BP 503 T

Pharmacology II
Unit - IV
❖ HYPOTHALAMIC AND PITUITARY
HORMONES
➢ The control of metabolism, growth, and reproduction is mediated by a
combination of neural and endocrine systems located in the hypothalamus
and pituitary gland.

➢ The pituitary weighs about 0.6 g and rests at the base of the brain.
➢ The pituitary consists of an anterior lobe (adenohypophysis) and a posterior

lobe (neurohypophysis).
➢ It is connected to the overlying hypothalamus by a stalk of neurosecretory
fiber sand blood vessels, including a portal venous system that drains the
hypothalamus and perfuses the anterior pituitary.

➢ The portal venous system carries small regulatory hormones from the
hypothalamus to the anterior pituitary (the hypothalamic hormone control
the release of homones from the pituitary gland)
➢ The posterior lobe hormones are synthesized in the hypothalamus and
transported via the neurosecretory fibers in the stalk of the pituitary to the
posterior lobe; from there they are released into the circulation.
The hypothalamic-pituitary endocrine system.
➢ Hormone is a substance of intense biological activity that is produced
by specific cells in the body and is transported through circulation to
act on its target cells.
➢ Hormones regulate body functions to bring about a programmed
pattern of life events and maintain homeostasis in the face of markedly
variable external/internal environment.
Drugs that mimic or block the effects of hypothalamic and pituitary
hormones have pharmacologic applications in three primary areas:

(1) as replacement therapy for hormone deficiency states;

(2) as antagonists for diseases caused by excess production of pituitary
hormones; and

(3) as diagnostic tools for identifying several endocrine abnormalities.

 ❖ Anterior pituitary

➢ Anterior pituitary (adenohypophysis), the master endocrine gland,

elaborates a number of important regulatory hormones.
➢ All of these are peptide in nature and act at extracellular receptors located
on their target cells.
➢ Their secretion is controlled by the hypothalamus through releasing and
release-inhibitory hormones that are transported via
hypothalamohypophyseal portal system, and is subjected to feedback
inhibition by the hormones of their target glands.
➢ Each anterior pituitary hormone is produced by a separate group of
cells, which according to their staining characteristic are either
acidophilic or basophilic.

➢ The acidophils are either somatotropes: GH; or lactotropes >Prolactin.

➢ The basophils are gonadotropes > FSH and LH; thyrotropes > TSH;
and corticotrope-lipotropes > ACTH.
 ❖ ANTERIOR PITUITARY HOTMONES

➢ Growth hormone (GH)

➢ Prolactin (Prl)
➢ Adrenocorticotropic hormone (ACTH, Corticotropin)
➢ Thyroid stimulating hormone (TSH, Thyrotropin)
➢ Gonadotropins—Follicle stimulating hormone (FSH) and Luteinizing
hormone (LH)
 ➢ Growth Hormone (GH)
➢ Growth hormone, an anterior pituitary hormone, is required during
childhood and adolescence for attainment of normal adult size and has
important effects throughout postnatal life on lipid and carbohydrate
metabolism, and on lean body mass and bone density.
➢ Its growth-promoting effects are primarily mediated via IGF-I (also known
as somatomedin C).
➢ Individuals with congenital or acquired deficiency of GH during childhood
or adolescence fail to reach their midparental target adult height and have
disproportionately increased body fat and decreased muscle mass.

➢ Adults with GH deficiency also have disproportionately low lean body

mass.
➢ Circulating endogenous GH has a half-life of approximately 20
minutes and is predominantly cleared by the liver.
➢ Recombinant human GH (rhGH) is administered subcutaneously 6–7
times per week.

