact tracing, 135, 139
contraception, 3574
barrier methods, 35, 3640
female, 3740
see also condom;
diaphragm/cervical cap
developing world, 42
Double Dutch method, 37
effectiveness measurement, 35
emergency see emergency
contraception
failure rate, 3536
history, 35
hormonal, 4269
frequency, 35
new developments, 69
see also combined oral contraceptives
(COC)
implants, 6365
see also Implanon
injectable, 62
see also injectable contraception
INDEX 257
intrauterine, 5459, 6669

types, 55
see also intrauterine device (IUD)
natural family planning see natural
family planning
progestogen-only, 6061, 6669
injectable, 6163
see also Implanon;
Mirena;
progestogen-only pill (POP)
sterilization, 6971
female, 7071
male, 6970
use frequency, 35
young people, 74
controlled ovarian hyperstimulation
(COH), 9596
complications, 100102
downregulation, 95
multiple pregnancy, 102
complications, 102
ovarian hyperstimulation syndrome see
ovarian hyperstimulation syndrome
(OHSS)
PCOS, 90
stimulation, 9596
Coopers suspensory ligaments, 11
Copper 7, 57
Copper T 220, 57
coronary heart disease (CHD),
financial burden, 106
HRT, 132
see also myocardial infarction (MI)
corpus luteum,
formation, 9
function, 27
progesterone secretion regulation, 29
C-reactive protein (CRP), 112113
Crinone, 122
cyclical mastalgia, 157, 159
Cyclogest, 122
cyst,
breast, 158
ovarian see polycystic ovary syndrome
(PCOS)
D
death, 113
dehydroepiandrosterone (DHEA) (female),
menopause, 31
secretion rates/concentration, 17
delayed puberty, 23
dementia, 118
demographics, menopause, 32
Depo-Provera, 6263
bleeding, management, 63
depression and sexual response, 172
developing world, contraception, 42
diagnostic procedures, radiation risks, 166
Dianette, 48
diaphragm/cervical cap, 3739
advantages, 37
efficacy, 37
insertion, 3839
patient advice, 38
practical considerations, 3839
spermicide, 38
STI protection, 37
types, 38
diet, menopausal health improvement,
130131
donor insemination (DI), 9495
dopamine, 14
drug interactions,
antibiotics, 47, 53
contraception
COC, 47, 53
Implanon, 64
injectables, 63
Mirena, 68
progestogen-only pill (POP), 60
duct ectasia, 157
Dutch cap, 37
dysmenorrhea, 48
dyspareunia, 178
E
early menopause, 23
ectopic pregnancy,
causes, 141
IUD, 58
egg donation, 99100
258 INDEX
donor screening, 99
ejaculation,
disorders, 86
low volume, 84
retrograde, 84
sperm after, 78
embryo,
formation, 80
transfer (ET), 87
emergency contraception, 7174
efficacy, 72
hormonal, 7273
combined, 7273
indications, 72
IUD, 55, 56, 73
methods, 7173
progestogen-only, 72
efficacy, 72
timing, 72
endocrine gland, infertility (male), 83, 85
86
indications, 86
endometrial cancer,
estrogen, 121
HRT, 121123
incidence, 121
protection, 48
endometrial hyperplasia,
assessment, 122123
estrogen, 121
HRT, 121123
incidence, 121
endometriosis, 9293
diagnosis, 93
etiology, 92
HRT, 124
symptoms, 93
treatment, 93
endometrium,
assessment, 122123
biopsy, 123
menstrual cycle changes, 2830
protection, 122123
shedding, 29
enterohepatic cycle, 107
environmental influences, menarche, 25
estradiol, 107
binding proteins, 15
FSH/LH control, 14
perimenopause, 31
postmenopausal, 107
decline, 14
estrogen, 106107
actions, 17
mechanism, 1719
bone mass, 114
cervical response, 5
cycle changes, 107
menstrual cycle, 27
perimenopause, 31
postmenopausal, 107
potency, 17
primary, 107
production sites, 107
sources, 19
stroke, 119
synthetic, 44
uterus response, 6
vaginal response, 4
estrogen deficiency,
associated disease, 106
bone mass, 114
cardiovascular disease, 113
states, 114
symptoms, 3133
see also menopause
estrogen receptor (ER), 17
activation, 128
menopause, 108, 109
structural domains, 18
tissue distribution, 19
types, 1819
estrogen replacement therapy (ERT),
cardiovascular disease, 113, 115
hot flashes, 108
osteoporosis, 116117
stroke, 120
estrone, 107
postmenopausal, 107
ethinylestradiol (EE), COC, 4345
exercise,
benefits, 131
INDEX 259

