ENDOCRINE SYSTEM

This system consist of

All endocrine glands
Hormone secreting cells example pancreas, ovaries, thymus, testis etc.
There are two types of glands in human body-
Exocrine glands- (exo- outside) secrete their products into ducts that carry the
secretions into body cavities, into the lumen of an organ, or to the outer surface of
the body.
Examples- sudoriferous (sweat), sebaceous (oil), mucous, and digestive glands.
Endocrine glands- (endo-within) secrete their products (hormones) into the
interstitial fluid surrounding the secretory cells rather than into ducts. From the
interstitial fluid, hormones diffuse into blood capillaries and blood carries them to
target cells throughout the body. Because most hormones are required in very
small amounts, circulating levels typically are low.
Example- pituitary gland, thyroid gland
Hormone (Greek hormaein—to stir up) is a substance of intense
biological activity that is produced by specific cells in the body and is
transported through circulation to act on its target cells.

1. Pituitary:
(a) Anterior:
Growth hormone (GH), Prolactin(Prl),
Adrenocorticotropic hormone (ACTH, Corticotropin),
Thyroid stimulating hormone (TSH, Thyrotropin),
Gonadotropins—Follicle stimulating hormone (FSH) and
Luteinizing hormone (LH).
(b) Posterior:
Oxytocin, Antidiuretic hormone (ADH, Vasopressin).

2. Thyroid:
Thyroxine (T4), Triiodothyronine(T3), Calcitonin.

3. Parathyroid: Parathormone (PTH).

4. Pancreas (Islets of Langerhans) Insulin, Glucagon.
5. Adrenals
(a) Cortex Glucocorticoids (hydrocortisone)
Mineralocorticoids (aldosterone)
Sex steroids (dehydroepiandrosterone)
(b) Medulla Adrenaline, Noradrenaline
6. Gonads
Androgens (testosterone)
Estrogens (estradiol)
Progestins (progesterone)
HORMONES are the chemical messengers, secreted in small amounts by the
endocrine glands which travel all over the body via blood to affect distant organ.
OR
A hormone is a mediator molecule that is released in one part of the body but
regulates the activity of cells in other parts of the body.
Chemically hormone may be peptides, steroids, amines or derivatives of amino
acid.

Hormone receptors-
Hormone influence their target cell by chemically bind with receptors.
Only the target cell have specific receptor for specific hormone.
The number of hormone receptor may decrease (down regulation) or increase
(up regulation) based on the condition/need.
Circulating Hormone- maximum endocrine hormone are circulating
hormone which carried through the blood stream to act on distant
target cells.
Local Hormone- they are other hormones which act locally on neighboring cells
or the same cells that secreted them without first entering the blood stream.
Example- interlukin-2 (IL-2), NO
Two types-
1. Paracrine- act on neighboring cells.
2. Autocrine- act on the same cell that secreted them.
 Classification of hormone on chemical basis-
It can be classified into two main classes-
1. Lipid Soluble hormone
2. Water Soluble hormone
Lipid Soluble hormone-
Chemical class Hormones Site of Secretion
Aldosterone, cortisol and androgens Adrenal cortex

Steroid Calcitriol Kidney

Hormone Testosterone Testis
Estrogen and Progesterone Ovaries
Thyroid T3 (triiodothyronine) & T4 Thyroid gland (follicular
hormone (thyroxine) cells)
Gas Nitric oxide (NO) Endothelial cells lining
blood vessels

Water Soluble hormone-

 Epinephrine & norepinephrine Adrenal Medulla
Melatonin Pineal Gland
Amines
Histamine Mast cells in conn. Tissue
Serotonin Platelets in blood
All hypothalamic releasing and inhibiting Hypothalamus
hormone
Oxytocin, Antidiuretic hormone (ADH) Posterior Pituitary

Human growth hormone, TSH, ACTH, FSH, LH,

MSH, Prolactin Anterior pituitary
Peptides & Insulin, glucagon, somatostatin, pancreatic Pancreas
Proteins polypeptide
Parathyroid hormone Parathyroid gland
Calcitonin Thyroid gland (parafollicular
Leptin cells)
Gastrin, secretin, cholecystokinin, GIP (glucose Adipose tissue
dependent insulinotropic peptides) Stomach and small intestine

Erythropoietin Kidney
Eicosanoids Prostaglandins, leukotriens All cells except RBC
 MECHANISM OF HORMONE ACTION-
There are two general mechanism of hormone action-

1) Lipid soluble hormone including steroid and thyroid hormone

affect cell function by altering gene expression.