➢ Peak levels occur in 2–4 hours, and active blood levels persist for
approximately 36 hours.
➢ Growth hormone mediates its effects via cell surface receptors of the
JAK/STAT cytokine receptor superfamily.
➢ The hormone has two distinct GH receptor binding sites. Dimerization
of two GH receptors is stimulated by a single GH molecule and
activates signaling cascades mediated by receptor-associated JAK
tyrosine kinases and STATs
▪ Cytokine/Growth receptors, like receptor tyrosine kinases, have extracellular and
intracellular domains and form dimers. However, after activation by an appropriate ligand,
separate mobile protein tyrosine kinase molecules (JAK) are activated, resulting in
phosphorylation of signal transducers and activation of transcription (STAT) molecules.
STAT dimers then travel to the nucleus, where they regulate transcription
 ❑ Physiological functions
➢ GH 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 protoplasm is formed.
➢ The positive nitrogen balance results from increased uptake of amino
acids by tissues and their synthesis into proteins.
➢ GH promotes utilization of fat and spares carbohydrates: uptake of
glucose by muscles is reduced while its output from liver is enhanced.
➢ The growth promoting, nitrogen retaining and certain metabolic actions of
GH are exerted indirectly through the elaboration of peptides called
Somatomedins or Insulin-like growth factors (mainly IGF-1, also IGF-2)
which are extracellular mediators of GH response.
➢ Liver is the major source of circulating IGF-1, while IGF- 1 produced by
other target cells acts locally in a paracrine manner.

➢ Like insulin, IGF-1 promotes lipogenesis and glucose uptake by muscles.

➢ The IGF-1 receptor also is structurally and functionally analogous to the
insulin receptor.
➢ GH acts directly as well to induce lipolysis in adipose tissue,
gluconeogenesis and glycogenolysis in liver and decreased glucose
utilization by muscles. These effects are opposite to those of IGF-1 and
insulin. As such, GH accentuates the metabolic derangement in diabetes.
 ❑ Regulation of secretion

➢ The hypothalamus produces GH releasing (GHRH) as well as release inhibitory

(somatostatin) hormones.
➢ Both are peptides. Somatostatin is also produced by D cells of islets of
Langerhans in the pancreas and by few other tissues.
➢ Receptors for GHRH and somatostatin are G protein coupled receptors (GPCRs)
which enhance or inhibit GH secretion by increasing or decreasing cAMP
formation respectively in pituitary somatotropes.
➢ Somatostatin has also been shown to inhibit Ca2+ channels and open K+
channels.
➢ Stimuli that cause GH release are—fasting, hypoglycaemia, exercise,
stress and i.v. infusion of arginine.

➢ GH secretion is inhibited by rise in plasma free fatty acid levels and by

high doses of glucocorticoids.
➢ Dopaminergic agents cause a brief increase in GH release in normal
subjects but paradoxically depress it in acromegalics.
➢ IGF-1 causes feedback inhibition of GH secretion.
 ❑ Pathological involvements

➢ Excess production of GH is responsible for gigantism in childhood

and acromegaly in adults.
➢ Hyposecretion of GH in children results in pituitary dwarfism.
➢ Adult GH deficiency is rare, but when it occurs, it results in low
muscle and bone mass, lethargy, decreased work capacity,
hyperlipidaemia and increased cardiovascular risk.
 ❑ Preparations and use

➢ The primary indication for GH is pituitary dwarfism—0.03–0.06 mg/kg

daily in the evening or on alternate days, upto the age of 20 years or more.
➢ Human GH produced by recombinant DNA technique (rhGH) somatropin
(191AA) is available for clinical use.
➢ Somatropin causes IGF-1 to appear in plasma after a delay of several
hours.
➢ IGF-1 then remains detectable for upto 48 hours. Early diagnosis and
institution of GH therapy restores stature to near normal. rhGH can also be

used in Turner’s syndrome and in children with renal failure.

➢ Somatropin has been tried in children with constitutional short stature
(only if epiphyses are open) with encouraging results.

➢ In adult GH deficient patients, rHGH 150–300 µg/day s.c. adjusted later

according to response increases lean body mass, decreases body fat,
improves energy and mentation and may reudce excess morbidity and
mortality, but stature is unaffected.
 ❑ Adverse effects

➢ Somatropin has low immunogenicity; allergic reactions or resistance to

treatment are not a problem.
➢ Pain at injection site, lipodystrophy, glucose intolerance, hypothyroidism,
salt and water retention, hand stiffness, myalgia, headache are the possible
adverse effects.