131
external genitalia (female), 12
external os, 4
F
Factor V Leiden mutation, 51
fallopian tubes, 6
family history, contraception, 4547
family planning,
natural see natural family planning
see also contraception
fecundability, 81
female lifecycle, 23
female maturation, 19
female sterilization, 7071
complications, 70
failure rate, 70
frequency, 35
reversal, 71
risks, 71
Femidom, 39
Femodene, 44
fertility,
indicators, 40
monitors, 42
fertilization, 7882
fusion, 79
fetal development, 7
fibrinolysis, 111112
fibroadenoma, 158
fibroids, 124
Fitz-Hugh-Curtis syndrome, 142
Flexi-T 300, 57
follicle(s), 79
antrum, 9
development stages, 7, 8, 25
Graafian, 89
primordial, 78
rupture, 26
follicle-stimulating hormone (FSH)
(female), 13
feedback control, 14
infertility, 8990
high, 89
low, 89
mechanism of action, 13
menstrual cycle, 27
perimenopause, 31
properties, 15
receptors, 13
secretion, 13
follicle-stimulating hormone (FSH) (male),
78
follicular decline, 31
follistatins, 21
forceps, Allis, 56
fornices, 3
fracture, HRT, 132
Fraser rules, 73
functional ovarian cysts (FOC), 48
fundus, 6
G
gamete intrafallopian transfer (GIFT), 87
genitalia,
external, 12
internal, 1, 24
genital tract,
infection, 133156
clinical features, 136
see also sexually transmitted infection
(STI)
infestations, 153
menopause symptoms, 108
genital ulcers, 146450
tropical causes, 150
genital warts, 150152
complications, 150
diagnosis, 151
emotional/psychosexual difficulties,
151
incubation, 151
persistent infection, 151
pregnancy, 151, 152
sites, 151
subclinical infection, 151
symptoms, 151
treatment, 151152
vaccine, 152
genitourinary medicine (GUM) clinic, 134
135
260 INDEX
Gillick competence, 73
glucose metabolism, 111
gonadotrophic cells, 13
gonadotrophin-releasing hormone (GnRH)
see luteinizing hormone-releasing
hormone (LHRH)
gonorrhea, 139142
antibiotic resistance, 140
complications, 140
diagnosis, 140
incubation period, 139
rate of infection, 139
regional variation, 139
symptoms, 139
testing, 137
treatment, 140
Graafian follicles, 89
granuloma inguinale, 150
gynecological procedure, PID
following, 142
GyneFix, 55
efficacy, 57
H
hatching, 80
health resources, 105
healthy user effect, 113
hepatitis, 156
herbs, 129130
herpes simplex virus (HSV), genital, 146
149
asymptomatic shedding, 147
diagnosis, 148149
HIV infection and, 148
immunocompromised patients, 148
management, 149
neonatal, 148
patient advice, 149
pregnancy, 148
prevalence, 147
primary, 147148
psychosexual complications, 149
recurrent, 147, 148
symptom relief, 149
terminology, 147
highly active antiretroviral therapy