2) Water soluble hormone, alter cell function by activating plasma

membrane receptors, which elicit production of second
messenger that activates various enzymes in the cell.
MOA of Lipid soluble hormone-
It bind to receptors within target cells. Their mechanism of action is as
follows-
1. A free lipid-soluble hormone molecule diffuses from the blood, through
interstitial fluid, and through the lipid bilayer of the plasma membrane into a
cell.
2. If the cell is a target cell, the hormone binds to and activates receptors
located within the cytosol or nucleus. The activated receptor–hormone
complex then alters gene expression: It turns specific genes of the nuclear
DNA on or off.
3. As the DNA is transcribed, new messenger RNA (mRNA) forms, leaves the
nucleus, and enters the cytosol. There, it directs synthesis of a new protein,
often an enzyme, on the ribosomes.
4. The new proteins alter the cell’s activity and cause the responses typical of
MOA of a typical water-soluble hormone-
A water-soluble hormone (the first messenger) diffuses from the blood through
interstitial fluid and then binds to its receptor at the exterior surface of a target
cell’s plasma membrane.
The hormone–receptor complex activates a membrane protein called a G
protein. The activated G protein in turn activates adenylate cyclase.
Adenylate cyclase converts ATP into cyclic AMP (cAMP). Because the enzyme’s
active site is on the inner surface of the plasma membrane, this reaction occurs in
the cytosol of the cell.
Cyclic AMP (the second messenger) activates one or more protein kinases,
which may be free in the cytosol or bound to the plasma membrane. A protein
kinase is an enzyme that phosphorylates (adds a phosphate group to) other
cellular proteins (such as enzymes). The donor of the phosphate group is ATP,
which is converted to ADP.
Activated protein kinases phosphorylate one or more cellular proteins.
Phosphorylation activates some of these proteins and inactivates others, rather like
turning a switch on or off.
Phosphorylated proteins in turn cause reactions that produce physiological
responses. Different protein kinases exist within different target cells and within
different organelles of the same target cell. Thus, one protein kinase might
trigger
glycogen synthesis, a second might cause the breakdown of triglyceride, a third
may promote protein synthesis, and so forth. phosphorylation by a protein kinase
can also inhibit certain proteins. For example, some of the kinases unleashed
when epinephrine binds to liver cells inactivate an enzyme needed for glycogen
synthesis.
After a brief period, an enzyme called phosphodiesterase inactivates cAMP.
Thus, the cell’s response is turned off unless new hormone molecules continue to
bind to their receptors in the plasma membrane.
 CONTROL OF HORMONE SECRETION
Hormone secretion is regulated by-
 Signals from the nervous system example- nerve impulses to the adrenal
medullae regulate the release of epinephrine
 Chemical changes in the blood example- blood Ca2+ level regulates the
secretion of parathyroid hormone
 Other hormones, example-; and a hormone from the anterior pituitary
(adrenocorticotropic hormone) stimulates the release of cortisol by the
adrenal cortex.
Note- Most hormonal regulatory systems work via negative feedback, but a few
operate via positive feedback. For example, during childbirth, the hormone
oxytocin stimulates contractions of the uterus, and uterine contractions in
turn stimulate more oxytocin release, a positive feedback effect.
Hormone Interactions-
Synergistic Effect- When the effect of two hormones acting together is
greater
or more extensive than the effect of each hormone acting alone, the two
hormones are said to have a synergistic effect.
Example- normal development of oocytes in the ovaries requires both follicle-
stimulating hormone from the anterior pituitary and estrogens from the ovaries.
Neither hormone alone is sufficient.