➢ Rise in intracranial tension occurs in few cases.

 ❑ Growth Hormone Antagonists
➢ Antagonists of GH are used to reverse the effects of Gh producing cells
(somatotrophs) in the anterior pituitary that tend to form GH-secreting
tumors.

➢ Hormone-secreting pituitary adenomas occur most commonly in adults.

➢ In adults, GH-secreting adenomas cause acromegaly, which is
characterized by abnormal growth of cartilage and bone tissue, and
many organs including skin, muscle, heart, liver, and the gastrointestinal
tract.
➢ When a GH-secreting adenoma occurs before the long bone epiphyses
close, it leads to a rare condition, gigantism.
➢ Larger pituitary adenomas produce greater amounts of GH and also can
impair visual and central nervous system function by encroaching on
nearby brain structures.
➢ The initial therapy of choice for GH-secreting adenomas is endoscopic
transsphenoidal surgery.
➢ Medical therapy with GH antagonists is introduced if GH hypersecretion
persists after surgery.
➢ These agents include somatostatin analogs and dopamine receptor
agonists, which reduce the production of GH, and the novel GH receptor
antagonist pegvisomant, which prevents GH from activating GH
signaling pathways.
➢ Radiation therapy is reserved for patients with inadequate response to
surgical and medical therapies.
➢ Somatostatin, a 14-amino-acid peptide, is found in the hypothalamus,
other parts of the central nervous system, the pancreas, and other sites in
the gastrointestinal tract.
➢ It functions primarily as an inhibitory paracrine factor and inhibits the
release of GH, TSH, glucagon, insulin, and gastrin.
➢ Somatostatin is rapidly cleared from the circulation, with a half-life of 1–
3 minutes.
➢ Somatostatin has limited therapeutic usefulness because of its short
duration of action and multiple effects in many secretory systems.
➢ Octreotide, the most widely used somatostatin analog, is 45 times more
potent than somatostatin in inhibiting GH release but only twice as potent
in reducing insulin secretion.
➢ Because of this relatively reduced effect on pancreatic beta cells,
hyperglycemia rarely occurs during treatment.
➢ The plasma elimination half-life of octreotide is about 80 minutes, 30 times
longer than that of somatostatin.
➢ Octreotide, 50–200 mcg given subcutaneously every 8 hours, reduces
symptoms caused by a variety of hormone-secreting tumors: acromegaly,
carcinoid syndrome, gastrinoma and ACTH-secreting tumor.
➢ Octreotide acetate injectable long-acting suspension is a slow release
microsphere formulation.

➢ Injections into alternate gluteal muscles are repeated at 4-week intervals

in doses of 10–40 mg.
➢ Adverse effects of octreotide therapy include nausea, vomiting,
abdominal cramps, flatulence, and steatorrhea with bulky bowel
movements.
➢ Biliary sludge and gallstones may occur after 6 months of use in 20–30%
of patients. However, the yearly incidence of symptomatic gallstones is
about 1%. Cardiac effects include sinus bradycardia (25%) and
conduction disturbances (10%).

➢ Pain at the site of injection is common, especially with the long-acting

octreotide suspension. Vitamin B12 deficiency may occur with long-term
use of octreotide.
➢ Lanreotide: Long-acting analogue of somatostatin, very similar in actions
and specificity to octreotide, on i.m. injection acts for 10–15 days. It is
indicated for pharmacotherapy 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
 ❖ PROLACTIN
➢ It is a 199 amino acid with three intra-molecular disulfide bonds, single chain
peptide of MW 23000; quite similar chemically to GH.
➢ It 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.