(HAART), 154
HIV see human immunodeficiency virus
(HIV)
hormone receptors, 164
hormone replacement therapy (HRT), 107
127
administration routes, 125
bleeding, 121123
assessment, 122123
breast cancer, 120122
cardiovascular disease, 113, 115
coagulation/fibrinolysis, 112
compliance, 124
contraindications, 120121
disease risk, 132
endometrial hyperplasia/cancer, 121
123
endometriosis, 124
estrogens, 125
fibroids, 124
lipid changes, 111
mortality, 132
oral, 125126
patient profiling, 126127
assessment, 126
review, 126
prescribing, 124127
progestogens, 125
risks, 120124
safer alternatives, 127128
side-effects, 125
smoking, 126
stroke, 120
therapy choice, 125126
thromboembolism, 123124
transdermal, 125126
hormones in reproduction, 1322
hot flashes, 107108
differential diagnosis, 32
increased risk, 108
men, 32
menopause, 32
treatment, 108
human immunodeficiency virus (HIV),
154156
herpes, 148
infertility treatment, 156
INDEX 261
management, 154
prevalence in pregnancy, 155
prophylaxis, 154
protection, 154
risk, 154
spermicide, 40
STI transmission, 133
testing, 137, 155
advantages/disadvantages, 155
early diagnosis, 155
routine, 155
vertical transmission prevention, 155
lactation, 155
human papillomavirus (HPV), 150152
see also genital warts
hyperprolactinemia, 89
hypo-estrogenism, 32
hypothalamus, 107
hysterectomy, 126
I
ICSI see intracytoplasmic sperm injection
(ICSI)
imiquimod, 151
immunocompromised patients, 148
see also human immunodeficiency
virus (HIV)
Implanon, 6365
bleeding pattern, 65
drug interactions, 64
examination, 64
fertility return, 65
history taking, 64
insertion, 65, 66
mode of action, 64
removal, 65
side-effects, 65
timing of injections, 6465
implantation, 8081
implants (contraceptive), 6365
infancy, 23
infection see blood-borne infection;
sexually transmitted
infection (STI)
infertility, 75104
absolute, 83
causes, 81
clinical evaluation, 83
defined, 81
diagnosis, 83
epidemiology, 8183
female/male see below
frequency, 75
tests, 83
treatment in HIV infection, 156
see also assisted reproductive
technologies (ART)
infertility (female), 8794
anovulation, 8889
classification, 89
assessment, 88
causes, 88
duration, 98
endometriosis see endometriosis
FSH, 8990
hyperprolactinemia, 89
PCOS see polycystic ovary syndrome
(PCOS)
tubal
damage, 87
evaluation, 88
obstruction, 92
unexplained, 9394
pregnancy rates, 93
treatment, 9394
infertility (male), 8387
azoospermia, 8485
treatment, 8687
distribution, 83
ejaculation disorders, 86
endocrine problem, 83
evaluation, 8586
indications, 86
history, 8384
hormonal tests, 85
obstruction disorders, 86
oligoasthenoteratospermia, 87
oligozoospermia, 85
physical examination, 8384
semen analysis, 8485
sperm leukocytes, 85
tests, 86
treatment, 8687, 87
262 INDEX
varicocele, 86
infundibulopelvic ligament, 6
inhibin, 21
FSH/LH control, 14
perimenopause, 31
secretion decline, 14
injectable contraception, 6163
choice, 6263
examination, 6263
history taking, 62
indications, 62
mode of action, 62
patient advice, 63
prescribing information, 6263
progestogen-only, 62
insulin,
hypersecretion, 90
metabolism, 111
PCOS, 9091
sensitizing drugs, 91
internal genitalia, 1, 24
interstitial (Leydig) cells, 78
intracytoplasmic sperm injection (ICSI),
9697
birth rates, 99
concerns, 97
indications, 87
pregnancy rate, 98
results, 98
intrauterine device (IUD), 5459
actinomycosis, 58
action mechanism, 55
complications/side-effects, 5658
copper-containing, 55
efficacy, 57
emergency, 56, 73
efficacy, 73
fitting, 73
expulsion, 56
frameless, 55
frequency, 35
history and examination, 56
insertion timing, 59
levonorgestrel-containing, 55
menstrual cycle effects, 58