Antagonistic action- When one hormone opposes the actions of another

hormone, the two hormones are said to have antagonistic effects.
Example- insulin, which promotes synthesis of glycogen by liver cells, and
glucagon, which stimulates breakdown of glycogen in the liver.
Permissive Effect- the actions of some hormones on target cells require a
simultaneous or recent exposure to a second hormone. In such cases,
the second hormone is said to have a permissive effect.
For example- epinephrine alone only weakly stimulates lipolysis (the
breakdown of triglycerides), but when small amounts of thyroid hormones (T3 &
T4) are present, the same amount of epinephrine stimulates lipolysis much more
powerfully.
Sometimes the permissive hormone increases the number of receptors for the
other hormone and sometimes it promotes the synthesis of an enzyme required for
the expression of the other hormone’s effects.
 HYPOTHALAMUS
It is master of Pituitary gland.
A major link between nervous system and endocrine system.
Hormones secreted by Hypothalamus are-

1) Growth hormone releasing hormone (GHRH/ Somatocrinin)

2) Growth hormone inhibiting hormone (GHIH/ Somatostatin)
3) Thyroid releasing hormone (TRH)
4) Gonadotropin releasing hormone (GnRH)
5) Prolactin releasing hormone (PRH)
6) Prolactin inhibiting hormone (PIH)
7) Corticotropin releasing hormone (CRH)
8) Oxytocin
9) Vasopressin / Antidiuretic hormone (ADH)
 PITUITARY GLAND
Also known as Hypophysis.
This is known as master endocrine gland because it secretes several
hormones that control other endocrine gland.
It is a pea shaped structure that measures 1 -1.5 cm in diameter.
Location- situated in hypophyseal fossa of sella turcica of sphenoid
bone.
It attaches to hypothalamus by a stalk known as infundibulum.
Divided into 3 parts- Pituitary
Gland

Pars Posterior
Anterior lobe
Intermedia Lobe
1. Anterior Lobe-
 also known as adenohypophysis.
It is around 75% wt of the gland.
It contains 5 types of cells-
a. Somatotrophs
b. Thyrotrophs
c. Lactotrophs
d. Gonadotrophs
e. Corticotrophs
Note- Tropic hormones/ tropins- the hormones that act on other
endocrine gland is termed as tropic hormones.
 hGH /
Somatotrophs Somatotroptin

Thyrotrophs TSH/ Thyrotropin

Lactotrophs Prolactin

Adenohypophysis
FSH
Gonadotrophs

LH

ACTH /
Corticotropin
Corticotrophs
MSH
a) Human Growth Hormone:
Physiological functions:
 Promotes growth of bones and all other organs by inducing hyperplasia.
 There is a proportionate increase in the size and mass of all parts,
 But in the absence of gonadotropins, sexual maturation does not take
place.
 It promotes retention of nitrogen, calcium and other tissue constituents:
more protoplasm is formed.
 The positive nitrogen balance results from increased uptake of amino
acids by tissues and their synthesis into proteins.
 Promotes utilization of fat and spares carbohydrates: uptake of glucose
by muscles is reduced while its output from liver is enhanced; fat is
broken down.
 The growth of brain and eye is independent of GH.
The growth promoting, nitrogen retaining and certain metabolic actions of
GH are exerted indirectly through the elaboration of peptides called
Somatomedins or Insulin-like growth factors (mainly IGF-1, also IGF-
2) which are extracellular mediators of GH response. Liver is the major
source of circulating IGF-1, while IGF1 produced by other target cells
acts locally in a paracrine manner.
Like insulin, IGF-1 promotes lipogenesis and glucose uptake by muscles.
The IGF-1 receptor also is structurally and functionally analogous to the
insulin receptor.
GH acts directly as well to induce lipolysis in adipose tissue, gluconeogenesis
and glycogenolysis in liver and decreased glucose utilization by muscles.
These effects are opposite to those of IGF-1 and insulin.
As such, GH accentuates the metabolic derangement in diabetes.
Regulation of secretion of hGH-
1 Low blood glucose 6 High blood glucose
(hypoglycemia) (hyperglycemia)
stimulates release of stimulates release of

GHRH GHIH

2 GHRH stimulates 7 GHIH inhibits

secretion secretion of
of hGH by hGH by
somatotrophs somatotrophs

hGH

Anterior
pituitary

3 hGH and IGFs speed 8 A low level of hGH and

up breakdown of liver IGFs decreases the rate
glycogen into glucose, of glycogen breakdown
which enters the blood in the liver and glucose
more rapidly enters the blood more
slowly

4 Blood glucose level 9 Blood glucose level

rises to normal falls to normal
(about 90 mg/100 mL) (about 90 mg/100 mL)

