Pathophysiology of Infertility in Men
Translated by: MuzaMil Hussain Kanju
Epidemiology of Infertility
Infertility affects approximately 25% of individuals with no identifiable cause, indicating
that both partners appear to be healthy. Among those with a known cause of infertility, in
25%, the male is solely responsible, and in another 25%, both partners contribute. Thus,
men are involved in about 50% of infertility cases, and women in 75% of cases where the
cause is identified.
Indications for Examining Infertile Couples:
1. Failure to conceive after one year of regular intercourse.
2. Advanced age (particularly women over 35 years old).
3. Suspected infertility due to previous medical history or examinations.
4. Known conditions that could impair fertility in either partner.
Infertility appears to be increasing, possibly due to environmental factors, pollutants, or
genetic changes, although whether infertility treatments transfer these genetic issues to
the next generation is not fully understood. This may reflect a broader trend similar to
vascular diseases, which also seem to be on the rise.
History of Male Infertility
Key points to explore in the male's history:
• Lifestyle history (including the duration of marriage and infertility)
• Medication use (including androgens, anti-androgens, and chemotherapy)
• Medical conditions (especially those that might impact fertility)
• Work-related exposure to toxins and hazards
• Past surgeries in the inguinal or scrotal areas (such as hernias or hydrocele
operations)
• History of trauma to the testicles
• Family history of infertility, which could suggest a genetic cause
Factors Affecting Male Fertility:
1. Chemical Pollutants: Exposure to chemicals like dyes, pesticides,
petrochemicals, and solvents can disrupt spermatogenesis.
2. Heat: Chronic exposure to heat (e.g., working near stoves or using saunas
frequently) has long been recognized as harmful to sperm production.
3. Electromagnetic Exposure: Though not definitively proven, concerns exist
regarding prolonged laptop use on the lap and proximity to mobile phones.
Occupational and Environmental Hazards:
• Smoking: While smoking fewer than 20 cigarettes a day might not significantly
impact sperm production, heavy smoking (more than 20 cigarettes/day) is known to
cause chromatin damage to sperm.
• Scrotal/inguinal conditions: Conditions such as undescended testicles,
hydrocele, and hernia surgeries, especially if untreated or occurring later in life, can
lead to infertility due to blockages or scarring.
• Testicular trauma: Physical injury, especially with hematoma formation, can
disrupt the blood-testis barrier and lead to autoimmune responses, including the
formation of antisperm antibodies.
Male Infertility Examination
A thorough examination involves assessing both general physical appearance and specific
indicators of fertility problems:
1. General Appearance:
a. Facial hair growth: Reduced or absent facial hair may indicate androgen
deficiency.
b. Signs of genetic syndromes: For instance, Klinefelter syndrome (extra X
chromosome) or myotonic dystrophy can be indicated by abnormal facial
features or early baldness.
c. Gynecomastia: Can be linked to hormone imbalances, including androgen
deficiency or elevated estrogen levels.
2. Physical Examination:
a. Neurological checks: For those with ejaculation disorders, neurological
tests of reflexes and sensation in the lower limbs, pubic area, and anal
region are crucial.
b. Examination of the genitalia: This includes assessing the penis, scrotum,
and testicles, both in a standing and lying position to detect scarring,
varicocele, hernia, or any structural issues like hypospadias.
c. Scrotal Examination: This is crucial for detecting conditions such as
varicocele, hydrocele, spermatocele, and testicular tumors. Varicocele, in
particular, requires maneuvers to identify it effectively, such as changing the
patient's position or increasing abdominal pressure.
d. Testicular size: Measured using an orchidometer, as it is directly related to
fertility. Small testicles may indicate reduced seminiferous tubules, which
are essential for sperm production.
3. Rectal Examination: Although often overlooked, this is vital for checking the
prostate and evaluating the reflex arc integrity for neurological disorders affecting
fertility.
Additional Diagnostic Tools:
• Ultrasound: To evaluate testicular masses, hydrocele, and other abnormalities in
the scrotal area.
• Hormonal and Genetic Testing: Depending on physical findings, testing for
testosterone levels or genetic conditions (e.g., Klinefelter's syndrome) may be
necessary.
Causes of Infertility in Men
Infertility in men can arise from a variety of causes. For clarity, these causes can be
categorized into two main groups: pre-ovoidal and post-ovoidal. Pre-ovoidal causes
include endocrine diseases, issues related to marital relationships, and mental health
disorders. Post-ovoidal causes involve issues affecting sperm function and transport.