➢ It is synthesized by lactotropes in the anterior pituitary gland.
➢ Prolactin is the principal hormone responsible for lactation.
➢ Milk production is stimulated by prolactin when appropriate circulating levels
of estrogens, progestins, corticosteroids, and insulin are present.
➢ A deficiency of prolactin—which can occur in rare states of pituitary
deficiency—is manifested by failure to lactate. No preparation of prolactin is
available for use in prolactin-deficient patients.
➢ Prolactin suppresses hypothalamo-pituitary-gonadal axis by inhibiting
GnRH release.
➢ Continued high level of prolactin during breastfeeding is responsible for
lactational amenorrhoea, 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
analogous to GH receptor:
❖ Action is exerted by transmembrane activation of JAK—
cytoplasmic tyrosine protein kinases and STAT.
❖ Placental lactogen and GH also bind to prolactin
receptor and exert similar effects, but prolactin does not
bind to GH receptor.
 ❖ 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.
Subsequently, high prolactin secretion is maintained by suckling: it falls if
breast feeding is discontinued. Stress, exertion and hypoglycaemia also
stimulate prolactin release.
 ❖ Physio-pathological involvement

➢ Hyperprolactinaemia is responsible for the galactorrhoea–amenorrhoea–

infertility syndrome in women. In males it causes loss of libido and
depressed fertility.

✓ The causes of hyperprolactinaemia are:

▪ Disorders of hypothalamus removing the inhibitory control over pituitary.
▪ Antidopaminergic and DA depleting drugs —these are a frequent cause
now.
▪ Prolactin secreting tumours—these may be microprolactinomas or
macroprolactinomas.

▪ Hypothyroidism with high TRH levels—also increases prolactin secretion.

Use: There are no clinical indications for prolactin.
 ❖ Prolactin inhibitors

➢ Adenomas that secrete excess prolactin usually retain the sensitivity to

inhibition by dopamine exhibited by normal pituitary lactotrophs, prolactin
secreting cells.
➢ Bromocriptine and cabergoline are ergot derivatives with a high affinity for
dopamine D2 receptors. Quinagolide, a drug approved in Europe, is a
nonergot agent with similarly high D2 receptor affinity.
➢ Dopamine agonists suppress prolactin release very effectively in patients with
hyperprolactinemia and GH release is reduced in patients with acromegaly,
although not as effectively.
➢ Newer, nonergot D2 agonists used in Parkinson’s disease (pramipexole and
ropinirole) have been reported to interfere with lactation, but they are not
approved for use in hyperprolactinemia
➢ Bromocriptine
This synthetic ergot derivative 2-bromo-ergocryptine is a potent dopamine agonist;
most of its actions are based on this property.

✓ Actions
▪ Decreases prolactin release from pituitary by activating dopaminergic receptors
on lactotrope cells: is a strong antigalactopoietic.

▪ Increases GH release in normal individuals, but decreases the same from

pituitary tumours that cause acromegaly.
▪ Has levodopa like actions in CNS—antiparkinsonian and behavioral effects.
▪ Produces nausea and vomiting by stimulating dopaminergic receptors in the
CTZ.
▪ Hypotension—due to central suppression of postural reflexes and weak
peripheral a adrenergic blockade.
▪ Decreases gastrointestinal motility.
❑ Pharmacokinetics
▪ 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 t½ is 3–6 hours.
➢ Uses
▪ Hyperprolactinemia, Acromegaly, Parkinsonims, Diabetes mellitus, Hepatic
coma.
▪ 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: Behavioral alterations, mental confusion, hallucinations, psychosis—are
more prominent than with levodopa. Abnormal movements, livedo reticularis.
➢ Cabergoline
▪ It is a newer D2 agonist; more potent; more D2 selective and longer
acting (t½ > 60 hours) than bromocriptine; needs to be given only twice

weekly.
▪ Incidence of nausea and vomiting is also lower; some patients not
tolerating or not responding to bromocriptine have been successfully
treated with cabergoline.

▪ It is preferred for treatment of hyperprolactinemia and acromegaly.