5 If blood glucose 10 If blood glucose

continues to increase, continues to decrease,
hyperglycemia inhibits hypoglycemia inhibits
release of GHRH release of GHIH
Pathological Involvements
Excess production of GH is responsible for gigantism in childhood and
acromegaly in adults.
Hyposecretion of GH in children results in pituitary dwarfism.
Adult GH deficiency is rare, but when it occurs, it results in low muscle and
bone mass, lethargy, decreased work capacity, hyperlipidaemia and
increased cardiovascular risk.
Pathological Involvements
Human GH produced by recombinant DNA technique (rhGH) somatropin
(191AA) is available for clinical use.
Somatropin causes IGF-1 to appear in plasma after a delay of several hours.
GH Inhibitors
Somatostatin
This 14 amino acid peptide inhibits the secretion of GH, prolactin, and TSH
by pituitary; insulin and glucagon by pancreas, and of almost all
gastrointestinal secretions including that of gastrin and HCl.
It also has adjuvant value in diabetic ketoacidosis (by inhibiting glucagon
and GH secretion).
Use of somatostatin in acromegaly is limited by its short duration of action
(t½ 2–3 min).
Surgical removal of pituitary adenomas is the preferred treatment modality,
but somatostatin analogues are being increasingly used.
Octreotide
This synthetic octapeptide surrogate of somatostatin is 40 times more potent
in suppressing GH secretion and longer acting (t½ ~90 min), but only a
weak inhibitor of insulin secretion.
It is preferred over somatostatin for acromegaly and secretory diarrhoeas
associated with carcinoid, AIDS, cancer chemotherapy or diabetes.
Lanreotide
Another long-acting analogue of somatostatin, very similar in actions and
specificity to octreotide.
Pegvisomant
This polyethylene glycol complexed mutant GH binds to the GH receptor but
does not trigger signal transduction: acts as a GH antagonist
b) Thyroid Stimulating Hormone (TSH)-
TSH stimulate synthesis and secretion of thyroid hormone from thyroid
gland.
Thyrotropin releasing hormone (TRH) from hypothalamus control TSH
secretion.
Secretion of TSH is inhibited via negative feedback mechanism.
Physiological function
TSH stimulates thyroid to synthesize and secrete thyroxine (T4) and
triiodothyronine (T3). Its actions are:
• Induces hyperplasia and hypertrophy of thyroid follicles and increases
blood supply to the gland.
• Promotes trapping of iodide into thyroid by increasing Na +: Iodide
symporter (NIS).
• Promotes organification of trapped iodine and its incorporation into T3
and T4 by increasing peroxidase activity.
• Enhances endocytotic uptake of thyroid colloid by the follicular cells and
proteolysis of thyroglobulin to release more of T3 and T4. This action
starts within minutes of TSH administration.

c) Follicle Stimulating Hormone (FSH) (Gonadotropin)-

In female initiate development of oocytes.
Induce ovarian secretion of estrogen.
In male stimulates testes to produce sperm.
Gonadotropin releasing hormone (GnRH) from hypothalamus stimulates
FSH release.
 Estrogen in female and testosterone in male

Inhibit GnRH and FSH release via negative feedback mechanism

d) Lutenizing hormone (Gonadotropin)-

In female-
Triggers ovulation
Stimulates secretion of estrogen and progesterone
Formation of corpus luteum
In male stimulates testis to produce testosterone.
Gonadotropin releasing hormone (GnRH) from hypothalamus
stimulates LH release.
GONADOTROPIN RELEASING HORMONE (GnRH): GONADORELIN

Synthetic GnRH injected i.v. (100 µg) induces prompt release of LH and
FSH followed by elevation of gonadal steroid levels.
It has a short plasma t½ (4–8 min) due to rapid enzymatic degradation;
has been used for testing pituitary gonadal axis in male as well as female
hypogonadism.
Superactive / long-acting GnRH agonists
Many analogues of GnRH, e.g. Goserelin, Leuprolide, Nafarelin,
Triptorelin, have been developed which are 15-150 times more potent
than natural GnRH and longer acting (t½ 2–6 hours) because of high
affinity for GnRH receptor and resistance to enzymatic hydrolysis.
Nafarelin This long-acting GnRH agonist is 150 times more potent than
native GnRH. It is used as intranasal spray from which bioavailability is
only 4–5%
Goserelin
Another long-acting GnRH agonist available as a depot s.c./i.m.
injection to be used both for endogenous Gn suppression before
ovulation induction, as well as for endometriosis, carcinoma
prostate, etc.

