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Pituitary for
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Growth Hormone Functions

GROWTH HORMONE (GH)

It is a 191 amino acid, single chain peptide of MW 22000.
Physiological functions During childhood and adolescence GH is required for normal growth and
attainment of adult stature. It promotes growth of bones and all other organs by inducing
hyperplasia. In general, 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. The growth of brain and
eye is independent of GH. It promotes retention of nitrogen, calcium and other tissue
constituents: more proto plasm is formed. The positive nitrogen balance results from increased
uptake of amino acids by tissues and their synthesis into proteins. In addition to protein
metabolism, GH affects carbohydrate and fat metabolism throughout life. It promotes utilization
of fat and spares carbohydrates. Uptake of glucose by muscles is reduced while its output from
liver is enhanced; blood glucose level tends to rise.
GH acts on cell surface JAKSTAT binding protein kinase receptors (see p. 59) which are present on
practically all types of cells. Binding of one GH molecule to the extracellular domain of a GH‐
receptor diamer results in the formation of a ternary complex which undergoes a conformational
change and activates the intracellular domain to associate with cytoplasmic JAKSTAT tyrosine‐
protein kinase resulting in metabolic effects as well as regulation of gene expression
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 (Fig. 17.1). Liver is the
major source of circulating IGF1, while IGF1 produced by other target cells acts locally in a
paracrine manner. Like insulin, IGF1 promotes lipogenesis and glucose uptake by muscles.
Moreover, the IGF1 recep tor is structurally and functionally analogous to the insulin receptor (see
p. 284).
GH acts directly as well, but induces lipolysis in adipose tissue, gluconeogenesis and
glycogenolysis in liver and decreased glucose utilization by muscles. These effects are opposite to
those of IGF1 and insulin. As such, GH accentuates the metabolic derange ment in diabetes.
Regulation of secretion The hypothalamus pro duces GH releasing (GHRH) as well as release
inhibitory (somatostatin) hormones. Both are peptides. Receptors for GHRH and somatostatin are
G protein coupled recep tors (GPCRs) which enhance or inhibit GH secretion by increasing or
decreasing cAMP formation respectively in pituitary somatotropes. IGF1 causes feedback
inhibition of GH secretion. Shortloop feedback inhibition of secretion by GH itself has also been
described.
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. Normal adult
height is not attained, muscle mass is low and body fat is increased. 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.
Uses
Availability of Somatropin, the recombinant human GH (rhGH) has considerably widened the
clinical application of GH. However, it should be used only by specialists.
1. Pituitary dwarfism: It is due to GH defi ciency which is noticed in early childhood as subnormal
height gain. Daily s.c. injec tion of somatropin (30–60 μg/kg), preferably in the evening, produces
highly gratifying results. Growth is accelerated and near
normal adult stature may be attained if therapy is instituted early and continued till the age of 20.

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 2. Turner syndrome: The short stature of girls can be largely corrected by rhGH treatment
combined with properly timed androgen and estrogen therapy.
3. Chronic renal insufficiency in children caus ing suboptimal growth: rhGH is approved for
restoring growth.
4. Constitutional (idiopathic) short stature children: Somatropin treatment has yielded
encouraging results, but entails longterm costly medication. Ethical, social and medical objections
have been raised.
5. GH deficiency in adults: rhGH treatment increases lean body mass, decreases body fat,
improves energy and metabolism.
6. AidS related wasting: Somatropin improves physical and mental health of affected patients. It
has also been used in other catabolic states like severe burns, bedridden patients,
chronic renal failure, etc.8
Somatropin is also being promoted for ageing, but benefits are uncertain. Its use by athletes is
banned, and it is one of the drugs included in ‘dope testing’.
Somatropin: NORDITROPIN, NORDILET 5, 10, 15 mg prefilled pen injector, HUMATROPE 6 mg, 12
mg car tridges, 1.33 and 5.33 mg vials.
Adverse effects Somatropin has low immunogenic ity; allergic reactions or resistance to treatment
are not a problem. Pain at injection site, lipodystrophy, glucose intolerance, hypothyroidism (due
to unmasking of TSH deficiency), salt and water retention, hand stiffness, myalgia, headache are
the possible adverse effects. Rise in intracranial tension occurs in few cases.
Mecasermin This is recently produced recombinant human IGF1 (rhIGF1), which is useful in
children with retardation unresponsive to rhGH and is due to GH recep tor/GH signaling pathway
abnormality.
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Growth Hormone (GH)

General Information

Structure: 191 amino acid, single-chain peptide with a molecular weight of 22,000.
Physiological Functions:
- Essential for normal growth and attainment of adult stature during childhood and
adolescence.
Promotes growth of bones and organs through hyperplasia.
Sexual maturation requires gonadotropins; GH does not affect brain and eye growth.
Promotes nitrogen, calcium, and other tissue constituent retention, leading to protein
synthesis and positive nitrogen balance.
Influences carbohydrate and fat metabolism by promoting fat utilization and sparing
carbohydrates. It increases glucose output from the liver and reduces muscle glucose
uptake, raising blood glucose levels.

Mechanism of Action

Receptors:
GH acts on JAK-STAT binding protein kinase receptors on almost all cell types.
Binding of GH to these receptors forms a ternary complex, causing conformational changes
and activation of intracellular domains.

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 This activation associates with cytoplasmic JAK-STAT tyrosine-protein kinase, leading to
metabolic effects and gene expression regulation.
Indirect Actions via IGFs:
GH indirectly promotes growth and metabolic actions through somatomedins (IGF-1 and
IGF-2).
Liver is the primary source of circulating IGF-1, while other cells produce IGF-1 locally.
IGF-1 promotes lipogenesis and glucose uptake in muscles, similar to insulin, and has
receptors analogous to insulin receptors.
GH's direct effects include lipolysis in adipose tissue, gluconeogenesis, and glycogenolysis
in the liver, and decreased glucose utilization in muscles, which contrasts with IGF-1 and
insulin effects.

Regulation of Secretion

Hypothalamus:
Produces GH-releasing hormone (GHRH) and somatostatin (release inhibitory hormone).
Both hormones are peptides acting on G protein-coupled receptors (GPCRs) in pituitary

In
somatotropes.
GHRH increases cAMP formation, enhancing GH secretion, while somatostatin decreases
cAMP, inhibiting GH secretion.
Feedback Inhibition:
IGF-1 provides feedback inhibition of GH secretion.
GH itself also provides short-loop feedback inhibition.

Pathological Involvements

Excess GH:
Childhood: Gigantism.
Adulthood: Acromegaly.
GH Deficiency:
Children: Pituitary dwarfism, characterized by low muscle mass, increased body fat, and
failure to reach normal adult height.
Adults: Rare but leads to low muscle and bone mass, lethargy, decreased work capacity,
hyperlipidemia, and increased cardiovascular risk.

Therapeutic Uses

Recombinant Human GH (rhGH): Somatropin

Indications:
P
.
T P 1. Pituitary Dwarfism: Subnormal height gain in childhood; daily subcutaneous
Comp injections of somatropin (30-60 μg/kg) in the evening.
2. Turner Syndrome: Short stature in girls corrected with rhGH and androgen/estrogen
Aplication T
therapy.
3. Chronic Renal Insufficiency in Children: Approved for restoring growth.
C 4. Constitutional Short Stature: Encouraging results, but long-term, costly, and
controversial.
5. Adult GH Deficiency: Increases lean body mass, decreases fat, improves energy and

AT metabolism.
6. AIDS-related Wasting: Improves physical and mental health; also used in severe
burns, bedridden patients, chronic renal failure.

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 Products: NORDITROPIN, NORDILET (5, 10, 15 mg prefilled pen injector), HUMATROPE (6
mg, 12 mg cartridges, 1.33 and 5.33 mg vials).

Adverse Effects
Lipolysis
Generally low immunogenicity. ↑
Possible effects: Injection site pain, lipodystrophy, glucose intolerance, hypothyroidism, salt and
-

water retention, hand stiffness, myalgia, headache, and increased intracranial tension in some
cases.
-

Mecasermin
-

Description: Recombinant human IGF-1 (rhIGF-1).

Use: Effective in children with growth retardation unresponsive to rhGH due to GH receptor/GH
signaling pathway abnormalities.

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. The g.i. action produces steatorrhoea, diarrhoea, hypochlorhydria, dyspepsia and
nausea as side effect. Somatostatin constricts splanchnic, hepatic and renal blood vessels. The
decreased g.i. mucosal blood flow can be utilized for controlling bleeding esopha geal varices and
bleeding peptic ulcer, but its analogue octreotide is preferred now due to longer duration of
action. The antisecretory action of somatostatin is beneficial in pancreatic, biliary or intestinal
fistulae; can also be used to reduce complications after pancreatic surgery. It 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 (t ⁄ 2–3 min), lack of
specific ity for inhibiting only GH secretion and GH rebound on discontinuation. Surgical removal
of pituitary adenomas is the preferred treatment modality, but somatostatin analogues are being
increasingly used.
Dose: (for upper g.i.bleeding) 250 μg slow i.v. injection over 3 min followed by 3 mg i.v. infusion
over 12 hours.
STILMEN, SOMATOSAN, SOMASTAT 250 μg and 3 mg amps.
Octreotide This synthetic octapeptide surrogate of somatostatin is 40 times more potent in sup‐
pressing GH secretion and longer acting (t ⁄ ~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. Control of diarrhoea is due to sup‐
pression of hormones which enhance intestinal
mucosal secretion.
Dose: Initially 50–100 μg s.c. twice daily, increased upto 200 μg TDS; for acromegaly maintain with
10–30 mg i.m. of microsphere formulation every 4 weeks.
Adverse effects are abdominal pain, nausea, steatorrhoea, diarrhoea, and gall stones (due to
biliary stasis). Hyperglycaemia is infrequent.
Octreotide injected i.v. (100 μg followed by
25–50 μg/hr) reduces hepatic blood flow and
helps stop esophageal variceal bleeding.
SANDOSTATIN, OCTRIDE 50 μg, 100 μg in 1 ml amps. SANDOSTATIN LAR (microsphere
formulation) 20 mg/5 ml inj.

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 Lanreotide Another longacting analogue of somatostatin, very similar in actions and specificity to
octreotide, which on i.m. injection acts for 10–15 days. It is indicated for pharma cotherapy of
acromegaly.
Pegvisomant This polyethylene glycol complexed mutant GH binds to the GH receptor but does
not trigger signal transduction: acts as a GH antagonist. It is approved for treatment of
acromegaly due to small pituitary adenomas.
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GH Inhibitors

Somatostatin

Structure: 14 amino acid peptide.

Functions:
Inhibits secretion of GH, prolactin, TSH by the pituitary gland.
Inhibits secretion of insulin and glucagon by the pancreas.
Reduces almost all gastrointestinal (GI) secretions including gastrin and hydrochloric acid
(HCl).
Side Effects:
Steatorrhea, diarrhea, hypochlorhydria, dyspepsia, nausea.
Constricts splanchnic, hepatic, and renal blood vessels.
Therapeutic Uses:
GI Bleeding: Controls bleeding esophageal varices and bleeding peptic ulcers due to
decreased GI mucosal blood flow.
Antisecretory Action: Beneficial in managing pancreatic, biliary, or intestinal fistulae and
reducing post-pancreatic surgery complications.
Diabetic Ketoacidosis: Adjuvant therapy by inhibiting glucagon and GH secretion.
Limitations:
Short duration of action (t1/2 2–3 minutes).
Lack of specificity for inhibiting only GH secretion.
GH rebound on discontinuation.
Surgical removal of pituitary adenomas is preferred, but somatostatin analogs are
increasingly used.
Dosage:
For upper GI bleeding: 250 μg slow IV injection over 3 minutes, followed by 3 mg IV infusion
over 12 hours.
Products: STILMEN, SOMATOSAN, SOMASTAT (250 μg and 3 mg amps).

Octreotide ****. university

Description: Synthetic octapeptide surrogate of somatostatin.
Potency: 40 times more potent than somatostatin in suppressing GH secretion.
Duration: Longer acting (t1/2 ~90 minutes).
Functions:
Weak inhibitor of insulin secretion.
Preferred for acromegaly and secretory diarrheas associated with carcinoid, AIDS, cancer
chemotherapy, or diabetes.
Controls diarrhea by suppressing hormones that enhance intestinal mucosal secretion.

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 Dosage:
Initially 50–100 μg subcutaneously (s.c.) twice daily, can be increased up to 200 μg three
times daily (TDS).
For acromegaly: 10–30 mg intramuscularly (i.m.) of microsphere formulation every 4 weeks.
* IV use for esophageal variceal bleeding: 100 μg followed by 25–50 μg/hr infusion.
Adverse Effects:
Abdominal pain, nausea, steatorrhea, diarrhea, gall stones (due to biliary stasis).
Infrequent hyperglycemia.
Products: SANDOSTATIN, OCTRIDE (50 μg, 100 μg in 1 ml amps), SANDOSTATIN LAR
(microsphere formulation, 20 mg/5 ml inj).

Lanreotide

Description: Another long-acting analog of somatostatin.

Actions: Similar to octreotide.
Duration: Acts for 10–15 days on i.m. injection.
Indications: Pharmacotherapy of acromegaly.

Pegvisomant

Description: Polyethylene glycol complexed mutant GH.

Mechanism: Binds to the GH receptor but does not trigger signal transduction, acting as a GH
antagonist.
Indications: Approved for treatment of acromegaly due to small pituitary adenomas.