▪ Some patients who achieve total regression of prolactinoma and
normalization of prolactin levels can stop cabergoline without

recurrence.
 ❖ 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). Its actions are:
▪ Induces hyperplasia and hypertrophy of thyroid follicles and increases blood
supply to the gland.
▪ Promotes trapping of iodide into thyroid by increasing Na+: Iodide symporter
(NIS).
▪ Promotes organification of trapped iodine and its incorporation into T3 and T4
by increasing peroxidase activity.
▪ Enhances endocytotic uptake of thyroid colloid by the follicular cells and
proteolysis of thyroglobulin to release more of T3 and T4. This action starts
within minutes of TSH administration.
▪ The TSH receptor present on thyroid cells is a GPCR which utilizes the
adenylyl cyclase-cAMP transducer mechanism (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 kinase C activation may
also mediate TSH action, particularly generation of H2O2 needed for

oxidation of iodide and iodination of tyrosil residues.

➢ Regulation of secretion
▪ Synthesis and release of TSH by pituitary is controlled by hypothalamus
primarily through TRH, while somatostatin inhibits TSH secretion.
▪ Dopamine also reduces TSH production induced by TRH.
▪ The TRH receptor on pituitary thyrotrope cells is a GPCR which is linked
to Gq protein and activates PLC–IP3/DAG–cytosolic Ca2+ pathway to
enhance TSH synthesis and release.
▪ The negative feedback for inhibiting TSH secretion is provided by the
thyroid hormones which act primarily at the level of the pituitary, but also
in the hypothalamus.

▪ T3 has been shown to reduce TRH receptors on the thyrotropes.

➢ 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.
▪ Contrary to earlier belief, TSH is not responsible for exophthalmos seen
in Graves’ disease because 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 differentiate myxoedema due to
pituitary dysfunction from primary thyroid disease.
❖ ADRENOCORTICOTROPIC HORMONE
(ACTH, CORTICOTROPIN)

It is a 39 amino acid single chain peptide, MW4500, derived from a larger

peptide pro-opiomelanocortin (MW 30,000) which also gives rise to
endorphins, two lipotropins and two MSHs.

▪ Physiological function ACTH promotes steroidogenesis in adrenal cortex by

stimulating cAMP formation in cortical cells (through specific cell surface
GPCRs) 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.
▪ 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
corticotropin-releasing 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.
▪ Arginine vasopressin (AVP) enhances the action of CRH on corticotropes and
augments ACTH release.
▪ AVP release and augmentation of ACTH action appears to be important during
stress.
❑ 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 non-endocrine
diseases.
➢ Use
▪ ACTH is used primarily for the diagnosis of disorders of pituitary adrenal
axis.
▪ Injected i.v. 25 IU causes increase in plasma cortisol if the adrenals are
functional.
▪ Direct assay of plasma ACTH level is now preferred.
▪ For therapeutic purposes, ACTH does not offer any advantage over
corticosteroids and is more inconvenient, expensive as well as less
predictable.
 ❖ GONADOTROPINS (Gns)

➢ The anterior pituitary secretes two Gns: FSH and LH.

➢ Both are glycoproteins containing 23–28% sugar and consist of two
peptide chains.

➢ The α-chain (92AA) is common between FSH and LH, but their β-
chains 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 promote gametogenesis and secretion of gonadal hormones.
✓ FSH
▪ In the female it induces follicular growth, development of ovum and
secretion of estrogens.
▪ 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 sustains
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 and stimulates gametogenesis and conversion of
cholesterol to pregnenolone - the first step in progesterone, testosterone
and estrogen synthesis.
▪ In the testes FSH receptor is expressed on seminiferous (Sertoli) cells
while LH receptor is expressed on interstitial (Leydig) cells.
▪ In the ovaries FSH receptors are present only on granulosa cells, while
LH receptors are widely distributed on interstitial cells, theca cells,
preovulatory granulosa cells and luteal cells.
➢ Regulation of secretion
▪ A single releasing factor (decapeptide designated GnRH) is produced by the
hypothalamus 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.