menstrual problems, 56
pelvic infection, 5859
perforation, 56
removal, 59
STI risk, 56, 5859
structure, 55
suitability assessment, 56
teratogenicity, 57
threads, lost, 59
use, worldwide, 55
intrauterine insemination (IUI), 9394, 94
95
indications, 87
rationale, 94
in vitro fertilization (IVF), 95100
birth rates, 99
downregulation, 95
egg donation, 99100
fertilization, 96
incubation, 96
indications, 87
natural cycle, 97
oocyte retrieval, 96
pre-embryo quality, 96
pregnancy rate, 98
results, 98
stimulation, 9596
in vitro maturation, 97
isoflavones, 129
isthmus, 4, 5
IUD see intrauterine device (IUD)
IVF see in vitro fertilization (IVF)
J
Japan, 32
L
labia majora, 1
labia minora, 12
lactation, 11
HIV transmission, 155
hormones required, 14
lactational amenorrhea method (LAM), 42
lactotrophic cells, 14
late menopause, 23
lesbians, STI, 135
INDEX 263
levator ani, 9
Levonelle-2, 72
follow-up, 72
prescribing, 72
timing, 72
Leydig cells, 78
libido, 170
life events, death risks, 162
life expectancy, 105107
health resources, 105
sexual dysfunction, 169
lipid changes, menopause, 110111
liver enzyme inducers, 47
low birth weight, assisted reproductive
technologies (ART), 103
luteinized unruptured follicle syndrome
(LUFS), 27
luteinizing hormone (LH) (female), 1314
detection, 88
feedback control, 14
mechanism of action, 13
menstrual cycle, 27
ovulation, 88
properties, 15
receptors, 13
secretion, 13
surge, 26
synthesis and release, 13
luteinizing hormone (LH) (male), 78
luteinizing hormone-releasing hormone
(LHRH), 13
function, 13
half-life, 13
pituitary suppression in COH, 95
properties, 15
lymphogranuloma venereum, 150
M
malathion, 153
male reproductive system, 7578
male sterilization, 6970
reversal, 69
mammography, breast cancer see under
breast cancer
Marvelon, 44
mastalgia, cyclical, 157, 159
maturation, female, 19
mefenamic acid, 56
Meissners corpuscles, 2
menarche,
age, 2324
body fat, 25
defined, 23
environment, 25
factors contributing to earlier, 2425
nutrition, 25
overweight, 25
preceding events, 24
underweight, 25
menopausal arthritis, 109
menopausal transition, 23
see also perimenopause
menopause, 3033, 105132
accentuating previous problems, 33
bleeding, 121123
assessment, 122123
causes, 123
cardiovascular system see
cardiovascular system,
menopausal symptoms
CNS changes, 117119
early, 23
estrogens, 106107
FSH/LH, plasma concentrations, 14
genitourinary/sexual symptoms, 33,
179180
gums, teeth, wound healing, 120
HRT see hormone replacement
therapy (HRT)
life event, 105106
mood, 107108
non-hormonal strategies, 128131
skin, connective tissue, cartilage, 109
surgical, 108
symptoms, 3133
cardiovascular see cardiovascular
system
long-term effects, 33
psychological, 3233
vasomotor, 3132, 107108
testosterone production, 20
urogenital system, 108109
see also estrogen deficiency
menorrhagia, 48, 68
264 INDEX
menstrual cycle,
anovulatory cycles, 30
blood loss, 30
breast changes, 11
cervical mucus changes, 5
clinical, 30
duration, 30
endometrial cycle, 2830
estrogen, 27
events sequence, 2530
flow constituents, 29
follicular phase, 2526, 29
FSH, 27
IUD effects, 5859
length, 30
LH, 27
luteal phase, 25, 27, 29
ovarian cycle, 25
ovary changes, 26
ovulation, 2627
preovulatory phase, 26
problems, 56
reproductive years, 25
serum hormone levels, 27
two-cell two gonadotrophin theory, 27
28
types, incidence, 30
Mercilon, 44
metabolism, 20
glucose, 111
metformin, 9192
Microgynon, 44
migraine, contraindications, 46
Minilyn, 43
Minovlar, 43
Minulet, 44
Mirena, 6769, 68
efficacy, 57, 68
follow-up, 68
history taking, 6667
indications, 6667, 122
mode of action, 66
PID risk, 58
Mittelschmerz, 40
molluscum contagiosum, 152153
morula, 80
mucus, cervical see cervix, mucus
Multiload 250, 57
Multiload 375, 57
Multiple Outcomes of Raloxifene
Evaluation (MORE), 128
myocardial infarction (MI), 4950
N
natural family planning, 4042
cervix changes, 4041
mucus changes, 40
temperature change, 4142
nipple, 11
discharge, 157, 159160
stimulation, 11
nonoxynol-9, 40
Noristerat, 62
North America, 32
NovaGard, 57
Nova T 200, 57
Nova T 380, 57
nutrition, 25
O
obesity, 91
oocytes, present at birth, 7
oral contraceptives see combined
oral contraceptives (COC)
orchidectomy, 32
orgasm, 2, 170171
disorders, 176177
multiple, 172
orgasmic platform, 171
osteoporosis, 114
age, 114
bone mass, 114
classification, 116
COC, 48
defined, 114
development, 114
financial burden, 106
gender differences, 114
risk, 116117
risk factors, 114
screening, 116
treatment, 116117
INDEX 265
antifracture activity, 117