PROLACTIN
It is a 199 amino acid, single chain peptide of MW 23000; quite similar chemically to GH. Prolactin
was originally described as the hormone which causes secretion of milk from crop glands of
pigeon and later found to be of considerable importance in human beings as well.
Physiological function Prolactin is the primary stimulus which in conjunction with estrogens,
progesterone and several other hor mones, causes growth and development of breast during
pregnancy. It promotes proliferation of ductal as well as acinar cells in the breast and induces
synthesis of milk proteins and lactose. After parturition, prolactin induces milk secretion, since the
inhibitory influence of high estrogen and progesterone levels is withdrawn.
Prolactin suppresses hypothalamopituitary gonadal axis by inhibiting GnRH release. Continuous
high level of prolactin during breastfeeding is responsible for lactational amen orrhoea, inhibition
of ovulation and infertility for several months postpartum. Prolactin may affect immune response
through action on T
lymphocytes.
A specific prolactin receptor is expressed on the surface of target cells, which is structurally and
functionally ana logous to GH receptor: action is exerted by transmembrane activation of JAK—
cytoplasmic tyrosine protein kinases and STAT.
Regulation of secretion Prolactin is under predominant inhibitory control of hypothalamus
through PRIH which is dopamine that acts on pituitary lactotrope D2 receptor. Dopaminergic
agonists (DA, bromocriptine, cabergoline) decrease plasma prolactin levels, while dopaminergic
antagonists (chlorpromazine, haloperidol, metoclopramide) and DA depleter (reserpine) cause
hyperprolactinemia.
Prolactin levels in blood are low in childhood, increase in girls at puberty and are higher in adult
females than in males. A progressive increase occurs during pregnancy, peaking at term.

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 Subsequently, high prolactin secretion is maintained by suckling: it falls if breast feeding is
discontinued.
Physio-pathological involvement Hyperpro lactinaemia is responsible for the galactorrhoea–
amenorrhoea–infertility syndrome in women. In males it causes loss of libido and depressed
fertility. The most important cause of hyper prolactinaemia is prolactin secreting tumours (micro‐
or macroprolactinomas). Others are— hypothalamic disorders weakening its inhibitory control
over pituitary, antidopaminergic drugs or high TRH levels (due to hypothyroidism) which
stimulates prolactin secretion.
Use There are no clinical indications for prolactin.
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Prolactin

General Information

Structure: 199 amino acid, single-chain peptide with a molecular weight of 23,000.
Chemical Similarity: Similar to Growth Hormone (GH).
Initial Discovery: Identified as the hormone responsible for milk secretion from crop glands of
pigeons; later recognized for its importance in humans.

Physiological Functions

Breast Development and Milk Production:

Primary stimulus for breast growth and development during pregnancy, in conjunction with
estrogens, progesterone, and other hormones.
Promotes proliferation of ductal and acinar cells in the breast.
Induces synthesis of milk proteins and lactose.
After childbirth, prolactin induces milk secretion as the inhibitory effects of high estrogen
and progesterone levels are removed.
Hypothalamo-Pituitary-Gonadal Axis:
Suppresses this axis by inhibiting GnRH release.
High prolactin levels during breastfeeding cause lactational amenorrhea, inhibit ovulation,
and lead to postpartum infertility for several months.
Immune Response:
May affect the immune response through actions on T-lymphocytes.

Receptor and Mechanism of Action

Prolactin Receptor:
Expressed on the surface of target cells.
Structurally and functionally similar to the GH receptor.
Exerts action through transmembrane activation of JAK—cytoplasmic tyrosine protein
kinases and STAT.

Regulation of Secretion

Inhibitory Control:

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 Predominantly regulated by the hypothalamus through Prolactin Release-Inhibiting
Hormone (PRIH), which is dopamine.
Dopamine acts on pituitary lactotrope D2 receptors to inhibit prolactin secretion.
Dopaminergic Agonists: Decrease prolactin levels (e.g., dopamine, bromocriptine,
cabergoline).
Dopaminergic Antagonists: Increase prolactin levels (e.g., chlorpromazine, haloperidol,
metoclopramide).
DA Depleter: Reserpine causes hyperprolactinemia.
Life Stages and Conditions:
Low levels during childhood.
Increase in girls at puberty; higher in adult females than males.
Progressive increase during pregnancy, peaking at term.
High secretion maintained by suckling; decreases if breastfeeding is discontinued.

Pathophysiological Involvements

Hyperprolactinemia:
Causes galactorrhea–amenorrhea–infertility syndrome in women.
Causes loss of libido and depressed fertility in men.
Major causes: Prolactin-secreting tumors (micro- or macroprolactinomas).
Other causes: Hypothalamic disorders, antidopaminergic drugs, high TRH levels (due to
hypothyroidism).

Clinical Use

Indications: There are no clinical indications for prolactin.

Prolactin inhibitors
Bromocriptine
This synthetic ergot derivative 2bromoα ergocryptine is a potent dopamine agonist. 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 of
bromocriptine are: 1. Decreases prolactin release from pituitary
and is a strong antigalactopoietic.
2. Increases GH release in normal individu als, but decreases the same from pituitary
tumours that cause acromegaly.
3. Has levodopa like actions in CNS—anti
parkinsonian and behavioural 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 a
adrenergic blockade.
6. Decreases gastrointestinal motility.
Only 1/3 of an oral dose of bromocriptine is absorbed; bioavailability is further lowered by high
first pass metabolism in liver. Metabolites are excreted mainly in bile. Its plasma t ⁄ is 3–6 hours.
PROCTINAL, PARLODEL, SICRIPTIN, 1.25 mg, 2.5 mg tabs.
Uses Bromocriptine is infrequently used now; has been largely superseded by newer D2 ago nists.
Conditions in which it can be used are:
1. Hyperprolactinemia due to microprolactino mas causing galactorrhoea, amenorrhoea and

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 infertility in women; gynaecomastia, impotence and sterility in men but has been replaced by
cabergoline.
2. Acromegaly Bromocriptine is indicated when acromegaly is due to small pituitary tumours and
for inoperable cases; but cabergoline is preferred now.
3. Parkinsonism Relatively higher doses are required, which are poorly tolerated. Newer D2
receptor agonists, ropinirole and pramipexole are used now.
4. Diabetes mellitus (DM) A new use of bromocriptine based on its dopamine D2 agonistic action
in the hypo thalamus has been found in type 2 DM, and it has been approved by USFDA as an
adjunctive drug.
Side effects: Side effects are frequent and dose related.
Early: Nausea, vomiting, constipation, nasal blockage. Postural hypotension may be marked at
initiation of therapy—syncope may occur if starting dose is high. Hypotension is more likely in
patients taking antihypertensives.
Late: Behavioural alterations, mental confusion, hallucinations, psychosis. These side effects are
more prominent than with levodopa. Abnormal movements, livedo reticularis.
Cabergoline
It is a newer D2 agonist; more potent; more selective for pituitary lactotrope D2 receptors, and
longer acting (t ⁄ > 60 hours) than bromocriptine. It needs to be given only twice weekly.
Incidence of nausea and vomiting is also lower; some patients not tolerating or not responding to
bromocriptine have been successfully treated with cabergoline. It is the first choice drug for
treatment of hyperprolactinaemia; serum prolactin levels fall to the normal range in 2–4 weeks,
and many women conceive within one year. Cabergoline should be stopped when pregnancy
occurs, though no teratogenic effect has been observed. Most micro and some macro‐
prolactinomas show regression during therapy, and neurological symptoms (visual field defects,
etc.) due to pressure on optic chiasma are relieved. Response is generally maintained only till the
drug is given, with recurrence on stoppage. Some patients who achieve total regression of
prolactinoma and normalization of prolactin levels can stop cabergoline without recurrence.
Cabergoline is also beneficial in acromegaly due to pituitary adenoma, but efficacy is lower. It may
be used to supplement surgery/radiation/
octreotide.
Dose: Start with 0.25 mg twice weekly; if needed increase after every 4–8 weeks to max. of 1 mg
twice weekly. CABERLIN 0.5 mg tab, CAMFORTE 0.5, 1 mg tabs. COLETTE 0.25, 0.5 mg tabs.
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&

Prolactin Inhibitors

Bromocriptine * M .

Description: Synthetic ergot derivative (2-bromo-α-ergocryptine); potent dopamine agonist.

Receptor Activity:
Primarily acts on D2 receptors.
Partial agonist or antagonist at certain D1 receptor sites in the brain.
Weak α-adrenergic blocker; not an oxytocic.
Actions:
1. Decreases prolactin release from the pituitary (strong antigalactopoietic).
2. Increases GH release in normal individuals, decreases GH from pituitary tumors causing
acromegaly.
3. Levodopa-like actions in the CNS; anti-parkinsonian and behavioral effects.

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 4. Induces nausea and vomiting by stimulating dopaminergic receptors in the chemoreceptor
trigger zone (CTZ).
5. Causes hypotension due to central suppression of postural reflexes and weak peripheral α-
adrenergic blockade.
6. Decreases gastrointestinal motility.
Pharmacokinetics:
Only 1/3 of an oral dose is absorbed.
High first-pass metabolism in the liver.
Metabolites excreted mainly in bile.
Plasma half-life: 3–6 hours.
Products: PROCTINAL, PARLODEL, SICRIPTIN (1.25 mg, 2.5 mg tabs).
Uses:
1. Hyperprolactinemia: Used for microprolactinomas causing galactorrhea, amenorrhea, and
infertility in women; gynecomastia, impotence, and sterility in men. Often replaced by
cabergoline.
DAPsonHe 2. Acromegaly: Indicated for small pituitary tumors and inoperable cases; cabergoline
preferred.
3. Parkinsonism: Requires higher doses, which are poorly tolerated. Newer D2 receptor
agonists (ropinirole, pramipexole) are now preferred.
4. Diabetes Mellitus (Type 2 DM): Approved by the US FDA as an adjunctive drug based on its
D2 agonistic action in the hypothalamus.
Side Effects: a

Early: Nausea, vomiting, constipation, nasal blockage, postural hypotension (marked at

therapy initiation; syncope may occur if starting dose is high).
Late: Behavioral alterations, mental confusion, hallucinations, psychosis (more prominent
than with levodopa), abnormal movements, livedo reticularis.

Cabergoline

Description: Newer D2 agonist; more potent and selective for pituitary lactotrope D2 receptors
than bromocriptine.
Duration: Longer acting (t1/2 > 60 hours); requires administration only twice weekly.
Advantages:
Lower incidence of nausea and vomiting.
Effective in patients not tolerating or responding to bromocriptine.
Primary Use: First choice drug for hyperprolactinemia.
Serum prolactin levels normalize in 2–4 weeks.
Many women conceive within one year.
Should be stopped when pregnancy occurs; no teratogenic effects observed.
Causes regression in most microprolactinomas and some macroprolactinomas.
Relieves neurological symptoms (e.g., visual field defects) due to pressure on the optic
chiasma.
Response generally maintained only during treatment; recurrence possible upon
discontinuation.
Some patients with total regression and normalized prolactin levels can stop therapy
without recurrence.
Additional Use: Beneficial in acromegaly due to pituitary adenoma (efficacy lower than
bromocriptine); may supplement surgery/radiation/octreotide.
Dosage:
Start with 0.25 mg twice weekly.
If needed, increase every 4–8 weeks to a maximum of 1 mg twice weekly.
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 Products: CABERLIN (0.5 mg tab), CAMFORTE (0.5, 1 mg tabs), COLETTE (0.25, 0.5 mg tabs).

GONADOTROPINS (Gns)
The anterior pituitary secretes two Gns viz. FSH and LH. Both are glycoproteins containing 23–28%
sugar and consist of two peptide chains. The αchain (92AA) is common between FSH and LH, but
their βchains are different: FSH (111 AA), LH (121 AA). Paradoxically the MW of FSH (~33KD) is
greater than that of LH (~30 KD), because of the sugar moieties.
Physiological functions FSH and LH act in concert to promote gametogenesis and secre tion of
gonadal hormones.
FSH In the female it induces follicular growth, development of ovum and secretion of estro gens.
In the male it supports spermatogenesis and has a trophic influence on seminiferous tubules.
Ovarian and testicular atrophy occurs in the absence of FSH.
LH It induces preovulatory swelling of the ripe graafian follicle and triggers ovulation followed by
luteinization of the ruptured follicle and sus tains the corpus luteum till the next menstrual cycle.
It is also probably responsible for atresia of the remaining follicles. Progesterone secretion occurs
only under the influence of LH. In the male LH stimulates testosterone secretion by the interstitial
cells and is designated interstitial
cell stimulating hormone (ICSH).
Distinct LH and FSH receptors are expressed on
the target cells. Both are G protein coupled receptors which on activation increase cAMP
production. This in turn stimulates gametogenesis and conversion of cholesterol to pregnenolone
—the first step in progesterone, testosterone and estrogen synthesis.
Regulation of secretion A single releasing factor (decapeptide designated GnRH) is produced by
the hypo thalamus which stimulates synthesis and release of both FSH and LH from pituitary. It is,
therefore, also referred
to as FSH/LH-RH or simply LHRH or gonadorelin. It has been difficult to explain how
hypothalamus achieves a divergent pattern of FSH and LH secretion in menstru ating women
through a single releasing hormone. Since GnRH is secreted in pulses and the frequency as well
as amplitude of the pulses differs during follicular (high frequency, low amplitude) and luteal
(lower frequency, higher amplitude) phases, it is considered that frequency and amplitude of
GnRH pulses determines whether FSH or LH or both will be secreted, as well as the amount of
each. Further, the feedback regulation of FSH and LH may be different. In general, feedback
inhibition of LH is more marked than that of FSH. In addition there are other regulatory
substances, e.g. inhibin—a peptide from ovaries and testes, selectively inhibits FSH release, but
not LH release. Dopamine inhibits only LH release. Testosterone is weaker than estrogens in
inhibiting Gn secretion, but has effect on both FSH and LH. GnRH acts on gonado tropes through
a Gprotein coupled receptor which acts by increasing intracellular Ca2+ through PIP2 hydrolysis.
The Gn secretion increases at puberty and is higher in women than in men. In men, the levels of
FSH and LH remain practically constant (LH > FSH) while in menstrua ting women they fluctuate
cyclically. During the follicular phase, moderate levels of FSH and low levels of LH prevail. There is
a midcycle surge of both, but more of LH, just before ovulation, followed by progressive fall
during the luteal phase. Gn levels are high in menopausal women due to loss of feedback
inhibition by sex steroids and inhibin.
Pathological involvement Disturbances of Gn secretion from pituitary may be responsible for
delayed puberty or precocious puberty in girls as well as in boys.
Inadequate Gn secretion results in amenorrhoea and sterility in women; oligozoospermia,
impotence and infertility in men. Excess production of Gn in adult women causes polycystic
ovaries.
Preparations