Triptorelin:
This long acting GnRH agonist is formulated as a regular release daily s.c.
injection for short term indications, such as female infertility, and as a
depot i.m. monthly injection or long-term Gn suppression in the treatment
of carcinoma prostate, endometriosis, precocious puberty and uterine
leiomyoma.

Leuprolide
This long acting GnRH agonist is injected s.c./i.m. daily or as a depot
injection once a month for palliation of carcinoma prostate alongwith an
androgen antagonist, as well as for other conditions needing long term Gn
suppression.
GnRH antagonists
Some more extensively substituted GnRH analogues act as GnRH receptor
antagonists.
They inhibit Gn secretion.
The early GnRH antagonists had the limitation of producing reactions due
to histamine release.
Later agents like ganirelix and cetrorelix have low histamine releasing
potential and are being clinically used as s.c. inj. in specialized centres for
inhibiting LH surges during controlled ovarian stimulation in women
undergoing in vitro fertilization.
Their advantages over long-acting GnRH agonists include:
• They produce quick Gn suppression by competitive antagonism, need to be
started only from 6th day of ovarian hyperstimulation.
• They carry a lower risk of ovarian hyperstimulation syndrome.
• They achieve more complete suppression of endogenous Gn secretion.
However, pregnancy rates are similar or may even be lower.
e) Prolactin-
 With other hormone (estrogen, progesterone, glucocorticoids, hGH), it
promote milk production by mammary gland.
 PRH from hypothalamus stimulate prolactin release.
 PIH i.e. Dopamine inhibit prolactin release.
Physio-pathological involvement
Hyperprolactinaemia is responsible for the galactorrhoea–amenorrhoea–
infertility syndrome in women. In males it causes loss of libido and
depressed fertility.
The causes of hyperprolactinaemia are:
(i) Disorders of hypothalamus removing the inhibitory control over pituitary.
(ii) Antidopaminergic and DA depleting drugs —these are a frequent cause
now.
(iii) Prolactin secreting tumours—these may be microprolactinomas or
macroprolactinomas.
(iv) Hypothyroidism with high TRH levels—also increases prolactin
secretion
Prolactin inhibitors: Bromocriptine
 This synthetic ergot derivative 2-bromo-α-ergocryptine is a potent
dopamine agonist; most of its actions are based on this property.
 It has greater action on D2 receptors, while at certain dopamine
sites in the brain it acts as a partial agonist or antagonist of D1
receptor.
 It is also a weak α-adrenergic blocker but not an oxytocic.
Actions
1. Decreases prolactin release from pituitary by activating
dopaminergic receptors on lactotrope cells: is a strong
antigalactopoietic.
2. Increases GH release in normal individuals, but decreases the same
from pituitary tumours that cause acromegaly.
3. Has levodopa like actions in CNS—antiparkinsonian and
behavioral effects.
4. Produces nausea and vomiting by stimulating dopaminergic
receptors in the CTZ.
5. Hypotension—due to central suppression of postural reflexes and
weak peripheral α adrenergic blockade.
6. Decreases gastrointestinal motility.
Cabergoline
It is a newer D2 agonist; more potent; more D2 selective and longer
acting (t½ > 60 hours) than bromocriptine; needs to be given only
twice weekly. Incidence of nausea and vomiting is also lower.
f) Adrenocorticotropic Hormone (ACTH)-
Stimulate secretion of glucocorticoids mainly cortisol.
CRH from hypothalamus stimulate ACTH release.
Glucorticoids inhibit CRH and ACTH release via negative feedback
mechanism.
Pathological involvement Excess production of ACTH from
basophil pituitary tumours is responsible for some cases of Cushing’s
syndrome.
Use ACTH is used primarily for the diagnosis of disorders of
pituitary adrenal axis.
g) Melanocyte Stimulating Hormone (MSH)-
Function is yet unknown but may be responsible for some activity
and when present in excess amount causes darkening of skin.
CRH stimulate MSH release and Dopamine inhibit MSH release.
2. Posterior Pituitary-
Also known as Neurohypophysis.
This part does not synthesize hormones.
Only store and release two hormones formed by neurosecretory
cells of hypothalamus.
Oxytocin ADH / Vasopressin
a) Oxytocin-
During and after delivery of baby affects uterus and breasts
Enhances smooth muscle contraction in wall of uterus
Stimulates milk ejection from mammary glands
Secreted in response to uterine distension and stimulation of nipples
(through suckling infants).

b) Antidiuretic hormone (ADH/ Vasopressin)-

Decreases urine production by causing the kidneys to return more water
to the blood
Also decreases water lost perspiration (Sweating).