ovarian hyperstimulation syndrome
(OHSS), 99
complications, 101
pathophysiology, 99
presentation, 101
severe, 101102
treatment, 102
see also controlled ovarian
hyperstimulation (COH)
ovarian reserve, 9899
decreased, 98
ovarian steroids, 1421
androgens see androgens
biosynthesis, 16
estrogen see estrogen
progesterone see progesterone
secretion rates, 17
ovarian stimulation, 94
see also controlled ovarian
hyperstimulation (COH)
ovary, 67
aging, 31
central medulla, 7
development, 7
inner hilum, 7
menstrual cycle interactions, 29
non-steroidal factors produced, 9
outer cortex, 7
premature failure, 127
regions, 7
structure and function, 7
overweight, menarche, 25
Oves cap, 39
Ovranette, 44
ovulation, 2627
indicators, 88
induction, 91
no response, 98
LH surge, 26
proof, 88
Ovysmen, 44
P
Pearl Index, 35
pelvic floor, 910
pelvic inflammatory disease (PID), 142

143
antibiotic resistance, 143
causes, 141, 142
COC, 48
complications, 142
diagnosis, 142143
findings, 142
follow-up, 143
hospital admission, 143
importance, 58
infertility, 87
IUD, 59
presentation, 142
protection, 142
testing, 137
treatment, 143
pelvic organ support, 910
pelvis, sagittal section, 3
perimenopause, 23
beginning, 30
hormonal changes, 3133
menstrual cycle changes, 31
periodic abstinence see natural family
planning
permethrin, 153
Persona, 42
phenothrin, 153
Phthirus pubis, 153
phytoestrogens,
beneficial effects, 129
daily consumption, 129
hot flashes, 108
pill (the pill) see combined oral
contraceptives (COC)
Pipelle, 123
pituitary, anterior, 13, 14
podophylotoxin, 151
polycystic ovary syndrome (PCOS), 90
diagnosis, 90
infertility, 9092
treatment, 90
insulin, 9091
metabolic features, 91
obesity, 91
pathogenesis, 90
prevalence, 90
266 INDEX
symptoms, 90
treatment, 9192
posterior commissure, 1
postmenopause, 23
disease risk, 132
pouch of Douglas, 3
precocious puberty, 23
pregnancy,
breast changes, 10
earliest recognition, 81
ectopic see ectopic pregnancy
genital warts, 151152
HIV rate, 155
HSV infection, 148
multiple , COH, 102
prolactin levels, 14
rates, 36
intracytoplasmic sperm injection
(ICSI), 98
in vitro fertilization (IVF), 98
sexual activity, 179
steps required, 81
uterus growth, 6
premature menopause, 23
premature ovarian failure (POF), 127
primary care, STI management, 134
progesterone,
action, 17
cervical mucus changes, 5
high plasma levels, 14
potency, 17
structure, 14
action mode, 60
choice of pill, 61
efficacy, 60
examination, 61
follow-up, 61
history taking, 60
indications, 60
side-effects, 61
progestogen, synthetic, 44
prolactin, 14
elevated, 89
inhibition, 14
pregnancy, 14
production, 14
properties, 15
release, 14
psychosexual difficulties,
genital warts, 151
herpes simplex virus infection, 149
see also sexual dysfunction
puberty (female), 23
breast development, 11
delayed, 23
hormones, 19, 23
mechanisms initiating, 23
precocious, 23
puberty (male), 78
pubic lice, 153
pudendal nerve, 2
puerperium, 179180
pulmonary embolism (PE),
cause, 123
HRT, 132
R
raloxifene, 128
breast cancer, 164
reproductive cycle, 2334
reproductive health, 32
reproductive life, 23
reproductive system (male), 7578
rheumatoid arthritis, 49
rifabutin, 47
rifampicin, 47
S
scabies, 153
Schering PC4, 72
follow-up, 73
prescribing, 73
timing, 72
schizophrenia, 172
selective estrogen receptor modulators
(SERS), 128
mechanism, 128
INDEX 267
semen,
analysis, 84
constituents, 78
Sertoli cells, 78
sex drive, 170
sex hormone-binding globulin (SHBG),
increase, 20
testosterone, 1415
sex steroids, 17
sexual assault, 135
sexual aversion disorders, 176
sexual desire, 170
factors, 176
problems, 175176
treatment, 179
age, 174
common problems, 175178
diagnosis and management, 178179
embarrassment, 169
epidemiology, 173174
iatrogenic causes, 177
menopause, 179180
organic causes, 177
pain disorders, 177178
physicians role, 169
pregnancy/puerperium, 179180
psychological causes, 177
sexual history, 174175
sexual response problems, 175178
women/men, 174
sexual history,
STI, 135136
sexuality, importance, 169
sexually transmitted infection (STI), 133
156
abstinence, 138
blood-borne, 153156
risk factors, 154
burden, 133
considerations, 134
contact tracing, 135, 139
diagnosis, 137138
amine testing, 137138
early, 133
examination, 137
impact, 134
pH testing, 137138
see also testing (below)
epidemiology, 133, 133
follow-up, 139
incurable viral, 139
IUD risks, 56, 5859
lesbians, 135
management in primary care, 134
protection
condom, 36
diaphragm, 37
female condom, 39
spermicide, 40
referral to GU clinic, 134135
sexual assault, 135
sexual history, 135136
specimen storage/transport, 138
testing
indications, 136137
limitations, 136
transmission, 133
treatment, 138139
antimicrobial, 138
delay in seeking, 133
epidemiological grounds, 138
see also specific diseases
sexual response, 169175
age, 171173
alcohol, 172
cycle, 170172
depression, 172
education, 174
epidemiology, 173174
excitement, 170
impaired, 176
factors, 173
marital status, 174
reasons to have sex, 169170
refractory period, 171172
resolution, 170171
social class, 173174
stress, 172
sickle cell disease, contraception, 46
skin, menopause, 109
smoking,
COC, 48
268 INDEX