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 All earlier gonadotropin preparations were administered by i.m. route. The newer more purified
preparations can be given s.c. They are partly metabolized, but mainly excreted unchanged in
urine: t ⁄ 2–6 hours.
1. Menotropins (FSH + LH): is a preparation obtained from urine of menopausal women:
PREGNORM, PERGONAL, GYNOGEN 75/150; 75 IU FSH + 75 IU LH activity per amp, also 150 IU FSH
+ 150 IU LH per amp.
2. Urofollitropin or Menotropin (pure FSH): METRODIN, FOLGEST, FOLICULIN, PUREGON 75 IU and
150 IU per amp. This preparation has been preferred over the combined FSH + LH preparation for
induction of ovula tion in women with polycystic ovarian disease. These patients have elevated
LH/FSH ratio; use of FSH alone is considered advantageous. This preparation is also claimed to
improve chances of obtaining good quality ova for in vitro fertilization. 3. Human chorionic
gonadotropin (hCG): is derived from urine of pregnant women.
CORION, PROFASI, PUBERGEN 1000 IU, 2000 IU, 5000IU, 10,000 IU, all as dry powder with
separate solvent for injection.
The foetal placenta secretes hCG which is absorbed in maternal circulation and maintains corpus
luteum of pregnancy. It is a glycoprotein with 33% sugar and 237 amino acids in two chains, MW
38000. It is excreted in urine by the mother from which it is commercially obtained. hCG binds to
LH receptor with equal avidity; action of hCG is indistinguishable from that of LH.
Recombinant human FSH (rhFSH or Follitropin α and follitropin β) and recombinant human LH
(rhLH or Lutropin) as well as recombinant hCG (rhCG or Choriogonadotropin α) have been
produced. These are more purified and have vertually replaced the urine derived preparations in
the developed countries. They are more expensive. Lutropin (rhLH) has been withdrawn.
Uses
1. Amenorrhoea and infertility Exogenous Gns may help when amenorrhoea/infertility is due to
deficient production of Gns by pituitary. Gns are generally tried when at tempts to induce
ovulation with clomiphene have failed or when nonovulation is due to polycystic ovaries. Several
protocols for use of Gns have been employed, one of which is to give 1 injection of menotropins
(75 IU FSH + 75 IU LH or 75 IU pure FSH)) i.m. daily for 10 days followed the next day by 10,000 IU
of hCG. Ovulation occurs within the next 24–48 hours in upto 75% cases and the woman may
conceive if inseminated at this time. However, rates of abortion and multiple pregnancy are high,
but not of teratogenesis.
To improve the predictability of time of ovulation (controlled ovarian stimulation), it is the
standard practice now to concurrently suppress endogenous FSH/LH secretion either by
continuous pretreatment with a superactive GnRH agonist or by a GnRH antagonist.
2. To aid in vitro fertilization Menotropins (FSH + LH or pure FSH) is used along the GnRH
agonist/antagonist (for suppressing endogenous FSH/LH) to induce simultaneous maturation of
several ova and to precisely time
ovulation so as to facilitate their harvesting for assisted reproductive techniques.
3. Male hypogonadotropic hypogonadism It manifests as delayed puberty or defective
spermatogenesis producing oligozoospermia and male sterility. Generally, sexual maturation is
induced by androgens and therapy with hCG is started when fertility is desired. Start with hCG i.m.
2–3 times a week (to stimulate testosterone secretion), add FSH 75 IU + LH 75 IU after 3–4 months
(to stimulate spermatogenesis) and reduce dose of hCG. Treatment is continued for 6–12 months
for optimum results, which nevertheless are not always impressive.
4. Cryptorchidism A 2–6 weeks course of hCG was used to treat undescended testes in early
childhood. However, this is not practiced now due to poor efficacy, risk of precocious puberty and
other concerns. Surgical correction is the preferred modality.
Adverse effects and precautions
Ovarian hyperstimulation syndrome is the most serious complication. Polycystic ovary, pain in
lower abdomen and even ovarian bleeding and shock can occur in females during ovulation
induction.
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 Multiple pregnancy is another complication.
Precocious puberty is a risk when given to children.
Allergic reactions have occurred and skin tests are advised. Hormone dependent malignancies
(prostate, breast) must be excluded.
Other side effects are edema, headache, mood changes.
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Gonadotropins (Gns)

Overview

The anterior pituitary secretes two gonadotropins: Follicle Stimulating Hormone (FSH) and
Luteinizing Hormone (LH).
Both are glycoproteins (23–28% sugar) with two peptide chains:
α-chain (92AA): Common between FSH and LH.
β-chain: Different between FSH (111 AA) and LH (121 AA).
FSH has a greater molecular weight (~33 kDa) than LH (~30 kDa) due to sugar moieties.

Physiological Functions

FSH:
Female: Induces follicular growth, development of ovum, and estrogen secretion.
Male: Supports spermatogenesis and has a trophic influence on seminiferous tubules.
Ovarian and testicular atrophy occurs without FSH.
LH:
Female: Induces preovulatory swelling, triggers ovulation, sustains the corpus luteum, and
is likely responsible for atresia of remaining follicles. Essential for progesterone secretion.
Male: Stimulates testosterone secretion by interstitial cells (ICSH).

Mechanism of Action

Distinct LH and FSH receptors are expressed on target cells.

Both receptors are G protein-coupled, increasing cAMP production to stimulate gametogenesis
and cholesterol conversion to pregnenolone.

Regulation of Secretion

GnRH: Single releasing factor (decapeptide) produced by the hypothalamus stimulates FSH and
LH release.
GnRH Secretion: Pulsatile, with frequency and amplitude differing in follicular (high
frequency, low amplitude) and luteal (lower frequency, higher amplitude) phases.
Feedback Inhibition:
LH inhibition is more marked than FSH.
Inhibin (from ovaries/testes): Selectively inhibits FSH release.
Dopamine: Inhibits LH release.
Testosterone: Weaker than estrogens in inhibiting Gn secretion but affects both FSH
and LH.
Gn Levels:

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 Increase at puberty, higher in women than men.
Men: Constant levels (LH > FSH).
Women: Cyclical fluctuations during the menstrual cycle.
Menopausal Women: High Gn levels due to loss of feedback inhibition by sex steroids and
inhibin.

Pathological Involvement

Disturbances in Gn secretion:
Delayed or Precocious Puberty: In both genders.
Inadequate Gn Secretion: Leads to amenorrhea and sterility in women; oligozoospermia,
impotence, and infertility in men.
Excess Gn Production: Causes polycystic ovaries in adult women.

Preparations

Administration: Intramuscular (i.m.) or subcutaneous (s.c.); partly metabolized, mainly excreted

unchanged in urine (t1/2 2–6 hours).

1. Menotropins (FSH + LH):

Obtained from urine of menopausal women.
Examples: PREGNORM, PERGONAL, GYNOGEN (75/150 IU).
2. Urofollitropin (Pure FSH):
Preferred for ovulation induction in polycystic ovarian disease.
Examples: METRODIN, FOLGEST, FOLICULIN, PUREGON (75 IU and 150 IU).
3. Human Chorionic Gonadotropin (hCG):
Derived from urine of pregnant women.
Examples: CORION, PROFASI, PUBERGEN (1000–10,000 IU).
hCG binds to LH receptor, action indistinguishable from LH.
4. Recombinant Hormones:
FSH (rhFSH): Follitropin α and β.
LH (rhLH): Lutropin (withdrawn).
hCG (rhCG): Choriogonadotropin α.
More purified, expensive, and have replaced urine-derived preparations in developed
countries.

Uses

1. Amenorrhea and Infertility:

Indicated for pituitary deficiency of Gns.
Protocol: Menotropins (75 IU FSH + 75 IU LH) daily for 10 days followed by 10,000 IU of hCG.
Success rate: Ovulation in 75% cases; higher abortion and multiple pregnancy rates.
2. In Vitro Fertilization:
Use of menotropins with GnRH agonist/antagonist for controlled ovarian stimulation.
Facilitates harvesting of ova for assisted reproductive techniques.
3. Male Hypogonadotropic Hypogonadism:
Therapy: Start with hCG (2–3 times a week), add FSH + LH after 3–4 months, continue for 6–
12 months.
4. Cryptorchidism:
hCG treatment used historically but not practiced now due to poor efficacy and risks.

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 Adverse Effects and Precautions

Ovarian Hyperstimulation Syndrome: Most serious complication.

Multiple Pregnancy: Common complication.
Precocious Puberty: Risk in children.
Allergic Reactions: Possible; skin tests advised.
Contraindications: Hormone-dependent malignancies (prostate, breast) must be excluded.
Other Side Effects: Edema, headache, mood changes.

GONADOTROPIN RELEASING HORMONE (GnRH) (GONADORELIN)

Synthetic human GnRH (gonadorelin) injected i.v. (100 μg) induces prompt release of LH and FSH
followed by elevation of gonadal steroid levels. It has a short plasma t ⁄ (4–8 min) due to rapid
enzymatic degradation. It has been used for testing pituitarygonadal axis in male as well as
female hypogonadism.
Only pulsatile exposure to GnRH induces FSH/LH secretion, while sustained exposure desensitizes
the pituitary gonadotropes resulting in loss of Gn release. Therapy with GnRH is not useful in the
treatment of 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 (t ⁄ 2–6 hours) because
of high affinity for GnRH receptor and resistance to enzymatic hydrolysis. Because physiological
release of GnRH is in pulses, whereas these agonists act continuously; they only initially trigger Gn
secretion. After 1–2 weeks they cause desensitization and down regulation of GnRH receptors
causing inhibition of FSH and LH secretion followed by suppression of gonadal function.
Spermatogenesis or ovulation cease and testosterone or estradiol levels fall to castration levels.
Recovery occurs within 2 months of stopping treatment.
The superactive GnRH agonists are used as nasal spray or injected s.c/i.m. Longacting
preparations for once a month s.c. injection have been produced (triptorelin, goserelin depot). The
resulting reversible pharmacologi cal oophorectomy/orchidectomy is being used in precocious
puberty, prostatic carcinoma, endometriosis, premenopausal breast cancer, uterine leiomyoma,
polycystic ovarian disease and to assist induced ovulation. They also have potential to be used as
contraceptive for both males and females.
Menopausal symptoms, viz. headache, sweat ing, hot flashes, mood changes, vaginal dryness
amenorrhoea and loss of libido can occur due to suppression of ovarian function. Use of GnRH
agonists for more than 6 months carries risk of developing osteoporosis.
Nafarelin This longacting GnRH agonist is 150 times more potent than native GnRH. It is used as
intranasal spray from which bioavail ability is only 4–5%.
NASAREL 2 mg/ml soln for nasal spray; 200 μg per actuation.
Down regulation of pituitary GnRH receptors occurs in10 days but peak inhibition of Gn release
occurs at one month. It is broken down in the body to shorter peptide segments; plasma t ⁄ is 2–3
hours. Uses are:
Assisted reproduction: Endogenous LH surge needs to be suppressed when controlled ovarian
stimulation is attempted by exogenous FSH and LH injection, so that precisely timed mature
oocytes can be harvested. This is achieved by 400 μg BD intranasal nafarelin, reduced to 200 μg
BD when menstrual bleeding occurs.
Uterine fibroids: Nafarelin 200 μg BD intra nasal for 3–6 months can reduce the size of leiomyoma
and afford symptomatic relief.
Endometriosis: 200 μg in alternate nostril BD for upto 6 months. It is as effective as danazol, but

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 second course cannot be given due to risk of osteoporosis.
Central precocious puberty: 800 μg BD by nasal spray; breast and genital development is arrested
in girls and boys. Treatment is generally carried out till the age of 11 years in girls or 12 years in
boys. The effect is reversible; pubertal changes resume when therapy is discontinued.
Adverse effects: Hot flashes, loss of libido, vaginal dryness, osteoporosis, emotional lability.
Goserelin Another longacting 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. To achieve pituitary desensitization before ovulation induction with
exogenous Gns; 3.6 mg of depot goserelin injection is given once in the anterior abdominal wall
1–3 weeks earlier.
For endometriosis and carcinoma prostate 3.6 mg is injected in the same way every 4 weeks or
10.8 mg is injected every 3 months. An androgen antagonist (bicalutamide) is given concurrently
for 3–4 weeks when goserelin is used for carcinoma prostate. This is needed to block the effect of
androgen secreted under the influence of enhanced Gn production by initial agonistic action of
the GnRH agonist on gonadotropes.
ZOLADEX 3.6 mg prefilled syringe, ZOLDEX L-A 10.8 mg vial depot injection.

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 for long‐
term Gn suppression in the treatment of carcinoma prostate, endometriosis, precocious puberty
and uterine leiomyoma. For prostate cancer, it is combined with an androgen antagonist
flutamide or bicalutamide to prevent the initial flare up of the tumour that occurs due to increase
in Gn secretion for the first 1–2 weeks.
Fibroids, endometriosis, carcinoma prostate: 3.75–7.5 mg i.m. every 4 weeks.
Precocious puberty: 50 μg/kg i.m. of depot inj. every 4 weeks.
Assisted reproduction: 0.1 mg s.c. daily for 10 days from 2nd day of cycle.
DECAPEPTYL DAILY 0.1 mg inj., DECAPEPTYL DEPOT 3.75 mg inj.
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 suppres sion. Daily s.c. injections are also used for assisted
reproduction.
LUPRIDE 1 mg inj., 3.75 mg depot inj., PROGTASE 1 mg/ ml inj.
GnRH antagonists Four analogues of GnRH, Ganirelix, Cetrorelix, Degarelix and Abarelix which are
more extensively substituted act as GnRH receptor antagonists. They inhibit Gn secretion without
causing initial stimulation. Ganirelix and Cetrorelix are relatively short acting. Administered daily
by s.c. injection, they are approved for inhibiting LH surges during controlled ovarian stimulation
in women undergoing in vitro fertilization. Their advan tages over longacting GnRH agonists
include:
• They produce quick Gn suppression by com
petitive antagonism, and need to be started only from 6th day of attempting ovarian stimulation
with Gns.
• They carry a lower risk of ovarian hyper stimulation syndrome.
• They achieve more complete suppression of endogenous Gn secretion.
However, pregnancy rates are similar or may even
be lower.
Degarelix and Abarelix are long acting GnRH antagonists, approved for androgen withdrawal
therapy of advanced carcinoma prostate.
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 Gonadotropin-Releasing Hormone (GnRH) (Gonadorelin)

Overview

Synthetic GnRH (Gonadorelin):

Injection: 100 μg i.v. induces prompt LH and FSH release, followed by elevated gonadal
steroid levels.
Plasma t1/2: 4–8 minutes due to rapid enzymatic degradation.
Used to test pituitary-gonadal axis in hypogonadism.
Pulsatile vs. Sustained Exposure:
Pulsatile: Induces FSH/LH secretion.
Sustained: Desensitizes pituitary gonadotropes, inhibiting Gn release.
Not useful for hypogonadism treatment.