▪ GnRH acts on gonadotropes through a G-protein coupled receptor which acts by
increasing intracellular Ca2+ through PIP2 hydrolysis.
▪ Inhibin - a peptide from ovaries and testes, selectively inhibits FSH release, but
not LH release.

▪ Dopamine inhibits only LH release.

▪ 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 menstruating women they fluctuate cyclically.
❑ Pathological involvement
▪ Disturbances of Gn secretion from pituitary may be responsible for
delayed puberty or precocious puberty both in girls and 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
▪ Menotropins (FSH + LH)
▪ Urofollitropin or Menotropin (pure FSH)
▪ Human chorionic gonadotropin (HCG)
▪ Recombinant human FSH
▪ Recombinant human LH
❑ Uses
▪ Amenorrhoea and infertility
▪ Hypogonadotrophic hypogonadism in males
▪ Cryptorchidism
▪ To aid in vitro fertilization
▪ Adverse effects and precautions
▪ Ovarian hyperstimulation - polycystic ovary, pain in lower abdomen and even
ovarian bleeding and shock can occur in females.

▪ 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.
❑ GONADOTROPIN RELEASING HORMONE (GnRH): GONADORELIN
▪ Synthetic GnRH injected i.v. (100 μg) induces prompt release of LH and FSH
followed by elevation of gonadal steroid levels.
▪ It has a short plasma t½ (4–8 min) due to rapid enzymatic degradation; has been
used for testing pituitary-gonadal axis in male as well as female hypogonadism.

▪ Since only pulsatile exposure to GnRH induces FSH/LH secretion, while

continuous exposure desensitizes pituitary gonadotropes resulting in loss of Gn
release, therapy with GnRH or its analogues 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 (t½ 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 increase Gn secretion.
▪ After 1–2 weeks they cause desensitization and down regulation of GnRH
receptors > inhibition of FSH and LH secretion > 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.
Long-acting preparations for once a month s.c. injection have been
produced (triptorelin, goserelin depot).

▪ The resulting reversible pharmacological 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.

❑ Adverse effects: Hot flashes, loss of libido, vaginal dryness, osteoporosis,

emotional lability.
❑ GnRH antagonists
▪ Some more extensively substituted GnRH analogues act as GnRH receptor
antagonists.
▪ They inhibit Gn secretion without causing initial stimulation.
▪ The early GnRH antagonists had the limitation of producing reactions due to
histamine release.
▪ Later agents like ganirelix and cetrorelix have low histamine releasing potential
and are being clinically used as s.c. inj. in specialized centres for inhibiting LH
surges during controlled ovarian stimulation in women undergoing in vitro
fertilization.
➢ Their advantages over long-acting GnRH agonists include:
• They produce quick Gn suppression by competitive antagonism
• They carry a lower risk of ovarian hyperstimulation syndrome
• They achieve more complete suppression of endogenous Gn secretion
❑THYROID HORMONE
 ❑ THYROID HORMONE

➢ The thyroid gland secretes 3 hormones—thyroxine (T4), triiodothyronine

(T3) and calcitonin.
➢ The former two are produced by thyroid follicles, have similar biological
activity and the term ‘thyroid hormone’ is restricted to these only.
➢ Calcitonin, the second type of thyroid hormone, is important in the
regulation of calcium metabolism.
 ❑ CHEMISTRY

▪ T4 and T3 are iodine containing derivatives of thyronine which is a

condensation product of two molecules of the amino acid tyrosine.
▪ T4 (Thyroxine) is 3, 5, 3´, 5´ - tetraiodothyronine while T3 is 3, 5, 3´
triiodothyronine.
▪ The thyroid hormones are synthesized and stored in the thyroid follicles
as part of thyroglobulin molecule - which is a glycoprotein synthesized
by thyroid cells, MW 660 KDa, contains 10% sugar.
 ❑ SYNTHESIS