Increases BP by constriction of arterioles.

 1 High blood osmotic 5 Low blood osmotic
pressure stimulates pressure inhibits
hypothalamic hypothalamic
osmoreceptors osmoreceptors
Osmoreceptors
2 Osmoreceptors
activate the 6 Inhibition of osmo-
neurosecretory cells receptors reduces or
that synthesize and stops ADH secretion
release ADH
Hypothalamus

3 Nerve impulses
liberate ADH from
Regulation of secretion axon terminals in
the posterior
pituitary into
the bloodstream
and actions of ADH-
ADH

Target tissues

4 Kidneys retain Sudoriferous Arterioles constrict,

more water, (sweat) glands which increases
which decreases decrease water blood pressure
urine output loss by perspiration
from the skin
 Thyroid Gland
H shaped / butterfly shaped gland.
Located inferior to larynx.
Bilobed- Right lateral lobe
 Left lateral lobe
These lobes are connected by Isthmus.
Thyroid gland consist of thyroid follicle
which is made up of two types of cell-
a) Follicular cells- secrete T3
(Triiodothyronine) and T4
(tetraiodothyronine or Thyroxine)
b) Parafollicular cells- secrete Calcitonin
(CT)
T3 and T4 combinedly known as Thyroid hormone.
T3 is- 3,5,3՛ triiodothyronine
T4 is- 3,5,3՛,5՛ tetraiodothyronine

Formation, storage and release of thyroid

hormone-
It occurs as follows-
1. Iodide trapping- Thyroid follicular cells trap iodide ions by actively
transporting them from the blood into the cytosol.
2. Synthesis of thyroglobulin (TGB)- thyroglobulin (TGB) is a large
glycoprotein that is produced in the rough endoplasmic reticulum,
modified in the Golgi complex, and packaged into secretory vesicles. The
vesicles then undergo exocytosis, which releases TGB into the lumen of
the follicle.
3. Oxidation of iodide- oxidation is done by membrane bound thyroid
peroxidase enzyme with the help of hydrogen peroxide.
4. Iodination of tyrosine- As iodine molecules form, they react with
tyrosyl residues that are part of thyroglobulin molecules.
Binding of one iodine atom yields monoiodotyrosine and a second
iodination produces diiodotyrosine.
The TGB with attached iodine atoms, a sticky material that accumulates
and is stored in the lumen of the thyroid follicle, is termed colloid.
5. Coupling of T1 and T2-
T2 + T2 T4 (more)
T1 + T2 T3 (comparatively less)
Note- during iodine deficiency, more T1 is available so more T3 is formed.

6. Pinocytosis and digestion of colloid- Droplets of colloid reenter

follicular cells by pinocytosis and merge with lysosomes. Digestive
enzymes in the lysosomes break down TGB, cleaving off molecules of T3.

7. Secretion of thyroid hormones- Because T3 and T4 are lipidsoluble,

they diffuse through the plasma membrane into interstitial fluid and then
into the blood.
T4 normally is secreted in greater quantity than T3, but T3 is several
times more potent. Moreover, after T4 enters a body cell, most of it is
converted to T3 by removal of one iodine.

8. Transport in the blood- More than 99% of both the T3 and the T4
combine with transport proteins in the blood, mainly thyroxine-binding
globulin ( TBG).
Regulation of secretion of Thyroid hormone-
Action of thyroid hormone-
The actions of T4 and T3 are qualitatively similar and are nicely depicted in
the features of hypo and hyperthyroidism. They affect the function of
practically every body cell.

Growth and Development

• T4 and T3 are essential for normal growth and development.
• Congenital deficiency of T4 and T3 resulting in cretinism emphasizes
their importance.
• In adult hypothyroidism also, intelligence is impaired and movements are
slow.