Superactive/Long-Acting GnRH Agonists

Examples: Goserelin, Leuprolide, Nafarelin, Triptorelin.

Potency: 15–150 times more than natural GnRH.
Duration: t1/2 2–6 hours due to high receptor affinity and enzymatic resistance.
Mechanism: Initial Gn secretion, followed by desensitization/downregulation of GnRH receptors,
leading to inhibition of FSH and LH secretion and suppression of gonadal function.
Recovery: Within 2 months of stopping treatment.

Uses

Conditions:
Precocious puberty. us continuous infusion > Lon as -

pitulary
Prostatic carcinoma.
responds to
Endometriosis.
Premenopausal breast cancer.
pulsatile GURH
Uterine leiomyoma.
Polycystic ovarian disease.
Assisted induced ovulation.
Potential Contraceptive: For both males and females.
Adverse Effects:
Menopausal symptoms: Headache, sweating, hot flashes, mood changes, vaginal dryness,
amenorrhea, and loss of libido.
Risk of osteoporosis with >6 months use.

Specific Agonists and Uses

1. Nafarelin:
Potency: 150 times more than native GnRH.
Administration: Intranasal spray (4–5% bioavailability).
Uses:
Assisted reproduction: 400 μg BD (reduce to 200 μg BD during menstrual bleeding).
Uterine
-
fibroids: 200 μg BD intranasal for 3–6 months.
Endometriosis: 200 μg in alternate nostril BD for up to 6 months.
-

Central precocious puberty: 800 μg BD by nasal spray.

Adverse Effects: Hot flashes, loss of libido, vaginal dryness, osteoporosis, emotional lability.

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 2. Goserelin:
Administration: Depot s.c./i.m. injection.
Uses:
Pituitary desensitization before ovulation induction: 3.6 mg depot injection.
Endometriosis, carcinoma prostate: 3.6 mg every 4 weeks or 10.8 mg every 3 months.
Prostate Cancer: Combine with an androgen antagonist (e.g., bicalutamide) initially.
3. Triptorelin:
Formulations: Regular release daily s.c. injection, monthly depot i.m. injection.
Uses:
Female infertility, prostate cancer, endometriosis, precocious puberty, uterine
leiomyoma.
Assisted reproduction: 0.1 mg s.c. daily for 10 days from the 2nd day of the cycle.
Prostate Cancer: Combine with an androgen antagonist (e.g., flutamide or bicalutamide).
4. Leuprolide:
Administration: s.c./i.m. daily or as a monthly depot injection.
Uses: Carcinoma prostate palliation, conditions needing long-term Gn suppression, assisted
reproduction.

GnRH Antagonists

Examples: Ganirelix, Cetrorelix, Degarelix, Abarelix.

Mechanism: GnRH receptor antagonists inhibit Gn secretion without initial stimulation.
Uses:
Ganirelix and Cetrorelix:
Short-acting, s.c. injections.
Inhibit LH surges during controlled ovarian stimulation in IVF.
Advantages: Quick suppression, lower risk of ovarian hyperstimulation, more
complete Gn suppression.
Degarelix and Abarelix:
Long-acting.
Approved for androgen withdrawal therapy of advanced carcinoma prostate.

THYROID STIMULATING HORMONE (TSH, THYROTROPIN)

It is a 210 amino acid, two chain glycoprotein (22% sugar), MW 30000.
Physiological function TSH stimulates thyroid to synthesize and secrete thyroxine (T4) and
triiodothyronine (T3) (see Fig. 18.1). 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 col
loid by the follicular cells and proteolysis of thyroglobulin to release more of T3 and T4. This action
starts within minutes of TSH administration.
The TSH receptor present on thyroid cells is a GPCR which utilizes the adenylyl cyclasecAMP
transducer mecha nism (by coupling to Gs protein) to produce its effects. In human thyroid cells
high concentration of TSH also induces PIP2 hydrolysis by the linking of TSH receptor to Gq
protein. The resulting increase in cytosolic Ca2+ and protein kinaseC activation may also mediate
TSH action, particularly generation of H O needed for oxidation of
22
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 iodide and iodination of tyrosil residues.
Regulation of secretion Synthesis and release of TSH
by pituitary is controlled by hypothalamus primarily through
TRH (see Fig. 18.3), while somatostatin inhibits TSH
secretion. The TRH receptor on pituitary thyrotrope cells
is a GPCR which is linked to Gq protein and activates
PLC–IP /DAG–cytosolic Ca2+ pathway to enhance TSH 3
synthesis and release. The negative feedback for inhibit ing TSH secretion is provided by the
thyroid hormones which act primarily at the level of the pituitary, but also in the hypothalamus.
Pathological involvement Only few cases of hypo or hyperthyroidism are due to inappropriate TSH
secretion. In majority of cases of myxoedema TSH levels are markedly elevated because of
deficient feedback inhibition. Graves’ disease is due to an immunoglobulin of the IgG class which
attaches to the thyroid cells and stimulates them in the same way as TSH. Consequently, TSH
levels are low.
Use Thyrotropin has no therapeutic use. Thyroxine is the drug of choice even when
hypothyroidism is due to TSH deficiency. The diagnostic application is to differen- tiate
myxoedema due to pituitary dysfunction from primary thyroid disease.
ADRENOCORTICOTROPIC HORMONE (ACTH, CORTICOTROPIN)
It is a 39 amino acid single chain peptide, MW 4500, derived from a larger peptide pro-opio
melanocortin (MW 30,000) which also gives rise to endorphins, two lipotropins and two MSHs.
Physiological function ACTH promotes steroidogenesis in adrenal cortex by stimulat ing cAMP
formation in cortical cells (through specific cell surface GPCRs). This inturn rapidly increases the
availability of cholesterol for conversion to pregnenolone which is the rate limiting step in the
production of gluco, mineralo and weakly androgenic steroids (see Fig. 20.1). Induction of
steroidogenic enzymes occurs after a delay resulting in 2nd phase ACTH action. The stores of
adrenal steroids are very limited and rate of synthesis primarily governs the rate of release. ACTH
also exerts trophic influence on adrenal cortex (again
through cAMP): high doses cause hypertrophy and hyperplasia. Lack of ACTH results in adrenal
atrophy. However, zona glomerulosa is little affected because angiotensin II also exerts trophic
influence on this layer and sustains aldosterone secretion.
Regulation of secretion Hypothalamus regulates ACTH release from pituitary through
corticotropinreleasing hormone (CRH). The CRH receptor on corticotropes is also a GPCR which
increases ACTH synthesis as well as release by raising cytosolic cAMP. Secretion of ACTH has a
circadian rhythm. Peak plasma levels occur in the early morning, decrease during day and are
lowest at midnight. Corticosteroids exert inhibitory feedback influence on ACTH production by
acting directly on the pituitary as well as indirectly through hypothalamus.
A variety of stressful stimuli, e.g. trauma, surgery, severe pain, anxiety, fear, blood loss, exposure
to cold, etc. generate neural impulses which converge on median eminence to cause elaboration
of CRH. The feedback inhibition appears to be overpowered during stress—rise in ACTH secretion
continues despite high plasma level of cortisol induced by it.
Pathological involvement Excess production of ACTH from basophil pituitary tumours is
responsible for some cases of Cushing’s syndrome. Hypocorticism occurs in pituitary insufficiency
due to low ACTH production. Iatrogenic suppression of ACTH secretion and pituitary adrenal axis
is the most common form of abnormality encountered currently due to the use of
pharmacological doses of glucocorticoids in nonendocrine diseases.
Use ACTH is used rarely for the diagnosis of disorders of pituitary adrenal axis. Direct assay of
plasma ACTH level is now preferred.
For therapeutic purposes, ACTH does not offer any advantage over corticosteroids.
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 Thyroid Stimulating Hormone (TSH, Thyrotropin)

Overview

Structure:
210 amino acid glycoprotein with two chains.
22% sugar, molecular weight (MW): 30,000.

Physiological Function

Primary Role: Stimulates thyroid to synthesize and secrete thyroxine (T4) and triiodothyronine
(T3).
Actions:
* Induces hyperplasia and hypertrophy: Increases thyroid follicles and blood supply.
* Promotes iodide trapping: Increases Na+: Iodide symporter (NIS) activity.
Enhances organification of iodine: Increases peroxidase activity.
Facilitates endocytotic uptake: Promotes proteolysis of thyroglobulin, releasing T3 and
T4.
Receptor Mechanism:
TSH receptor on thyroid cells is a GPCR.
Uses adenylyl cyclase-cAMP transducer mechanism via Gs protein.
At high concentrations, induces PIP2 hydrolysis via Gq protein, increasing cytosolic Ca2+
and protein kinase C, aiding iodide oxidation and tyrosine iodination.

Regulation of Secretion

Hypothalamic Control:
TRH stimulates TSH release via GPCR linked to Gq protein, activating PLC–IP3/DAG–cytosolic
Ca2+ pathway.
Somatostatin inhibits TSH secretion.
Negative Feedback:
Thyroid hormones (T3 and T4) inhibit TSH secretion at the pituitary and hypothalamic levels.

Pathological Involvement

Hypothyroidism: Most cases of myxedema involve elevated TSH due to deficient feedback
inhibition.
Graves’ Disease: Caused by IgG class immunoglobulin mimicking TSH, resulting in low TSH
levels.

Uses

Diagnostic: Differentiates myxedema due to pituitary dysfunction from primary thyroid disease.
Therapeutic: No therapeutic use; thyroxine is preferred even when hypothyroidism is due to TSH
deficiency.

Adrenocorticotropic Hormone (ACTH, Corticotropin)

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 Overview

Structure:
39 amino acid single chain peptide.
MW: 4,500, derived from pro-opiomelanocortin (MW 30,000).

Physiological Function

Primary Role: Promotes steroidogenesis in the adrenal cortex.

Actions:

f Stimulates cAMP formation: In adrenal cortical cells via specific GPCRs.

Increases cholesterol availability: For conversion to pregnenolone, the rate-limiting step
in steroid production.

↓
Induces steroidogenic enzymes: Delayed effect, resulting in the second phase of ACTH
action.
Exerts trophic influence: On adrenal cortex, causing hypertrophy and hyperplasia; lack of
ACTH leads to adrenal atrophy (except zona glomerulosa due to angiotensin II).

Regulation of Secretion

Hypothalamic Control:
CRH regulates ACTH release via GPCR, raising cytosolic cAMP.
Circadian Rhythm:
Peak plasma levels in the early morning, lowest at midnight.
Feedback Mechanism:
Corticosteroids inhibit ACTH production at the pituitary and hypothalamus.
Stress Response:
Stressful stimuli (e.g., trauma, surgery, pain, anxiety) override feedback inhibition,
increasing ACTH secretion despite high cortisol levels.

Pathological Involvement

Cushing’s Syndrome: Excess ACTH production from pituitary tumors.

Hypocorticism: Due to low ACTH production in pituitary insufficiency.
Iatrogenic Suppression: Common due to pharmacological glucocorticoid use.

Uses

Diagnostic: Rarely used; direct assay of plasma ACTH preferred.

Therapeutic: No advantage over corticosteroids for treatment.

These notes provide a detailed yet concise overview of TSH and ACTH, including their structure,
physiological functions, regulation, pathological involvement, and uses. This format allows for easy
revision and updates as needed.

Ch-18 · Thy. Hormones 30

Transport, Metabolism and Excretion
Thyroid hormones are avidly bound to plasma proteins—only 0.03–0.08% of T4 and 0.2–0.5% of T3
are in the free form. Almost all protein bound iodine (PBI) in plasma is thyroid hormone, of which
90–95% is T4 and the rest T3. Binding occurs to 3 plasma proteins in the following decreasing
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 order of affinity for T4:
(i) Thyroxine binding globulin (TBG)
(ii) Thyroxinebindingprealbumin(transthyre
tin)
(iii) Albumin
The normal concentration of PBI is 4–10 μg/ dl; only 0.1–0.2 μg/dl of this is T3, rest is T4. During
pregnancy thyroxine binding globulin is increased—PBI levels are elevated, but there is no effect
on thyroid status because the con centration of free hormone remains unaltered.
Only the free hormone is available for action as well as for metabolism and excretion. Metabolic
inactivation of T4 and T3 occurs by deiodination and glucuronide or sulfate con jugation of the
hormones as well as that of their deiodinated products. Liver is the primary site (also salivary
glands and kidneys). The conjugates are excreted in bile, of which a significant fraction is
deconjugated in intestines and reabsorbed (enterohepatic circulation) to be finally excreted in
urine.
Plasma t ⁄ of T4 is 6–7 days, while that of T3 is 1–2 days. The halflives are shortened in
hyperthyroidism and prolonged in hypothyroidism due respectively to faster and slower
metabolism.