➢ Iodide uptake
▪ The total body content of I2, obtained from food and water, is 30–50 mg,
out of which about 1/5 is present in the thyroid.
▪ Concentration of iodide in blood is low (0.2–0.4 μg/dl) but thyroid cells
have an active transport process Na+:: iodide symporter (NIS) to
concentrate this anion; this trapping is stimulated by TSH to exceed a
gradient of more than 100 fold by inducing and activating NIS.
▪ The I2 content of thyroid gland somehow regulates the uptake mechanism:
meagre store activating and large store inhibiting it.
▪ The iodide concentrating mechanism is not peculiar to thyroid. Skin,
salivary glands, gastric mucosa, intestine, mammary glands and placenta
also possess it, but uptake in these organs is not stimulated by TSH.
➢ Oxidation and iodination
▪ Iodide trapped by follicular cells is carried across the apical membrane by
another transporter termed ‘pendrin’ and oxidized by the membrane

bound thyroid peroxidase enzyme to iodinium (I+) ions or hypoiodous

acid (HOI) or enzyme-linked hypoiodate (E-OI) with the help of H2O2.
▪ These forms of iodine combine avidly with tyrosil residues of
thyroglobulin, apparently without any enzymatic intervention, to form
monoiodotyrosine (MIT) and diiodotyrosine (DIT) while these residues
are still attached to the thyroglobulin chains.
➢ Coupling
▪ Pairs of iodinated tyrosil residues couple together to form T3 and T4.
▪ Normally much more T4 than T3 is formed, but during I2 deficiency
relatively more MIT is available and a greater proportion of T3 is formed.

▪ Thus, more active hormone is generated with lesser amount of I2.

▪ Coupling is an oxidative reaction and is catalysed by the same thyroid
peroxidase.

▪ Thyroglobulin is the most efficient protein, compared to other similar

proteins, in supporting coupling by providing favourable spatial
configuration to facilitate the reaction.

▪ Oxidation of iodide and coupling are both stimulated by TSH.

➢ Storage and release
▪ Thyroglobulin containing iodinated tyrosil and thyronil residues is
transported to the interior of the follicles and remains stored as thyroid
colloid till it is taken back into the cells by endocytosis and broken down by
lysosomal proteases.
▪ The T4 and T3 so released is secreted into circulation while MIT and DIT
residues are deiodinated and the iodide released is reutilized.

▪ Normal human thyroid secretes 60–90 μg of T4 and 10–30 μg of T3 daily.

➢ Peripheral conversion of T4 to T3
▪ Peripheral tissues, especially liver and kidney, convert T4 to T3.
▪ About 1/3 of T4 secreted by thyroid undergoes this change and most of the T3
in plasma is derived from liver.
▪ Target tissues take up T3 from circulation for their metabolic need, except
brain and pituitary which take up T4 and convert it to T3 within their own

cells.
▪ The T4 to T3 conversion is carried out by the enzyme iodothyronine deiodinase
which exists in 3 forms (D1, D2, D3).
▪ These forms differ in their organ and cellular localization as well as product
formed.

▪ Type 2 deiodinase (D2) generates T3 and D3 generates rT3, the D1 form

generates both T3 and rT3.
❑ Mechanism of action
▪ Both T3 and T4 penetrate cells by active transport and produce majority of
their actions by combining with a nuclear thyroid hormone receptor (TR)

which belongs to the steroid and retinoid superfamily of intracellular

receptors.
▪ Two TR isoform families (TRα and TRβ) have been identified.
▪ Both bind T3 and function in similar manner, but their tissue distribution
differs, which may account for quantitative differences in the sensitivity of
different tissues to T3.
▪ In contrast to the steroid receptor, the TR resides in the nucleus even in the
unliganded inactive state.
▪ It is bound to the ‘thyroid hormone response element’ (TRE) in the enhancer
region of the target genes along with corepressors (this keeps gene

transcription suppressed).
▪ When T3 binds to the ligand-binding domain of TR, it heterodimerizes with
retinoid X receptor (RXR) and undergoes a conformation change releasing
the corepressor and binding the coactivator.
▪ This induces gene transcription → production of specific mRNA and a
specific pattern of protein synthesis → various metabolic and anatomic