131
social class, sexual response, 173174
spermatogenesis, 75, 78
disruptions, 78
spermatozoa, 75
cervix entry, 78
count, 84
defects, 8485
donation, 94
leukocytes, 85
structure, 75, 77
head, 75
tail, 7778
survival, 78
travel in uterus, 78
spermicide, 38, 3940
infections, 40
sterility, 83
sterilization, 7072
female see female sterilization
reversal, 70
steroid hormones,
action mechanism, 15, 1719
see also ovarian steroids;
individual hormones
St Johns wort, 129130
stress, sexual response, 172
stroke,
cause, 119
COC and, 50
ERT/HRT, 120, 132
estrogen, 119
incidence, 119
risks, 50
study, 119
surgical castration, 14
syphilis, 149150
complications, long-term, 150
congenital, 150
consequences, 150
diagnosis, 150
presentation, 149
systemic symptoms, 149150
testing, 137
T
tamoxifen, 128
breast cancer, 164
temperature measurement see basal body
temperature (BBT)
termination, HIV rate, 155
terminology, 2324
testis, 75
testosterone (female),
circulating, 20
menopause, 31
production, 20
postmenopause, 20
premenopause, 20
testosterone (male), 78
testosterone patches, 180
thromboembolism see venous
thrombophilia,
familial, 124
prevalence, 123124
Today sponge, 39
Trichomonas vaginalis, 137
trichomoniasis, 146
tropical disease, 150
T-Safe Cu, 57
tubal obstruction, 92
Turners syndrome, 127
U
ulcers, genital see genital ulcers
underweight, menarche, 25
urethral tests, 137
urethrovaginal septa, 23
urge syndrome, 108
urinary tract, menopause symptoms, 108
109
uteroovarian ligament, 6
uterus, 46
anterior view, 6
body, 56
frontal section, 4
growth potential, 6
INDEX 269
parts, 4
perforation, 58
pregnancy, 6
sperm travel, 78
see also endometrium
Utrogestan, 122
V
Vabra, 123
vagina, 24
age, 172
blood supply, 4
epithelium, 34
cell types, 4
flora, 143
histology, 34
infection, 143146
length, 3
menopause symptoms, 33, 108
pH, 4, 143
STI, 137138
vaginal discharge,
abnormal, 143
STI, 137138, 143
vaginal swab, 137
vaginismus, 177178
vaginosis, bacterial see bacterial vaginosis
(BV)
varicocele, 86
vasectomy, 6970
advice, 69
complications, 69, 70
procedure, 69
reversal, 69
failed, 84
vault cap (Dumas), 37
venous disease, 47
venous thromboembolism (VTE),
COC, 51
common form, 123
Dianette, 48
family history, 51
HRT, 123124
risks, 51
vesicovaginal septa, 23
vestibule, 1
vimule, 37
viral infection,
genital tract, 150153
incurable, 139
see also herpes simplex virus (HSV),
genital;
human immunodeficiency virus (HIV)
vitamin D, 130
vulva, 2
vulvar vestibulitis, 178
vulvectomy, 2
vulvo-vaginal candidiasis, 144146
diagnosis, 145
factors, 144
prophylaxis, 145146
recurrent, 145
testing, 137
treatment, 145146
W
warts, genital see genital warts
weight,
131
under/overweight, menarche, 25
World Health Organization (WHO),
osteoporosis classification, 116
Y
Yasmin, 4445
young people, contraception, 7374
Young syndrome, 85
Z
zidovudine, 155
zona pellucida (ZP), 79
zygote intrafallopian transfer (ZIFT), 87