Regulation of Secretion
The secretion of hormones from the thyroid is controlled by anterior pituitary by the elabo ration
of TSH, while TSH secretion itself is regulated by TRH produced in hypothalamus (see p. 265).
Somatostatin elaborated by hypo thalamus inhibits not only GH and prolactin, but also TSH
secretion from pituitary. The relation between thyroid, anterior pituitary and hypothalamus is
depicted in Fig. 18.3. The negative feedback by the thyroid hormones is exercised directly on the
pituitary as well as through hypothalamus. The action of TRH on pituitary and that of TSH on
thyroid cells is mediated by enhanced cAMP synthesis. High concentration of TSH also acts via
IP3/ DAG–increased intracellular Ca2+ pathway in the thyroid cells.
The blood iodine level and iodine content of thyroid also regulate thyroid function (see p. 277).
Create detailed and revisable notes on the above paragraphs

Thyroid Hormones: Transport, Metabolism, and Excretion

Transport

Protein Binding:
Thyroid hormones (T4 and T3) are predominantly bound to plasma proteins.
Only 0.03–0.08% of T4 and 0.2–0.5% of T3 are free (unbound).
Protein Bound Iodine (PBI):
Represents almost all thyroid hormone in plasma.
90–95% is T4, remainder is T3.
Binding Proteins:
1. Thyroxine Binding Globulin (TBG) - highest affinity for T4.
2. Thyroxine Binding Prealbumin (Transthyretin).
3. Albumin.
PBI Concentration:
Normal range: 4–10 μg/dl.
Only 0.1–0.2 μg/dl is T3, rest is T4.
Pregnancy:

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 Increased TBG raises PBI levels, but free hormone concentration remains unchanged,
so thyroid status is unaffected.

Metabolism

Free Hormone:
Only the free hormone is biologically active and available for metabolism and excretion.
Metabolic Inactivation:
Occurs via deiodination and conjugation (glucuronide or sulfate) of T4 and T3 and their
deiodinated products.
Primary Site: Liver (also occurs in salivary glands and kidneys).
Excretion:
Conjugates are excreted in bile.
A significant fraction undergoes enterohepatic circulation (deconjugation and reabsorption
in intestines) before final excretion in urine.

Half-Life

T4: Plasma half-life is 6–7 days.

T3: Plasma half-life is 1–2 days.
Conditions:
Hyperthyroidism: Shortened half-lives due to faster metabolism.
Hypothyroidism: Prolonged half-lives due to slower metabolism.

Regulation of Thyroid Hormone Secretion

Hierarchical Control

Thyroid Secretion:
Controlled by TSH from the anterior pituitary.
TSH secretion is regulated by TRH from the hypothalamus.

Hormonal Pathways

Somatostatin:
Inhibits TSH secretion from the pituitary, in addition to GH and prolactin.
Feedback Mechanism:
Negative Feedback:
Thyroid hormones (T3 and T4) directly inhibit TSH secretion at the pituitary level.
Also exert feedback inhibition through the hypothalamus.
Action Mechanism:
TRH stimulates TSH secretion via enhanced cAMP synthesis in the pituitary.
TSH acts on thyroid cells via cAMP and IP3/DAG pathways, increasing intracellular
Ca2+.

Additional Regulation

Blood Iodine Level and Thyroid Iodine Content:

These factors also play a crucial role in regulating thyroid function.

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 Colloid
follicle .

Pencein
 These detailed notes cover the essential aspects of thyroid hormone transport, metabolism, excretion,
and regulation of secretion, providing a comprehensive overview for study and reference.

Actions
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.
1. Growth and development T4 and T3 are essential for normal growth and development. The
most remarkable action is metamorphosis of tadpole to frog: the tail is usedup to build lungs,
limbs and other organs. The actions
cannot be broadly labelled as catabolic or ana bolic, and are exerted through a critical control of
protein synthesis in the translation of the genetic code. Congenital deficiency of thyroid hormone
resulting in cretinism emphasizes its importance. The milestones of development are delayed and
practically every organ and tis sue of the body suffers. The greatest sufferer, however, is the
nervous system. Retardation and nervous deficit is a consequence of paucity of axonal and
dendritic ramification, synapse formation and impaired myelination. In adult hypothyroidism also,
intelligence is impaired and movements are slow.
2. Intermediary metabolism Thyroid hormo nes have marked effect on lipid, carbohydrate and
protein metabolism.
Lipid T4 and T3 indirectly enhance lipolysis by potentiating the action of catecholamines and other
lipolytic hormones. As a result plasma free fatty acid levels are elevated. Lipogenesis is also
stimulated. All phases of cholesterol metabolism are accelerated, but its conversion to bile acids
dominates. Thus, hyperthyroidism is characterized by hypocholesterolemia. Plasma LDL levels are
reduced.
Carbohydrate Carbohydrate metabolism is also stimulated. Though utilization of sugar by tissues
is increased (mainly secondary to increased BMR), glycogenolysis and gluconeo genesis in liver as
well as faster absorption of glucose from intestines more than compensate it producing
hyperglycaemia and a diabeticlike state with insulin resistance in hyperthyroidism.
Protein Synthesis of certain proteins is increa sed, but the overall effect of T3 is catabolic—
increased amounts of protein being used as energy source. Prolonged action results in negative
nitrogen balance and tissue wasting. Weight loss is a feature of hyperthyroidism. T3, T4 inhibit
mucoprotein synthesis which so characteristically accumulates in myxoedema.
3. 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. The mechanism of
calorigenesis was believed to be uncoupling of oxidative phosphorylation: excess energy being
released as heat. However, this occurs only at very high doses and is not involved in mediating the
physiological actions of T3, T4.

4. 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. Heart rate, contractil ity and output
are increased resulting in a fast, bounding pulse. T and T stimulate heart by direct action on
contractile elements (increasing the myosin fraction having greater Ca'* ATPase activity) as well as
by up regulation of ß adrenergic receptors. Atrial fibrillation and other irregularities are common
in hyperthyroidism.
Thyroid hormones can also precipitate CHF and angina. BP, specially systolic, is often raised.
Myocardial O, consumption can be markedly reduced by induction of hypothyroidism.
5. Nervous system T, T, 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.
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 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
1, 14. Hypothyroid patients are often constipated, while diarrhoea is common in hyperthyroidism.
Kidney I, and T, do not cause diuresis in euthyroid individuals, but the rate of urine flow is often
increased when myxoedematous patients are treated with it.
Haemopoiesis Hypothyroid patients suffer from some degree of anaemia which is restored only
by I, treatment. Thus, I, appears to be facilitatory to erythropoiesis.

10. Reproduction Thyroid has an indirect effect on reproduction. Fertility is impaired in

hypothyroidism and women suffer from oligo menorrhoea. Normal thyroid function is required
for maintenance of pregnancy and lactation.
Create detailed and revisable notes on the above paragraphs

Actions of Thyroid Hormones (T4 and T3)

1. Growth and Development

Essential Roles:
Crucial for normal growth and development.
Notably involved in metamorphosis (e.g., tadpole to frog), where the tail is reabsorbed to
form new organs.
Congenital Deficiency:
Results in cretinism, characterized by delayed developmental milestones and severe organ
and tissue impairments.
Nervous system suffers the most, leading to mental retardation and deficits in axonal and
dendritic growth, synapse formation, and myelination.
Adult Hypothyroidism:
Also impacts intelligence and movement, causing sluggishness and impaired cognitive
function.

2. Intermediary Metabolism

Lipid Metabolism:
Increases lipolysis indirectly through potentiation of catecholamines and other lipolytic
hormones.
Stimulates lipogenesis and accelerates cholesterol metabolism, favoring conversion to bile
acids, leading to hypocholesterolemia in hyperthyroidism.
Carbohydrate Metabolism:
Increases sugar utilization by tissues.
Promotes glycogenolysis, gluconeogenesis in the liver, and faster glucose absorption from
the intestines, resulting in hyperglycemia and insulin resistance in hyperthyroidism.
Protein Metabolism:
Enhances synthesis of certain proteins.
Overall effect is catabolic, increasing protein utilization as an energy source.
Prolonged action leads to negative nitrogen balance and tissue wasting, contributing to
weight loss in hyperthyroidism.
Inhibits mucoprotein synthesis typical of myxedema.

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 3. Calorigenesis

Basal Metabolic Rate (BMR):

Increases BMR by stimulating cellular metabolism and resetting the energy state.
Essential for maintaining body temperature.
Mechanism:
Originally thought to involve uncoupling of oxidative phosphorylation, releasing excess
energy as heat, but this occurs only at high doses and is not physiologically relevant for T3
and T4 actions.

4. Cardiovascular System (CVS)

Hyperdynamic State:
Increases peripheral demand and directly affects cardiac function.
Effects:
Increases heart rate, contractility, and cardiac output, leading to a fast, bounding pulse.
Directly stimulates the heart by enhancing contractile elements and upregulating ß-
adrenergic receptors.
Clinical Manifestations:
Can cause atrial fibrillation and other arrhythmias.
May precipitate congestive heart failure (CHF) and angina.
Blood Pressure (BP):
Often elevates systolic BP.

5. Nervous System

Central Nervous System (CNS):

Profound effects on CNS function.
Effects:
Mental retardation in cretinism.
Behavioral changes such as nervousness, anxiety, tremors, and hyperreflexia in
hyperthyroidism.
Myxedema:
Sluggishness and other cognitive deficits.

6. Skeletal Muscle

Muscle Tone:
Flabby and weak muscles in myxedema.
Increased muscle tone, tremors, and weakness due to myopathy in thyrotoxicosis.

7. Gastrointestinal Tract (GIT)

GI Motility:
Increases propulsive activity in the gut in hyperthyroidism.
Hypothyroidism often causes constipation, while diarrhea is common in hyperthyroidism.

8. Kidney

Diuresis:
Does not cause diuresis in euthyroid individuals.

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 Increases urine flow rate when treating myxedematous patients.

9. Hematopoiesis

Erythropoiesis:
Facilitates erythropoiesis, restoring anemia in hypothyroid patients.

10. Reproduction

Fertility:
Impaired fertility and oligomenorrhea in hypothyroidism.
Normal thyroid function is essential for maintenance of pregnancy and lactation.

These comprehensive notes outline the multifaceted actions of thyroid hormones (T4 and T3) on
various physiological systems and metabolic pathways, providing a detailed understanding of their
crucial roles in health and disease.

Pharmacokinetics and interactions

Oral bioavailability of lthyroxine is ~ 75%, but severe hypothyroidism can reduce oral absorption.
It should be administered in empty stomach to avoid interference by food. Sucralfate, iron,
calcium and proton pump inhibitors also reduce lthyroxine absorption. CYP3A4 inducers like
rifampin, phenytoin and carbamazepine accelerate metabolism of T4; dose of lthyroxine may
need enhancement.

Uses
The most important use of thyroid hormone is for replacement therapy in deficiency states.
Synthetic lthyroxine is the preparation of choice:
1. Cretinism It is either due to failure of thyroid development or a defect in hormone synthesis
(sporadic cretinism) or due to extreme iodine deficiency (endemic cretinism). Cretinism is usually
detected during infancy or childhood; but screening of neonates is the best preventive strategy.
Treatment with thyroxine (8–12 μg/kg) daily should be started as early as possible, because
mental retardation that has already ensued is only partially reversible. Response is dramatic:
physical growth and development are restored and further mental retardation is prevented.
2. Adult hypothyroidism (Myxoedema) This is one of the commonest endocrine disorders which
develops as a consequence of autoim mune thyroiditis or thyroidectomy. It may accompany
simple goiter if iodine deficiency is severe. Antibodies against thyroid peroxidase or thyroglobulin
are responsible for majority of cases of adult hypothyroidism. Important drugs that can cause
hypothyroidism are 131I, iodides, lithium and amiodarone.
Treatment with T4 is most gratifying. Though in younger patients, full replacement doses may be
started from the beginning, in those >50 years it is wise to start with a lower dose (50 μg/day),
while in the elderly or in those with heart disease, the initial dose should be 12.5–25 μg/day.
Doses may be increased every 2–3 weeks to an optimum of 100–150 μg/day (adjusted by clinical
response as well as serum TSH and free T4 levels). Further dose adjust ments are made at 4–6
week intervals needed for reaching steadystate. Individualization of proper dose is critical, aiming
at normaliza tion of serum TSH levels. Increase in dose is mostly needed during pregnancy.
Subclinical hypothyroidism characterized by euthyroid status and normal free serum thyroxine
(FT4) level (> 9 pmol/L) but raised TSH level (>10 mU/L) should be treated with T4. For TSH level
between 6–10 mU/L, replacement therapy is optional. Replacement is preferable if patient has

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 other cardiovascular risk factors.
3. Myxoedema coma It is an emergency; characterized by progressive mental deterioration due to
acute hypothyroidism: carries significant mortality. Rapid thyroid replacement is crucial. Though
liothyronine (T3) acts faster, its use is attended by higher risk of cardiac arrhythmias, angina, etc.
Drug of choice is l-thyroxine (T4) 200–500 μg i.v. followed by 100 μg i.v. OD till oral therapy can be
instituted. Some authori ties recommend adding low dose i.v. T3 10 μg 8 hourly in younger
patients with no arrhythmia or ischaemia. Alternatively oral T4 500 μg load ing dose followed by
100–300 μg daily may be used, but in severe hypothyroidism, oral absorption is delayed and
inconsistent.
Other essential measures needed are—warming the patient, i.v. corticosteroids to cover
attendant adrenal insufficiency, ventilatory and cardio- vascular support, correction of
hyponatraemia and hypoglycaemia.
4. Nontoxic goiter This is characterized by enlargement of thyroid with euthyroid status. It may be
endemic or sporadic. Endemic is due to iodine deficiency which may be accentuated by factors
present in water (excess calcium), food or milk (goitrin, thiocyanates). A defect in hormone
synthesis may be responsible for sporadic cases. In both types, deficient produc tion of thyroid
hormone leads to excess TSH → thyroid enlarges, more efficient trapping of iodide occurs and
probably greater proportion of T3 is synthesized → enough hormone to meet peripheral
demands is produced so that the patient is clinically euthyroid. Thus, treatment with T4 is in fact
replacement therapy in this condi tion as well, despite no overt hypothyroidism. Full maintenance
doses must be given. Most cases of recent diffuse enlargement of thyroid regress. Longstanding
goiter with degenerative and fibrotic changes and nodular goiter regress little or not at all.
Thyroxine therapy may be withdrawn after a year or so in some cases if adequate iodine intake is
ensured. Others need
lifelong therapy.
Endemic goiter and cretinism due to iodine deficiency
in pregnant mother is preventable by ensuring daily ingestion of 150–200 μg of iodine. This is best
achieved by iodizing edible salt by adding iodate (preferred over iodide). In India iodization of
table salt (100 μg iodine/g salt) is required under the National Programme, but recently
mandatory iodization rule has been withdrawn.
5. Thyroid nodule Certain benign functioning nodules regress when TSH is suppressed by T4
therapy. Nonfunctional nodules and those nonresponsive to TSH (that are associated with low TSH
levels) do not respond and should not be treated with levothyroxine. T4 therapy should be
stopped if the nodule does not decrease in size within 6 months, as well as when it stops
regressing after the initial response.
6. Papillary carcinoma of thyroid This type of cancer is often responsive to TSH. In nonresectable
cases, full doses of T4 suppress endogenous TSH production and may induce temporary
regression.
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/nonhealing ulcers.
Obstinate constipation.
Thyroxine is not to be used for obesity and as a hypo cholesterolemic agent.
Create detailed and revisable notes on the above paragraphs

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 Pharmacokinetics and Interactions

Oral Bioavailability and Absorption

Bioavailability: Approximately 75% for l-thyroxine (T4), but severe hypothyroidism can reduce
oral absorption.
Administration: Best taken on an empty stomach to avoid interference by food.
Interference: Substances like sucralfate, iron, calcium, and proton pump inhibitors can reduce
T4 absorption.
Metabolism: Inducers of CYP3A4 (e.g., rifampin, phenytoin, carbamazepine) accelerate T4
metabolism, potentially requiring dose adjustments.