Pre-Ovoidal Causes of Male Infertility
1. Endocrine Diseases
a. Hypogonadotropic Hypogonadism (H-H): A condition where there is
insufficient secretion of gonadotropins (LH, FSH) from the pituitary gland. A
high or constant level of these hormones can lead to infertility. In
hypogonadotropic hypogonadism, a deficiency in gonadotropins leads to a
lack of sexual maturity, though the condition may not be apparent until
infertility is diagnosed.
b. Kallman Syndrome: A genetic disorder associated with H-H. It affects the
hypothalamus and is often accompanied by facial midline anomalies, color
blindness, cryptorchidism, and anosmia.
c. Fertile Eunuch Syndrome: Involves a deficiency in LH, with normal levels of
FSH. This results in insufficient testosterone levels to trigger secondary
sexual characteristics but may still allow spermatogenesis.
d. Secondary Hypogonadotropic Hypogonadism: Often linked to prolactin-
secreting tumors, which inhibit normal gonadotropin release and can impair
fertility.
e. Congenital Adrenal Hyperplasia (CAH): This condition can lead to infertility
due to disruptions in gonadotropin release. Although more common in
women, CAH can cause low testosterone levels in men, resulting in low
sperm count and poor sperm quality.
f. Thyroid Disorders: While thyroid issues generally contribute minimally to
infertility in men, thyroid hormone imbalances may occasionally impact
reproductive health, particularly in cases of hyperthyroidism.
g. Other Functional Disorders: Mental health disorders (depression, anxiety),
extreme dieting, intense physical activity, and sleep disorders can disrupt
the pulsatile secretion of GnRH, impacting sperm production and fertility.
Post-Ovoidal Causes of Male Infertility
1. Genetic and Chromosomal Disorders
a. Klinefelter Syndrome (47XXY): Characterized by small, firm testes,
gynecomastia, and elevated gonadotropin levels. This condition is caused by
an extra X chromosome, leading to fibrosis and sclerosis of the seminiferous
tubules, which impairs sperm production. Some men with Klinefelter
syndrome may have a mosaic form, allowing for fertility through assisted
reproductive technology (ART).
b. XX Males: A rare condition in which men have a karyotype of XX
chromosomes but appear male with small, hard testes. Infertility is
common, and sperm production is typically absent.
c. XYY Syndrome: Men with this condition tend to be tall and may exhibit
aggressive behavior. Although some men with XYY syndrome may achieve
natural fertility, many exhibit delayed sperm maturation or severe sperm
production issues.
d. Y Chromosome Microdeletions: Deletions in the AZF (azoospermia factor)
regions on the Y chromosome (AZFa, AZFb, AZFc) are associated with severe
oligospermia or azoospermia. Deletion of multiple AZF regions generally
worsens sperm production prospects.
e. Noonan Syndrome: Also known as Male Turner Syndrome, this condition
does not involve chromosomal abnormalities but shares phenotypic
features with Turner syndrome. Fertility is rare due to cryptorchidism and
testicular atrophy.
2. Infections
a. Orchitis (Mumps or Mumps Orchitis): If mumps orchitis occurs after
puberty, it can lead to infertility by damaging the germinal cells of the testes.
Bilateral orchitis increases the risk of infertility, with one-third of men
experiencing this issue post-puberty.
3. Exposure to Chemical and Environmental Agents
a. Chemical Exposure: Certain substances, including flutamide acetate,
cyproterone, spironolactone, and cimetidine, can negatively affect
spermatogenesis.
b. Chemotherapy: Antimetabolites and alkylating agents used in cancer
treatment can disrupt sperm production and potentially lead to
azoospermia. Pre-treatment sperm storage is advised for men undergoing
chemotherapy.
c. Radiation: Exposure to radiation, particularly to the testes, can lead to
azoospermia. Testes are more sensitive to radiation before puberty, and
exposure may cause temporary infertility until normal spermatogenesis
resumes.
d. Uremic Syndrome and Chronic Liver Disease: In men with uremia or
chronic liver disease, elevated prolactin, estradiol, and parathormone levels,
alongside low testosterone, can cause impotence, oligospermia, or
azoospermia.