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Female Reproductive Health

Female Reproductive Health

The Parthenon Publishing Group

Library of Congress Cataloging-in-Publication Data

ISBN 0-203-59669-2 (Adobe eReader Format)

The female reproductive systemanatomy and physiology

The female reproductive cycle

Menopause, hormone replacement therapy and non-hormonal

Sexually transmitted infections and common genital tract infections

Benign breast conditions and screening for breast cancer

Sexual function and dysfunction

Appendix I: Currently available combined oral contraceptive pills in

Appendix II: Prevention of pelvic inflammatory disease at the time

2 FEMALE REPRODUCTIVE HEALTH

THE FEMALE REPRODUCTIVE SYSTEM 3

4 FEMALE REPRODUCTIVE HEALTH

THE FEMALE REPRODUCTIVE SYSTEM 5

possesses multiple circumferential folds, or rugae. The folds become less

6 FEMALE REPRODUCTIVE HEALTH

THE FEMALE REPRODUCTIVE SYSTEM 7

8 FEMALE REPRODUCTIVE HEALTH

THE FEMALE REPRODUCTIVE SYSTEM 9

The ovary has a complex structure and function, being an organ of

10 FEMALE REPRODUCTIVE HEALTH

Stimulates FSH release

THE FEMALE REPRODUCTIVE SYSTEM 11

luteum secretes estrogen and progesterone. In the absence of pregnancy, the

12 FEMALE REPRODUCTIVE HEALTH

also produces a number of other substances in addition to steroid hormones. Some

THE FEMALE REPRODUCTIVE SYSTEM 13

14 FEMALE REPRODUCTIVE HEALTH

16 FEMALE REPRODUCTIVE HEALTH

gonadotropin (hCG). The subunit is encoded by a single gene located on

18 FEMALE REPRODUCTIVE HEALTH

Hormone Secreted from Acts upon

20 FEMALE REPRODUCTIVE HEALTH

Menstrual cycle Representative PR* (mg/day)

0.2 (200 pmol/

Type of steroid and relative potency*

Prepare uterus to receive embryo

Induce growth of androgen-dependent

22 FEMALE REPRODUCTIVE HEALTH

Figure 2.2 A schematic representation of the subcellular effects of estrogen (E) in

contrast, ER is predominantly found in ovarian granulosa cells and the prostate.

24 FEMALE REPRODUCTIVE HEALTH

in plasma, binding 66% of total circulating testosterone. SHBG is increased by

and suppressed by testosterone, glucocorticoids, excessive growth hormone, high

26 FEMALE REPRODUCTIVE HEALTH

with age. The age-related decrease in androgen production starts

28 FEMALE REPRODUCTIVE HEALTH

Menarche: first menses (mean age 13 years, range 10.516)

THE FEMALE REPRODUCTIVE CYCLE 29

30 FEMALE REPRODUCTIVE HEALTH

THE FEMALE REPRODUCTIVE CYCLE 31

increase in the levels of 17--hydroxyprogesterone, testosterone,

32 FEMALE REPRODUCTIVE HEALTH

THE FEMALE REPRODUCTIVE CYCLE 33

34 FEMALE REPRODUCTIVE HEALTH