Uses of Thyroid Hormones

1. Cretinism
Cause: Due to thyroid developmental failure or hormone synthesis defects.
Treatment: Early initiation of thyroxine (8–12 μg/kg/day) helps prevent further mental
retardation and restores physical growth and development.
2. Adult Hypothyroidism (Myxoedema)
Causes: Autoimmune thyroiditis, thyroidectomy, or severe iodine deficiency.
Treatment: Initiated with lower doses (e.g., 50 μg/day in >50 years; 12.5–25 μg/day in
elderly or those with heart disease) and gradually titrated based on clinical response and
TSH levels (optimum dose: 100–150 μg/day). Adjustments are crucial, especially during
pregnancy.
3. Myxoedema Coma
Emergency: Characterized by acute hypothyroidism with significant mortality risk.
Treatment: Immediate thyroid hormone replacement, preferably with l-thyroxine (T4)
intravenously (200–500 μg followed by 100 μg daily) until oral therapy is feasible. Consider
adjunctive low-dose intravenous T3 in select cases.
4. Nontoxic Goiter
Definition: Enlarged thyroid with euthyroid status.
Treatment: In endemic or sporadic cases, T4 therapy serves as replacement despite
euthyroid status. Long-standing goiters may regress minimally. Therapy may be withdrawn
if adequate iodine intake is ensured.
5. Thyroid Nodule
Response: Benign functioning nodules may regress with TSH suppression by T4.
Nonfunctional or TSH-non-responsive nodules do not respond to T4 therapy and should not
be treated.
Monitoring: Discontinue T4 therapy if nodules do not decrease in size within 6 months or
stop regressing.
6. Papillary Carcinoma of Thyroid
Treatment: TSH-sensitive; T4 therapy may suppress endogenous TSH production and
induce temporary regression, particularly in non-resectable cases.
7. Empirical Uses
Conditions: T4 has been empirically used in refractory anemias, mental depression,
menstrual disorders, infertility, chronic ulcers, and obstinate constipation, although
responses are unpredictable.
Caution: Not recommended for obesity or as a hypocholesterolemic agent.

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 These detailed notes cover the pharmacokinetics of l-thyroxine, its interactions with other substances,
and its various therapeutic uses, emphasizing the critical role of T4 in treating thyroid disorders and
related conditions.

Pharmacokinetics and interactions

Oral bioavailability of lthyroxine is ~ 75%, but severe hypothyroidism can reduce oral absorption.
It should be administered in empty stomach to avoid interference by food. Sucralfate, iron,
calcium and proton pump inhibitors also reduce lthyroxine absorption. CYP3A4 inducers like
rifampin, phenytoin and carbamazepine accelerate metabolism of T4; dose of lthyroxine may
need enhancement.

Uses
The most important use of thyroid hormone is for replacement therapy in deficiency states.
Synthetic lthyroxine is the preparation of choice:
1. Cretinism It is either due to failure of thyroid development or a defect in hormone synthesis
(sporadic cretinism) or due to extreme iodine deficiency (endemic cretinism). Cretinism is usually
detected during infancy or childhood; but screening of neonates is the best preventive strategy.
Treatment with thyroxine (8–12 μg/kg) daily should be started as early as possible, because
mental retardation that has already ensued is only partially reversible. Response is dramatic:
physical growth and development are restored and further mental retardation is prevented.
2. Adult hypothyroidism (Myxoedema) This is one of the commonest endocrine disorders which
develops as a consequence of autoim mune thyroiditis or thyroidectomy. It may accompany
simple goiter if iodine deficiency is severe. Antibodies against thyroid peroxidase or thyroglobulin
are responsible for majority of cases of adult hypothyroidism. Important drugs that can cause
hypothyroidism are 131I, iodides, lithium and amiodarone.
Treatment with T4 is most gratifying. Though in younger patients, full replacement doses may be
started from the beginning, in those >50 years it is wise to start with a lower dose (50 μg/day),
while in the elderly or in those with heart disease, the initial dose should be 12.5–25 μg/day.
Doses may be increased every 2–3 weeks to an optimum of 100–150 μg/day (adjusted by clinical
response as well as serum TSH and free T4 levels). Further dose adjust ments are made at 4–6
week intervals needed for reaching steadystate. Individualization of proper dose is critical, aiming
at normaliza tion of serum TSH levels. Increase in dose is mostly needed during pregnancy.
Subclinical hypothyroidism characterized by euthyroid status and normal free serum thyroxine
(FT4) level (> 9 pmol/L) but raised TSH level (>10 mU/L) should be treated with T4. For TSH level
between 6–10 mU/L, replacement therapy is optional. Replacement is preferable if patient has
other cardiovascular risk factors.
3. Myxoedema coma It is an emergency; characterized by progressive mental deterioration due to
acute hypothyroidism: carries significant mortality. Rapid thyroid replacement is crucial. Though
liothyronine (T3) acts faster, its use is attended by higher risk of cardiac arrhythmias, angina, etc.
Drug of choice is l-thyroxine (T4) 200–500 μg i.v. followed by 100 μg i.v. OD till oral therapy can be
instituted. Some authori ties recommend adding low dose i.v. T3 10 μg 8 hourly in younger
patients with no arrhythmia or ischaemia. Alternatively oral T4 500 μg load ing dose followed by
100–300 μg daily may be used, but in severe hypothyroidism, oral absorption is delayed and
inconsistent.
Other essential measures needed are—warming the patient, i.v. corticosteroids to cover
attendant adrenal insufficiency, ventilatory and cardio- vascular support, correction of
hyponatraemia and hypoglycaemia.
4. Nontoxic goiter This is characterized by enlargement of thyroid with euthyroid status. It may be
endemic or sporadic. Endemic is due to iodine deficiency which may be accentuated by factors
Printed using Save ChatGPT as PDF, powered by PDFCrowd HTML to PDF API. 30/45
 present in water (excess calcium), food or milk (goitrin, thiocyanates). A defect in hormone
synthesis may be responsible for sporadic cases. In both types, deficient produc tion of thyroid
hormone leads to excess TSH → thyroid enlarges, more efficient trapping of iodide occurs and
probably greater proportion of T3 is synthesized → enough hormone to meet peripheral
demands is produced so that the patient is clinically euthyroid. Thus, treatment with T4 is in fact
replacement therapy in this condi tion as well, despite no overt hypothyroidism. Full maintenance
doses must be given. Most cases of recent diffuse enlargement of thyroid regress. Longstanding
goiter with degenerative and fibrotic changes and nodular goiter regress little or not at all.
Thyroxine therapy may be withdrawn after a year or so in some cases if adequate iodine intake is
ensured. Others need
lifelong therapy.
Endemic goiter and cretinism due to iodine deficiency
in pregnant mother is preventable by ensuring daily ingestion of 150–200 μg of iodine. This is best
achieved by iodizing edible salt by adding iodate (preferred over iodide). In India iodization of
table salt (100 μg iodine/g salt) is required under the National Programme, but recently
mandatory iodization rule has been withdrawn.
5. Thyroid nodule Certain benign functioning nodules regress when TSH is suppressed by T4
therapy. Nonfunctional nodules and those nonresponsive to TSH (that are associated with low TSH
levels) do not respond and should not be treated with levothyroxine. T4 therapy should be
stopped if the nodule does not decrease in size within 6 months, as well as when it stops
regressing after the initial response.
6. Papillary carcinoma of thyroid This type of cancer is often responsive to TSH. In nonresectable
cases, full doses of T4 suppress endogenous TSH production and may induce temporary
regression.
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/nonhealing ulcers.
Obstinate constipation.
Thyroxine is not to be used for obesity and as a hypo cholesterolemic agent.
Create detailed notes on the above paragraphs

M . .
O A of Thy . Hormone G Kel .

Physiology
Uses of Thyroid Hormones

1. Cretinism

Definition: Due to thyroid developmental failure, hormone synthesis defects, or severe iodine
deficiency.
Detection: Usually identified in infancy or childhood; neonatal screening is crucial for
prevention.
Treatment:
Thyroxine Dosage: 8–12 μg/kg/day.
Objective: Prevent further mental retardation and restore physical growth.
Response: Dramatic improvement in growth and development; irreversible mental
retardation can be partially reversed.

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 2. Adult Hypothyroidism (Myxoedema)

Causes: Autoimmune thyroiditis, thyroidectomy, severe iodine deficiency.

Antibodies: Against thyroid peroxidase or thyroglobulin.
Treatment:
Initiation: Start younger patients with full replacement doses of T4.
Elderly or Cardiac Patients: Initiate with lower doses (e.g., 50 μg/day) to minimize
cardiovascular strain.
Titration: Increase dose every 2–3 weeks until optimal (100–150 μg/day), guided by clinical
response, serum TSH, and free T4 levels.
Pregnancy: Requires dose adjustments due to increased hormone requirements.

3. Myxoedema Coma

Emergency: Acute hypothyroidism with progressive mental deterioration.

Treatment:
Choice: Intravenous l-thyroxine (T4) 200–500 μg, followed by 100 μg daily until oral therapy
feasible.
Adjuncts: Consider low-dose intravenous T3 in select cases.
Supportive Measures: Warmth, corticosteroids for adrenal insufficiency, cardiovascular
and ventilatory support, correction of electrolyte imbalances.

4. Nontoxic Goiter

Characteristics: Enlarged thyroid with euthyroid status.

Types: Endemic (due to iodine deficiency) or sporadic (hormone synthesis defect).
Pathophysiology: Increased TSH stimulates thyroid enlargement.
Treatment:
Goal: Maintain euthyroid state with full replacement doses of T4.
Outcome: Recent diffuse enlargements regress; long-standing nodular goiters regress
minimally.
Duration: Some cases may discontinue therapy with adequate iodine intake; others require
lifelong treatment.

5. Thyroid Nodule

Response: Benign functioning nodules regress with TSH suppression by T4.

Nonfunctional Nodules: Do not respond to TSH suppression; avoid T4 therapy.
Monitoring: Discontinue T4 if nodule does not regress within 6 months.

6. Papillary Carcinoma of Thyroid

Treatment:
TSH Sensitivity: Responds to T4 therapy by suppressing endogenous TSH production.
Nonresectable Cases: T4 therapy may induce temporary regression.

7. Empirical Uses

Conditions: T4 used without established rationale; responses unpredictable.

Refractory anemias, mental depression, menstrual disorders, infertility, chronic ulcers,
obstinate constipation.

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 Caution: Not recommended for obesity or as a hypocholesterolemic agent.

These notes provide a comprehensive overview of the uses of thyroid hormones, particularly l-
thyroxine (T4), in managing various thyroid disorders and related conditions. The emphasis is on
tailored dosing, therapeutic goals, and considerations for different patient populations and clinical
scenarios.

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 due to production of
an IgG class of antibody called ‘thyroid stimulating immunoglobulin.’ It binds to the TSH receptor
and causes long lasting stimulation of the thyroid cells. The exophthalmos of Graves’ disease
appears to be due to stimulation of TSH receptors on the periorbital tissues. Due to feed-back
inhibition, TSH levels are low.
Toxic nodular goiter, which produces thyroid hormone independent of TSH, is less common and
mostly supervenes on old nontoxic goiters. It is more common in the elderly; ocular changes are
generally absent.
The thioamide antithyroid drugs and ionic inhibitors are also called goitrogens because, if given in
excess, they cause enlargement of thyroid by feedback release of TSH.
In addition, certain drugs used in high doses for pro longed periods cause hypothyroidism/goiter
as a side effect: • Lithium: inhibits thyroid hormone release.
• Amiodarone: inhibits peripheral conversion of T4 to T3;
also interferes with thyroid hormone action.
• Sulfonamides, paraaminosalicylic acid: inhibit thyro
globulin iodination and coupling reaction.
• Phenobarbitone, phenytoin, carbamazepine, rifampin:
induce metabolic degradation of T4/T3. Goitrin—found in plants (cabbage, turnip, mustard, etc.),
is the cause of goiter in cattle who feed on these plants. Goitring may contribute to endemic
goiter in certain iodine deficient regions.
Create detailed and revisable notes on the above paragraphs

Thyroid Inhibitors

Overview

Purpose: Used to lower the functional capacity of the hyperactive thyroid gland.
Primary Causes of Thyrotoxicosis:
1. Graves' Disease:
ele
Type: Autoimmune disorder.
Mechanism: Production of thyroid-stimulating immunoglobulin (IgG class) that binds
to TSH receptors, causing prolonged stimulation of thyroid cells.
Symptoms: Includes exophthalmos due to TSH receptor stimulation in periorbital
tissues.
TSH Levels: Low due to feedback inhibition.

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 2. Toxic Nodular Goiter:
-
Type: Produces thyroid hormone independent of TSH.
Occurrence: Common in the elderly and usually follows old nontoxic goiters.
Symptoms: Generally, ocular changes are absent.

Thioamide Antithyroid Drugs and Ionic Inhibitors (Goitrogens)

Effect: Can cause thyroid enlargement by feedback release of TSH if given in excess.

Drugs Causing Hypothyroidism/Goiter as Side Effects

LASii @ PG

** 1. Lithium:
-

Mechanism: Inhibits thyroid hormone release.