Intermediary metabolism
• Thyroid hormones have marked effect on lipid, carbohydrate and protein
metabolism.
• T4 and T3 indirectly enhance lipolysis by potentiating the action of
catecholamines and other lipolytic hormones, probably by suppressing a
phosphodiesterase → increased cAMP.
• Hyperthyroidism is characterized by hypocholesterolemia.
• LDL levels in blood are reduced.
Carbohydrate
• Carbohydrate metabolism is also stimulated. Though utilization of
sugar by tissues is increased (mainly secondary to increased BMR),
glycogenolysis and gluconeogenesis in liver as well as faster
absorption of glucose from intestines more than compensate it →
hyperglycaemia and diabetic-like state with insulin resistance occur
in hyperthyroidism.
Protein
• Synthesis of certain proteins is increased, but the overall effect of T3
is catabolic— increased amounts of protein being used as energy
source.
Calorigenesis
• T3 and T4 increase BMR by stimulation of cellular metabolism and
resetting of the energystat.
• This is important for maintaining body temperature.
• However, metabolic rate in brain, gonads, uterus, spleen and lymph
nodes is not significantly affected.
CVS
• T3 and T4 cause a hyperdynamic state of circulation which is partly
secondary to increased peripheral demand and partly due to direct
cardiac actions.
• Rate, Contractility and cardiac output are increased resulting in a fast,
bounding pulse.

Nervous system
• T3, T4 have profound functional effect on CNS. Mental retardation is
the hallmark of cretinism; sluggishness and other behavioral features are
seen in myxoedema.
• Hyperthyroid individuals are anxious, nervous, excitable, exhibit
tremors and hyperreflexia.

Skeletal muscle
• Muscles are flabby and weak in myxoedema, while thyrotoxicosis
produces increased muscle tone, tremor and weakness due to myopathy.
GIT
Propulsive activity of gut is increased by T3/T4.
Hypothyroid patients are often constipated, while diarrhoea is common
in hyperthyroidism.
Kidney
T3 and T4 do not cause diuresis in euthyroid individuals, but the rate of
urine flow is often increased.
Haemopoiesis
Hypothyroid patients suffer from some degree of anaemia which is
restored only by T4 treatment. Thus, T4 appears to be facilitatory to
erythropoiesis.
Reproduction
Thyroid has an indirect effect on reproduction. Fertility is impaired in
hypothyroidism and women suffer from oligomenorrhoea. Normal
thyroid function is required for maintenance of pregnancy and
lactation.
 Mechanism of Action of Thyroid Hormone

Fig. 18.4: Mechanism of action of thyroid hormone on nuclear thyroid hormone

receptor (TR).
T3—Triiodothyronine; T4—Thyroxine; TRE—Thyroid hormone response element; RXR
—Retinoid X receptor; mRNA—Messenger ribonucleic acid; 5’DI—5’Deiodinase (See
text for explanation)
Relation between T4 and T3-
• Thyroid secrete more T4 than T3.
• T4 is the major circulating hormone because it is 15 times more
tightly bound to plasma proteins.
• T3- five time more potent than T4.
• Peak effect of T3 comes in 1-2 days while T4 takes 6 to 8 days.
• T3 more avidly bind to nuclear receptor than T4.

Conclusion-
• T3- an active hormone
• T4- mainly a transport hormone function as pro-hormone.
THYROID INHIBITORS
These are drugs used to lower the functional capacity of the hyperactive
thyroid gland.
Thyrotoxicosis is due to excessive secretion of thyroid hormones. The two
main causes are Graves’ disease and toxic nodular goiter.

Graves’ disease is an autoimmune disorder: IgG class of antibodies to the

TSH receptor are detected in blood. They bind to and stimulate thyroid
cells, and produce other TSH like effects. Due to feedback inhibition,
TSH levels are low. The accompanying exophthalmos is due to
autoimmune inflammation of periorbital tissues.

Toxic nodular goiter, which produces thyroid hormone independent of

TSH, mostly supervenes on old nontoxic goiters. It is more common in
the elderly; ocular changes are generally absent.
CLASSIFICATION
1. Inhibit hormone synthesis (Antithyroid drugs)
Propylthiouracil, Methimazole, Carbimazole.
2. Inhibit iodide trapping (Ionic inhibitors)
Thiocyanates (–SCN), Perchlorates (–ClO), Nitrates (–NO).
3. Inhibit hormone release
Iodine, Iodides of Na and K, Organic iodide.
4. Destroy thyroid tissue
Radioactive iodine (I131,I125, I123).