4. Lifestyle Factors
a. Alcohol Consumption: Excessive alcohol intake can impair testosterone
synthesis, leading to reduced fertility.
b. Varicocele: A varicocele, or enlarged veins in the scrotum, is a well-
established cause of male infertility. Surgery to correct the condition may
improve fertility outcomes.
5. Cryptorchidism: This condition, in which one or both testicles fail to descend into
the scrotum, can result in infertility. The associated abnormalities, such as poor
sperm production and testicular atrophy, further compromise fertility.
Post-Ovoidal Causes of Male Infertility
1. Sperm Transfer Disorders These involve issues with the transport of sperm from
the testes to the outside of the body.
a. Mechanical Obstruction: Obstructions in the genital tract, either congenital
or acquired, can prevent sperm from reaching the seminal fluid. Congenital
causes include atresia of the epididymis or vas deferens. Acquired causes
often stem from infections (such as tuberculosis) or surgeries (e.g.,
vasectomy).
2. Congenital Mechanical Obstruction
a. Atresia of the Epididymis and Vas Deferens: Incomplete development of
the male reproductive tract, such as in cystic fibrosis or diethylstilbestrol
exposure, can lead to blocked ducts and infertility.
3. Acquired Mechanical Obstruction
a. Infections: Before antibiotics, sexually transmitted diseases (STDs) often
led to blockage in the reproductive tract. In high tuberculosis prevalence
areas, tuberculosis of the genital tract may result in obstructive
azoospermia.
b. Vasectomy: One of the most common causes of acquired mechanical
obstruction. After vasectomy, some men may develop antisperm antibodies
due to the immune response triggered by sperm exposure.
c. Other Surgical and Iatrogenic Factors: Previous surgeries, such as pelvic or
inguinal surgeries, can damage the vas deferens or other parts of the
reproductive tract, making reconnection or repair difficult.
4. Sperm Function Disorders
a. Oligoasthenoteratozoospermia (OAT): In men with idiopathic infertility,
sperm may have abnormal motility, morphology, and concentration, yet no
clear cause can be identified. These cases may involve normal sexual desire
and functioning, with testicles of normal size and no signs of varicocele or
other reproductive health issues.
5. Immunological Causes
a. Antisperm Antibodies: In cases of post-vasectomy infertility, the immune
system may produce antibodies against sperm, preventing fertilization.
These antibodies may also appear after certain infections or as a result of
genital tract blockage.
Infertility of Unknown Cause
In approximately 25% of cases, no identifiable cause of male infertility is found despite
thorough examination. These men may have normal sperm count and motility, but
infertility persists, suggesting that factors beyond standard testing may be at play.
Diagnosis Methods in Male Infertility
1. Spermogram (Semen Analysis) After an appropriate history and physical
examination, spermogram testing is typically the next step in evaluating male
infertility. At least two spermogram samples, taken from different periods of
spermatogenesis (more than three months apart), are necessary to form a
conclusive judgment. Cooling the semen or delaying the test may cause changes in
sperm motility. The maximum time to transport the sample to the laboratory is 30
minutes, with the sample kept at body temperature during transit. The abstinence
period before collecting the sample, known as "abstinence," is crucial for effective
sperm analysis. The recommended abstinence period ranges from 2 to 3 days,
although some studies suggest 1-2 days as optimal. This period should be
consistent for each patient for proper comparison of results. Typically, samples
with a 2-5 day interval are acceptable.
The sperm count should be at least 20 million sperm per cc of semen, with a total semen
count of 40 million. A standard 4-part grading system is used to assess sperm motility:
a. Grade 1: Completely immobile sperm
b. Grade 2: Vibrating, non-progressive sperm
c. Grade 3: Slow, progressive sperm
d. Grade 4: Fast, progressive sperm
A natural sperm sample should have more than 50% of spermatozoa showing progressive
motility (Grade 3 or 4) within 2 hours. According to the World Health Organization (WHO)
classification, natural forms above 14% are considered normal. In Kruger’s classification,
stricter criteria, above 4%, are deemed normal.
The volume of semen is considered normal if it is between 2 and 5 cc. Semen pH is not
particularly useful in infertility diagnosis but becomes alkaline in case of infection. The
normal pH of semen is around 2.7. Low semen volume with acidic pH may indicate
ejaculatory duct obstruction or the absence of seminal vesicles, while low volume with
normal pH could suggest retrograde ejaculation.