2. -
Amiodarone:
Mechanism: Inhibits peripheral conversion of T4 to T3 and interferes with thyroid hormone
action.
3. Sulfonamides, Para-aminosalicylic Acid:
-
Mechanism: Inhibit thyroglobulin iodination and coupling reaction.
4. Phenobarbitone,
-
Phenytoin, Carbamazepine, Rifampin:
Mechanism: Induce metabolic degradation of T4/T3.
5. Goitrin:
-

Source: Found in plants such as cabbage, turnip, mustard, etc.

Effect: Causes goiter in cattle and may contribute to endemic goiter in iodine-deficient
regions.

Detailed Notes on Thyroid Inhibitors

Mechanism of Action

Thioamide Antithyroid Drugs:

&
Inhibit the synthesis of thyroid hormones by blocking the iodination of tyrosine residues in
thyroglobulin and coupling of iodotyrosines.
Examples: Methimazole, Propylthiouracil (PTU).
O they peroxidase
Ionic Inhibitors:
Block the uptake of iodide by the thyroid gland.
Examples: Potassium perchlorate, thiocyanate.

Clinical Applications

1. Graves' Disease:
Treatment Goal: Reduce excessive thyroid hormone production.
Medications: Thioamide antithyroid drugs are often used as first-line treatment.
2. Toxic Nodular Goiter:
Treatment Goal: Manage hyperthyroidism, often less responsive to antithyroid drugs
compared to Graves' disease.
Management: May require radioactive iodine therapy or surgery.

Monitoring and Side Effects

Regular Monitoring: Required to adjust dosages and prevent hypothyroidism.

Potential Side Effects:
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 Hepatotoxicity: Particularly with propylthiouracil.
Agranulocytosis: A rare but serious side effect, necessitating regular blood counts.
Rashes and Allergic Reactions: Common with thioamide drugs.

-
Special Considerations

Pregnancy:
PTU is preferred in the first trimester due to lower teratogenic risk compared to
methimazole.
Methimazole is preferred in the second and third trimesters to avoid liver toxicity
associated with PTU.
Elderly: Require careful monitoring due to higher risk of side effects and comorbid conditions.

Environmental and Dietary Factors

Goitrin: Found in cruciferous vegetables; excessive intake may contribute to goiter, especially in
iodine-deficient areas.
Endemic Goiter: Ensuring adequate iodine intake is crucial in prevention and management.

These detailed notes provide a comprehensive understanding of thyroid inhibitors, their mechanisms,
clinical applications, side effects, and considerations for specific populations.

THIOAMIDES (Antithyroid drugs)

By convention, only the thioamide hormone synthesis inhibitors are called ‘antithyroid drugs’,
though this term has also been applied to all
thyroid inhibitors.
Thiourea derivatives were found to produce goiter
and hypothyroidism in rats in the 1940s. Open chain thiourea compounds were found to be toxic.
Subsequently, methyl and propyl thiouracil and thioimidazole derivatives methimazole and
carbimazole were found to be safe and effective.
Thioamides bind to the thyroid peroxidase and prevent oxidation of iodide and 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). Thyroid
colloid is depleted over time and blood levels of T3/T4 are progressively lowered.
Thioamides do not interfere with trapping of iodide and do not modify the action of T3 and T4 on
peripheral tissues or on pituitary. Goiter that occurs with higher doses is not the result of
potentiation of TSH action on thyroid, but is due to increased TSH release as a consequence of
reduction in feedback inhibi tion. No goiter occurs if antithyroid drugs are
given to hypophysectomised animals or if T4 is given along with them. Antithyroid drugs do not
affect release of T and T —their effects
34
are not apparent till thyroid is depleted of its
hormone content.
Propylthiouracil also inhibits peripheral con
version of T4 to T3 by D1 type of 5-DI, but not by D2 type. This may partly contribute to its
antithyroid effects. Methimazole and car bimazole do not have this action (Table 18.1).
Pharmacokinetics The antithyroid drugs are quickly absorbed orally, widely distributed in the

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 body, enter milk and cross placenta; are meta bolized in liver and excreted in urine primarily as
metabolites. All are concentrated in thyroid; the intrathyroid t ⁄ is longer: effect of a single dose
lasts longer than would be expected from the plasma t ⁄ . 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 this is reversible
on stopping the drug. Enlargement of thyroid is an indication of hypothyroidism and is due to
excess feedback TSH production. Goiter does not develop with appropriate doses which restore T4
concentration to normal so that feedback TSH inhibition is maintained. Important side effects are:
g.i. intolerance, skin rashes and joint pain. Liver damage can occur, especially with
propylthiouracil.
Loss or graying of hair, loss of taste and fever are infrequent. A rare but serious adverse effect is
agra nulocytosis (1 in 500 to 1000 cases); It is mostly reversible. There is partial cross reactivity
between propylthiouracil and carbimazole.
Preparations and dose
Propylthiouracil: 50–150 mg TDS followed by 25–50 mg BD–TDS for maintenance. PTU 50 mg tab.
Methimazole: 5–10 mg TDS initially, maintenance dose 5–15 mg daily in 1–2 doses.
Carbimazole: 5–15 mg TDS initially, maintenance dose 2.5–10 mg daily in 1–2 divided doses, NEO
MERCAZOLE, THYROZOLE, ANTITHYROX 5, 10, 20 mg tab.
Carbimazole is used in India while methimazole is not marketed. Since popylthiouracil has shorter
duration of action and carries risk of severe hepatitis, it should be reserved for use in early
pregnancy (due to less placental transfer than carbimazole) and in thyroid storm for its inhibitory
action on peripheral conversion of T4 to more active T3. It may be tried in patients developing
adverse effects with carbimazole.
Use Antithyroid drugs control thyrotoxicosis in both Graves’ disease and toxic nodular goiter.
Clinical improvement starts after 1–2 weeks or more (depending on hormone con tent of thyroid
gland). Iodide loaded patients (who have received iodide containing contrast media/cough
mixtures, amiodarone) are less responsive. Maintenance doses are titrated on the basis of clinical
status of the patient. The following strategies are adopted.
(i) As definitive therapy (a) Remission may occur in upto half of the patients of Graves’ disease
after 1–2 years of treatment: the drug can then be withdrawn. If symptoms recur— treatment is
reinstituted. This is preferred in young patients with a short history of Graves’ disease and a small
goiter.
(b) Remissions are rare in toxic nodular goi ter; surgery (or 131I) is preferred. However, in frail
elderly patients with multinodular goiter who may be less responsive to 131I, permanent
maintenance therapy with antithyroid drugs can be employed.
(ii) Preoperatively Surgery in thyrotoxic patients is risky. Young patients with florid
hyperthyroidism and substantial goiter are rendered euthyroid with carbimazole before
performing subtotal thyroidectomy.
(iii) Along with 131I Initial control with antithy roid drug—1 to 2 weeks gap—radioiodine dos ing—
resume antithyroid drug after 5–7 days and gradually withdraw over 3 months as the response to
131I develops. This approach is preferred in older patients and in those with heart disease who
are to be treated with 131I, but require prompt control of severe hyperthyroidism. This will also
prevent initial disease flare-up follow ing 131I due to release of stored T4. Advantages of
antithyroid drugs over surgery and 131I are:
(a) No surgical risk, scar or chances of injury to parathyroid glands or recurrent laryngeal nerve.
(b) Hypothyroidism, if induced, is reversible.
(c) Can be used even in children and young adults. Disadvantages are:
(a) Prolonged (often lifelong) treatment is need ed because relapse rate is high.
(b) Not practicable in uncooperative/unintelligent patient.
(c) Drug toxicity.
Thyroidectomy and 131I are contraindicated during pregnancy. With antithyroid drugs risk of
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 3MXX
foetal hypothyroidism and goiter is there. However, low doses of propylthiouracil may be used: its
greater protein binding allows less transfer to the foetus. However, methimazole has also now
been found safe during pregnancy.
Propylthiouracil is used in thyroid storm as well (see p. 279).
Create detailed and revisable notes on the above paragraphs

Thioamides (Antithyroid Drugs)

Overview

Purpose: Lower functional capacity of the hyperactive thyroid gland, mainly in thyrotoxicosis.
Common Causes of Thyrotoxicosis: Graves' disease and toxic nodular goiter.

History and Development

Discovery: Thiourea derivatives were discovered in the 1940s to produce goiter and
hypothyroidism in rats.
Initial Compounds: Open chain thiourea compounds were toxic.
Safe Derivatives: Methyl and propyl thiouracil, thioimidazole derivatives methimazole, and
carbimazole were found to be safe and effective.

Mechanism of Action

Binding: Thioamides bind to thyroid peroxidase, preventing oxidation of iodide and iodotyrosyl
residues.
Primary Actions:
1. Inhibit iodination of tyrosine residues in thyroglobulin.
2. Inhibit coupling of iodotyrosine residues to form T3 and T4.
Action (ii) occurs at lower concentrations than action (i).
Effects:
Thyroid Colloid Depletion: Progressive lowering of T3 and T4 blood levels.
- Increased TSH Release: Due to reduction in feedback inhibition, leading to goiter if not
properly managed.
~ Peripheral Conversion: Propylthiouracil inhibits peripheral conversion of T4 to T3 by D1
type 5-DI but not D2 type. Methimazole and carbimazole lack this action.

Pharmacokinetics

Absorption: Quickly absorbed orally, widely distributed, crosses placenta, and enters milk.
Metabolism: Metabolized in the liver, excreted in urine mainly as metabolites.
Intrathyroid t ⁄ : Longer than plasma t ⁄ , leading to prolonged effect.
Carbimazole: Acts by converting to methimazole, longer acting than propylthiouracil.

Adverse Effects

Common:
Hypothyroidism and goiter (reversible on stopping the drug).
Gastrointestinal intolerance, skin rashes, joint pain.
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 Liver damage (notably with propylthiouracil).
Less Common:
Loss or graying of hair, loss of taste, fever.
Agranulocytosis (rare but serious, 1 in 500 to 1000 cases, mostly reversible).
Cross Reactivity: Partial between propylthiouracil and carbimazole.

Preparations and Dosage

Propylthiouracil (PTU):
Initial: 50–150 mg TDS.
Maintenance: 25–50 mg BD–TDS.
Methimazole:
Initial: 5–10 mg TDS.
Maintenance: 5–15 mg daily in 1–2 doses.
Carbimazole:
Initial: 5–15 mg TDS.
Maintenance: 2.5–10 mg daily in 1–2 divided doses.
Available Brands: NEO MERCAZOLE, THYROZOLE, ANTITHYROX 5, 10, 20 mg tab.
Usage Notes:
Propylthiouracil is preferred in early pregnancy and thyroid storm.
Methimazole is not marketed in India.

Clinical Use

~1. Definitive Therapy:

YGraves’ Disease: Potential remission after 1-2 years of treatment.
Toxic Nodular Goiter: Surgery or 131I is preferred; antithyroid drugs for frail elderly
patients as maintenance therapy.

-2. Preoperative Use:

Render thyrotoxic patients euthyroid before subtotal thyroidectomy.
3. Combined with 131I:
~ Initial control with antithyroid drugs, followed by a 1-2 week gap, then radioiodine dosing.
Resumption of antithyroid drugs after 5-7 days, gradually withdrawn over 3 months.

Advantages of Antithyroid Drugs

No surgical risk, scarring, or risk of injury to parathyroid glands or recurrent laryngeal nerve.
Induced hypothyroidism is reversible.
Suitable for children and young adults.

Disadvantages of Antithyroid Drugs

Prolonged treatment often needed due to high relapse rate.

Not practical for uncooperative or unintelligent patients.
Potential for drug toxicity.

Use in Pregnancy

Antithyroid Drugs: Risk of fetal hypothyroidism and goiter.

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 Preferred Drug: Low doses of propylthiouracil due to less placental transfer; methimazole also
considered safe.

Special Use in Thyroid Storm

Propylthiouracil is preferred for its inhibitory action on peripheral conversion of T4 to T3.

These notes provide detailed and revisable information on thioamides, covering their history,
mechanisms, pharmacokinetics, adverse effects, preparations, clinical use, advantages, and special
considerations.

IONIC INHIBITORS
Certain monovalent anions inhibit iodide trapping by NIS into the thyroid. Consequently, T4/T3
cannot be synthesized. Perchlorate is 10 times more potent than thiocyanate in blocking NIS,
while nitrate is very weak.
These ions are toxic and not clinically used.
IODINE AND IODIDES
Though iodine is a constituent of thyroid hor mones, it is the fastest acting thyroid inhibitor. In
Graves’ disease the gland, if enlarged, shrinks, becomes firm and less vascular. The thyroid status
starts returning to normal at a rate commensu rate with complete stoppage of hormone release
from the gland. The thyroid gland involutes and colloid is restored. The response to iodine and
iodides is identical, because elemental iodine is reduced to iodide in the intestines. With daily
administration, peak effects are seen in 10–15 days, after which ‘thyroid escape’ occurs and
thyrotoxicosis may return with greater vengeance. Worsening of hyperthyroidism occurs,
especially in multinodular goiter.
All facets of thyroid function seem to be affected, but the most important action is inhibition of
hormone release—‘thyroid constipa tion’. Endocytosis of colloid and proteolysis of thyroglobulin
comes to a halt. 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. In addition, it attenuates
TSH and cAMP induced thyroid stimulation. Excess iodide rapidly and briefly interferes with
iodination of tyrosil and thyronil residues of thyroglobulin (probably by altering redox potential of
thyroid cells) result ing in reduced T3/T4 synthesis (WolffChaikoff effect). However, within a few
days, the gland ‘escapes’ from this effect and hormone syn thesis resumes.
Preparations and dose Lugol’s solution (5% iodine in 10% Pot. iodide solution): LUGOL’S
SOLUTION, COLLOID IODINE 10%: 5–10 drops/day. COLLOSOL 8 mg iodine/5 ml liq.
Iodide (Sod./Pot.) 100–300 mg/day before thyroidectomy, 5–10 mg/day (prophylactic) for endemic
goiter.
Uses
1. Preoperative preparation for thyroidectomy in Graves’ disease: Iodine is generally given for 10
days just preceding surgery. The aim is to make the gland firm, less vascular and easier to operate
on. Though iodide itself will lower the thyroid status, it cannot be relied upon to attain
euthyroidism which is done by use of carbimazole before starting iodide. Propranolol may be
given additionally for rapid control of symptoms.
2. Thyroid storm Lugol’s iodine (6–10 drops) or iodine containing radiocontrast media (iopa noic
acid/ipodate) orally are used to stop any further release of T3/T4 from the thyroid and to decrease
T4 to T3 conversion.
3. Prophylaxis of endemic goiter It is generally used as “iodized salt”(see p. 274).
4. Antiseptic As tincture iodine, povidone iodine, etc. (see Ch. 67).
Adverse effects

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 1. Acute reaction It occurs only in rare individu als sensitive to iodine, and can be triggered even
by a minute quantity. Manifestations are swelling of lips, eyelids, angioedema of larynx (may be
dangerous), fever, joint pain, petechial haemorrhages, thrombocytopenia, lymphadenopathy.
Further exposure to iodine should be stopped immediately.
2. Chronic overdose (iodism) Inflammation of mucous membranes, salivation, rhinorrhoea,
sneezing, lacrimation, swelling of eyelids, burning sensation in mouth, headache, rashes, g.i.
symptoms, etc. The symptoms regress on stopping iodide ingestion.
Longterm use of high doses can cause hypothyroidism and goiter.
Iodide may cause flaring of acne in adoles- cents. Given to pregnant or nursing mothers, it may
be responsible for foetal/infantile goiter and hypothyroidism. Thyrotoxicosis may be aggravated
in multinodular goiter.
Create detailed and revisable notes on the above paragraphs

Ionic Inhibitors

Overview

Function: Inhibit iodide trapping by the sodium-iodide symporter (NIS) in the thyroid.
Effect: Prevent synthesis of T4 and T3.
Examples:
Perchlorate: 10 times more potent than thiocyanate.