Compounds in groups 1 and 2 may be collectively called goitrogens

because, if given in excess, they cause enlargement of thyroid by feedback
release of TSH.
ANTITHYROID DRUGS (Thioamides)
By convention, only the hormone synthesis inhibitors are called antithyroid
drugs, though this term has also been applied to all thyroid inhibitors.
Antithyroid drugs bind to the thyroid peroxidase and prevent oxidation of
iodide/ iodotyrosyl residues, thereby;
(i) Inhibit iodination of tyrosine residues in thyroglobulin
(ii) Inhibit coupling of iodotyrosine residues to form T3 and T4.
Action (ii) has been observed at lower concentration of antithyroid drugs
than action (i).
Thioamides do not interfere with trapping of iodide and do not modify the
action of T3 and T4 on peripheral tissues or on pituitary.
Pharmacokinetics
All antithyroid drugs are quickly absorbed orally, widely distributed in the
body, enter milk and cross placenta; are metabolized in liver and excreted
in urine primarily as metabolites.
Carbimazole acts largely by getting converted to methimazole in the body
and is longer acting than propythiouracil.
Adverse effects
Hypothyroidism and goiter can occur due to overtreatment, but is
reversible on stopping the drug.
Important side effects are: g.i. intolerance, skin rashes and joint pain.
USES
1. Cretinism
2. Adult hypothyroidism (Myxoedema)
3. Myxoedema coma
4. Nontoxic goiter
5. Thyroid nodule
6. Papillary carcinoma of thyroid
7. Empirical uses

T4 has been sometimes used in the following conditions without any rationale; response is
unpredictable.
Refractory anaemias.
Mental depression
Menstrual disorders, infertility not corrected by usual
treatment.
Chronic/non-healing ulcers.
Obstinate constipation.
IODINE AND IODIDES
Though iodine is a constituent of thyroid hormones, it is the fastest acting
thyroid inhibitor.
In Grave’s disease the gland, if enlarged, shrinks, becomes firm and less
vascular.
The thyroid status starts returning to normal at a rate commensurate with
complete stoppage of hormone release from the gland.
The response to iodine and iodides is identical, because elemental iodine is
reduced to iodide in the intestines.
The mechanism of action is not clear. Excess iodide inhibits its own
transport into thyroid cells by interfering with expression of NIS on the cell
membrane.
Uses:
1. Preoperative preparation
2. Thyroid storm
3. Prophylaxis of endemic goiter
4. Antiseptic
RADIOACTIVE IODINE
The stable isotope of iodine is I. Its radioactive isotope of medicinal
127

importance is:
I131: physical half-life 8 days.
The chemical behaviour of 131I is similar to the stable isotope.
I emits X-rays as well as ß particles.
131

The ß particles penetrate only 0.5–2 mm of tissue. The thyroid follicular

cells are affected from within, undergo pyknosis and necrosis followed by
fibrosis when a sufficiently large dose has been administered, without
damage to neighbouring tissues.
Advantages
1. Treatment with I131 is simple, conveniently given on outpatient
basis and inexpensive.
2. No surgical risk, scar or injury to parathyroid glands/recurrent
laryngeal nerves.
3. Once hyperthyroidism is controlled, cure is permanent.

Disadvantages

[Link]
[Link] latent period of response.
[Link] during pregnancy
[Link] suitable for young patients
ß ADRENERGIC BLOCKERS
Propranolol (and other nonselective ß blockers) have emerged as an
important form of therapy to rapidly alleviate manifestations of
thyrotoxicosis that are due to sympathetic overactivity, viz. palpitation,
tremor, nervousness, severe myopathy, sweating.
They have little effect on thyroid function and the hypermetabolic state.
They are used in hyperthyroidism in the following situations.
(i) While awaiting response to propylthiouracil/carbimazole or I.
(ii) Along with iodide for preoperative preparation before subtotal
thyroidectomy.
(iii) Thyroid storm (thyrotoxic crisis)
Advantages and Disadvantages
P’kinetics
Uses
ADR and Interactions