Semen coagulation time and the presence of protease are also assessed. Prolonged
coagulation may indicate a lack of protease secretion by the prostate.
2. Fructose Test Fructose is secreted by the seminal vesicles under androgen
stimulation, and its level is tested when semen volume is low. A decrease or
absence of fructose indicates blockage of the ejaculatory ducts, underdevelopment
of the seminal vesicles, or lack of androgens. This test helps assess the
functionality of the seminal vesicles and androgen production.
Pyospermia is indicated by the presence of leukocytes (more than 10-15 per HPF or more
than 1 million per cc of semen). It suggests infection, inflammation, or autoimmune
disorders affecting sperm function.
3. Immunological Tests Immunological tests are particularly useful for cases of
asthenospermia (reduced sperm motility) or unexplained infertility, especially
when there is a history of frequent miscarriage. Any disruption of the testicular
blood barrier can lead to the production of antibodies against sperm, affecting their
motility, penetration into cervical mucus, and fertilization capability. These tests
are recommended if risk factors such as vasectomy, epididymitis, orchitis, or
genital trauma are present.
4. Hormonal Tests Hormonal examinations for male infertility include tests for LH,
FSH, testosterone, and prolactin, as these hormones directly influence
spermatogenesis. Hormonal testing is performed mainly in cases where the sperm
concentration is below 5 million per cc. The best time to measure these hormones
is in the morning after breakfast.
Thyroid hormones are tested only if there are clinical symptoms indicative of thyroid
dysfunction.
5. Genetic Tests Chromosomal abnormalities, such as Klinefelter syndrome and
Noonan syndrome, may cause infertility. Y chromosome deletions and other
chromosomal disorders are also implicated. A karyotype test is recommended in
cases of oligospermia (sperm count below 5 million) to evaluate possible genetic
causes of infertility.
6. Testicular Biopsy Testicular biopsy is recommended in cases of azoospermia
(absence of sperm in the semen). Even with non-identical testicles, bilateral
sampling should be done to determine the cause and decide the best course of
action.
7. Radiological Evaluation Imaging methods like ultrasound and TRUS (transrectal
ultrasound) are used to detect anatomical obstructions, especially in cases of
azoospermia where spermatogenesis is present in testicular biopsy. TRUS can help
identify blockages in the ejaculatory ducts and guide further diagnostic or
therapeutic interventions.
Medical Treatments for Male Infertility
1. Specific Treatments
a. These are aimed at treating a clearly identified cause of infertility. For
example, administering pituitary hormones to address secondary pituitary
failure causing azoospermia.
b. Other treatments target specific conditions such as varicocele, where
surgical intervention may be the preferred approach rather than relying
solely on medication.
2. Experimental Treatments
a. In cases where no specific cause is identified, treatments are considered
experimental. For instance, carnitine may be prescribed for cases of low
sperm motility, although the efficacy of such treatments remains uncertain.
b. Medical treatments in male infertility typically offer limited success,
especially when applied to cases with clear, identifiable causes. Even with
continuous treatment, the spermogram may show improvement only after
64 days, corresponding to the spermatogenesis cycle.
3. Assisted Reproductive Methods Assisted reproduction has revolutionized the
treatment of infertility, with high success rates for many patients. These methods
should be considered after all natural conception attempts have failed.
a. Intrauterine Sperm Insemination (IUI): In this procedure, sperm is injected
directly into the uterus using a centrifuge to isolate motile sperm, preventing
inflammatory substances from entering the uterus. IUI is most effective in
patients with unexplained infertility or minor male factor infertility. However,
inappropriate use or incorrect patient selection may lead to increased failure
rates and emotional distress for the patient.
b. In Vitro Fertilization (IVF): IVF has been a major breakthrough in infertility
treatment. Over the years, its success rates have improved significantly,
reaching up to 40% under optimal conditions. IVF is particularly helpful for
cases of severe male infertility, such as azoospermia or significant sperm
motility issues. However, IVF should not be used prematurely before
addressing any identifiable causes of infertility.
In summary, diagnosing male infertility involves a series of clinical, laboratory, and
sometimes genetic tests to identify the root cause. Once a diagnosis is made, treatments
can be specific (for known causes) or experimental (for unknown causes). Assisted
reproductive technologies like IUI and IVF play a crucial role in overcoming male infertility
when natural conception is not possible.