I Thiocyanate: Effective but less potent than perchlorate.

Nitrate: Very weak inhibitor.
Usage: Not used clinically due to toxicity.

Iodine and Iodides

Overview

Fast-Acting Inhibitor: Iodine is the fastest-acting thyroid inhibitor.

Effect on Graves' Disease: Reduces gland size, makes it firm, less vascular, and stops hormone
release.
Thyroid Status: Returns to normal rate corresponding to the stoppage of hormone release.
Colloid Restoration: Thyroid gland involutes and colloid is restored.
Identical Response: Iodine and iodides have identical responses since elemental iodine is
reduced to iodide in the intestines.
Peak Effect: Seen in 10–15 days, followed by 'thyroid escape' and potential return of
thyrotoxicosis, especially in multinodular goiter.

Mechanism of Action

Primary Action: Inhibition of hormone release ('thyroid constipation').

Endocytosis and Proteolysis: Halted, stopping the release of T3/T4.
Transport Inhibition: Excess iodide inhibits its own transport by interfering with NIS expression.
Thyroid Stimulation: Attenuates TSH and cAMP induced stimulation.
Wolff-Chaikoff Effect: Excess iodide briefly reduces T3/T4 synthesis by altering redox potential
of thyroid cells, but the gland escapes this effect within days.

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 Preparations and Dosage

Lugol’s Solution: 5% iodine in 10% potassium iodide solution.

Brands: LUGOL’S SOLUTION, COLLOID IODINE 10%.
Dosage: 5–10 drops/day.
Iodide (Sodium/Potassium):
Before Thyroidectomy: 100–300 mg/day.
Prophylactic for Endemic Goiter: 5–10 mg/day.

Uses

1. Preoperative Preparation for Thyroidectomy in Graves’ Disease:

Purpose: Make the gland firm, less vascular, and easier to operate on.
Administration: Generally given for 10 days before surgery.
Combination: Use with carbimazole to achieve euthyroidism and propranolol for rapid
symptom control.
2. Thyroid Storm:
Usage: Lugol’s iodine (6–10 drops) or iodine-containing radiocontrast media (iopanoic
acid/ipodate) orally.
Purpose: Stop further release of T3/T4 and decrease T4 to T3 conversion.
3. Prophylaxis of Endemic Goiter:
Form: Generally used as "iodized salt."
4. Antiseptic:
Forms: Tincture iodine, povidone iodine.

Adverse Effects

-
1. Acute Reaction:
Occurrence: Rare, in sensitive individuals.
Symptoms: Swelling of lips, eyelids, angioedema of larynx, fever, joint pain, petechial
hemorrhages, thrombocytopenia, lymphadenopathy.
Action: Stop further exposure immediately.
2. Chronic Overdose (Iodism):
~
Symptoms: Inflammation of mucous membranes, salivation, rhinorrhea, sneezing,
lacrimation, eyelid swelling, burning mouth sensation, headache, rashes, gastrointestinal
symptoms.
Resolution: Symptoms regress on stopping iodide ingestion.
Long-term Use: Can cause hypothyroidism and goiter.
Other Effects: May cause acne flare-ups in adolescents and fetal/infantile goiter and
hypothyroidism if given to pregnant or nursing mothers. Thyrotoxicosis may be aggravated
in multinodular goiter.

These notes provide detailed and revisable information on ionic inhibitors and iodine/iodides,
covering their functions, mechanisms, pharmacokinetics, adverse effects, preparations, clinical use,
and special considerations.

RADIOACTIVE IODINE
The stable isotope of iodine is 127I. Its radioac tive isotope of medicinal importance is:

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 131I: physical halflife 8 days.
The chemical behaviour of 131I is similar to that of the stable isotope.
131I emits γrays (higher energy Xrays emitted by atomic nuclei), as well as β particles (electrons).
The former are useful in tracer studies, because they traverse the tissues and can be monitored
by a counter, while the latter are utilized for their destructive effect on thyroid cells. 131I is
concentrated by thyroid and incorporated in the colloid. Thus, it emits radiation from within the
follicles. The β 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. With carefully selected doses, it is
possible to achieve partial ablation of thyroid.
Radioactive iodine is administered as sodium salt of 131I dissolved in water and taken orally.
Diagnostic 25–100 μ curie is given; counting or scanning is done at intervals. No damage to
thyroid cells occurs at this dose.
Therapeutic The most common indication is hyperthyroidism due to Graves’ disease or toxic
nodular goiter. The average therapeutic dose is 3–6 m curie—calculated on the basis of pre vious
tracer studies and thyroid size. Higher doses are generally required for toxic multi nodular goiter
than for Graves’ disease. The clinical response is slow—starts after 2 weeks and gradually
increases, reaching peak at 3 months or so. Thyroid status is evaluated after 3 months, and a
repeat dose, if needed, is given. About 20–40% patients require one or more repeat doses.
Advantages
1. Treatment with 131I 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
1. Hypothyroidism: About 5–10% patients of Graves’ disease treated with 131I become
hypothyroid every year (upto 50% or more patients may ultimately require supple mental
thyroxine treatment). This probably reflects the natural history of Graves’ disease, because only
few patients of toxic nodular goiter treated with 131I develop hypothyroid ism. Moreover,
eventual hypothyroidism is
a complication of subtotal thyroidectomy/
prolonged carbimazole therapy as well.
2. Long latent period of response.
3. Contraindicated during pregnancy—foetal
thyroid will also be destroyed resulting in cretinism, other abnormalities if given dur ing first
trimester.
4. Not suitable for young patients: they are more likely to develop hypothyroidism later and would
then require lifelong T4 treatment.
131I is the treatment of choice after 25 years of age and if CHF, angina or any other contra‐
indication to surgery is present.
Metastatic carcinoma of thyroid (especially papillary or those cases of follicular carcinoma which
concentrate iodine), 131I may be used as palliative therapy after thyroidectomy. Much higher
doses are required and prior stimulation with TSH is recommended.
Create detailed and revisable notes on the above paragraphs

Radioactive Iodine (131I)

Overview

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 Stable Isotope: 127I
Radioactive Isotope: 131I (physical half-life: 8 days)
Emissions:
γ-rays: Useful for tracer studies.
β-particles: Destructive effect on thyroid cells.

Mechanism of Action

Concentration and Incorporation: 131I is concentrated in the thyroid and incorporated into the
colloid.
Radiation Effects:
γ-rays: Traverse tissues, monitored by counters.
β-particles: Penetrate 0.5–2 mm of tissue, causing localized cell destruction.
Cell Damage: Follicular cells undergo pyknosis and necrosis followed by fibrosis.

Administration

Form: Sodium salt of 131I dissolved in water, taken orally.

Diagnostic Dose: 25–100 μ curie, no damage to thyroid cells.
Therapeutic Dose: 3–6 m curie, calculated based on previous tracer studies and thyroid size.

Therapeutic Use

Indications: Hyperthyroidism due to Graves’ disease or toxic nodular goiter.

Response: Clinical response starts after 2 weeks, peaks at 3 months.
Repeat Doses: 20–40% of patients may need one or more repeat doses.

Advantages

1. Simple and Convenient: Outpatient basis, inexpensive.

2. No Surgical Risks: No risk of surgical complications or injury to parathyroid glands/recurrent
laryngeal nerves.
3. Permanent Cure: Once controlled, hyperthyroidism cure is permanent.

Disadvantages

1. Hypothyroidism:
Incidence: 5–10% of Graves’ disease patients treated with 131I become hypothyroid each
year (up to 50% may require supplemental thyroxine treatment).
Comparison: Few patients of toxic nodular goiter develop hypothyroidism.
2. Long Latent Period: Slow response to treatment.
3. Pregnancy: Contraindicated due to risk of fetal thyroid destruction, cretinism, and other
abnormalities if given during the first trimester.
4. Young Patients: Not suitable due to a higher likelihood of developing hypothyroidism and
requiring lifelong T4 treatment.

Specific Use Cases

Preferred Treatment: After 25 years of age or if contraindications to surgery (e.g., CHF, angina)
are present.
Metastatic Carcinoma of the Thyroid:

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 Types: Especially effective for papillary carcinoma or follicular carcinoma that concentrates
iodine.
Therapy: Used as palliative therapy post-thyroidectomy with higher doses and prior
stimulation with TSH.

These notes provide detailed and revisable information on radioactive iodine (131I), covering its
mechanism of action, administration, therapeutic uses, advantages, disadvantages, and specific use
cases.

β ADRENERGIC BLOCKERS
Propranolol (and other nonselective β blockers) have emerged as an important form of therapy to
rapidly alleviate manifestations of thyrotoxi cosis 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.
(a) While awaiting response to carbimazole or 131I.
(b) Along with iodide for preoperative prepara tion before subtotal thyroidectomy.
(c) Thyroid storm (thyrotoxic crisis): This is an emergency due to decompensated hyper‐
thyroidism. Vigorous treatment with the following is indicated:
Nonselective β blockers (e.g. propranolol) are the most valuable measure. They afford dramatic
symptomatic relief. In addition, higher doses reduce peripheral conversion of T4 to T3.
Propranolol 1–2 mg slow i.v. may be followed by 40–80 mg oral every 6 hours. It may be
withdrawn gradually when T4 levels normalise.
• Propylthiouracil 200–300 mg oral 6 hourly:
reduces hormone synthesis as well as peri
pheral T4 to T3 conversion.
• Iopanoic acid (0.5–1 g OD oral one hour
after propylthiouracil) or ipodate are iodine containing radiocontrast media. They are potent
inhibitors of thyroid hormone release from thyroid, as well as of peripheral T4 to T3 conversion.
• Corticosteroids (hydrocortisone 100 mg i.v. 8 hourly followed by oral prednisolone): help to tide
over crisis, cover any adrenal insufficiency and reduce conversion of T4 to T3 in periphery.
• Diltiazem 60–120 mg BD oral may be added if tachycardia is not controlled by propra nolol alone,
or when it is contraindicated.
• Rehydration, anxiolytics, external cooling and appropriate antibiotics are the other measures.
Create detailed and revisable notes on the above paragraphs

β Adrenergic Blockers in Thyrotoxicosis

Overview

Purpose: Alleviate symptoms of sympathetic overactivity in thyrotoxicosis (e.g., palpitation,

tremor, nervousness, severe myopathy, sweating).
Effect on Thyroid Function: Minimal; primarily provide symptomatic relief without significantly
affecting thyroid function or hypermetabolic state.

Uses in Hyperthyroidism

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 1. Awaiting Response to Carbimazole or 131I
Used as a symptomatic treatment while waiting for the effects of primary therapies.
2. Preoperative Preparation with Iodide
Used in combination with iodide to prepare patients for subtotal thyroidectomy.
3. Thyroid Storm (Thyrotoxic Crisis)
An emergency condition due to decompensated hyperthyroidism.
Requires vigorous treatment with multiple interventions.

Treatment of Thyroid Storm

Nonselective β Blockers (e.g., Propranolol)

Symptomatic Relief: Provides rapid relief from symptoms.
Dose: Propranolol 1–2 mg slow i.v., followed by 40–80 mg oral every 6 hours.
Additional Effect: Higher doses reduce peripheral conversion of T4 to T3.
Withdrawal: Gradually withdrawn when T4 levels normalize.
Propylthiouracil
Dose: 200–300 mg oral every 6 hours.
Mechanism: Reduces hormone synthesis and peripheral conversion of T4 to T3.
Iodine-Containing Radiocontrast Media (e.g., Iopanoic Acid, Ipodate)
Dose: Iopanoic acid 0.5–1 g OD oral one hour after propylthiouracil.
Mechanism: Inhibit thyroid hormone release from the thyroid and peripheral conversion of
T4 to T3.
Corticosteroids
Dose: Hydrocortisone 100 mg i.v. every 8 hours, followed by oral prednisolone.
Benefits: Help manage crisis, cover adrenal insufficiency, and reduce peripheral conversion
of T4 to T3.
Diltiazem
Dose: 60–120 mg oral BD.
Use: Added if tachycardia is not controlled by propranolol alone or if propranolol is
contraindicated.
Additional Measures
Rehydration
Anxiolytics
External Cooling
Appropriate Antibiotics

These notes provide detailed and revisable information on the use of β adrenergic blockers in
thyrotoxicosis, including their specific applications, especially in managing thyroid storm, and the
additional supportive treatments involved.
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