effects.
✓ Apart from the nuclear T3 receptor, other sites of thyroid hormone action
have been described.
✓ It acts on cell membrane to enhance amino acid and glucose entry and on
mitochondria to increase oxygen consumption. At these sites T4 appears
to be equipotent to T3, while at the nuclear receptor T4 has much lower
affinity, and even when bound to the TR, T4 does not promote gene
transcription.
❑ METABOLISM
▪ Thyroid hormones 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 order of affinity for T4:
(i) Thyroxine binding globulin (TBG)
(ii) Thyroxine binding prealbumin (transthyretin)
(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 concentration 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/sulfate conjugation 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 t½ of T4 is 6–7 days, while that of T3 is 1–2 days. The half-lives are
shortened in hyperthyroidism and prolonged in hypothyroidism due

respectively to faster and slower metabolism.

❑ ACTIONS
➢ T4 and T3 are essential for normal growth and development.
➢ Thyroid hormones have marked effect on lipid, carbohydrate and protein metabolism.
➢ T3 and T4 increase BMR by stimulation of cellular metabolism.
➢ Heart rate, contractility and output are increased resulting in a fast pulse. T3 and T4 stimulate
heart by direct action on contractile elements (increasing the myosin fraction having greater
Ca2+ ATPase activity) and probably by up regulation of β adrenergic receptors.
➢ Required for the nervous development and skeletal muscle working.
➢ Propulsive activity of gut is increased.
➢ Hypothyroid patients suffer from some degree of anaemia which is restored only by T4
treatment. Thus, T4 appears to be facilitatory to erythropoiesis.
➢ Thyroid has an indirect effect on reproduction. Fertility is impaired in hypothyroidism and
women suffer from oligomenorrhoea. Normal thyroid function is required for maintenance of
pregnancy and lactation.
❑ REGULATION OF SECRETION
➢ The secretion of hormones from the
thyroid is controlled by anterior pituitary
by the elaboration of thyrotropin, while
TSH secretion itself is regulated by TRH
produced in hypothalamus.
➢ Somatostatin inhibits TSH secretion from
pituitary.

➢ The negative feedback by the thyroid

hormones is exercised directly on the
pituitary as well as through
hypothalamus.
❑ Relation between T4 and T3
▪ Thyroid secretes more T4 than T3, but in iodine deficient state this difference is reduced.
▪ T4 is the major circulating hormone because it is 15 times more tightly bound to plasma
proteins.
▪ T3 is 5 times more potent than T4 and acts faster. Peak effect of T3 comes in 1–2 days
while that of T4 takes 6–8 days.
▪ T3 is more avidly bound to the nuclear receptor than T4 and the T4-receptor complex is
unable to activate/derepress gene transcription.
▪ About 1/3 of T4 is converted to T3 in the thyroid cells, liver and kidney by type 1
deiodinase (D1) and released into circulation. In addition, T3 is generated within the
target cells (skeletal muscle, heart, brain, pituitary) by another type (D2) of deiodinase.
➢ Thus, it may be concluded that T3 is the active hormone, while T4 is mainly a transport
form; functions as a prohormone of T3. However, it may directly produce some
nongenomic actions.
➢ l-thyroxine sodium and Liothyronine (triiodothyronine)
➢ Clinically, l-thyroxine is preferred for all indications over liothyronine because of more
sustained and uniform action as well as lower risk of cardiac arrhythmias.
➢ Oral bioavailability of l-thyroxine 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 l-thyroxine
absorption. CYP3A4 inducers like rifampin, phenytoin and carbamazepine accelerate
metabolism of T4; dose of l-thyroxine may need enhancement.
➢ Used in the management of : Cretinism, Adult hypothyroidism (Myxoedema),
Myxoedema coma, Nontoxic goiter.
 ❑ THYROID INHIBITORS
➢ These are drugs used to lower the functional capacity of the hyperactive
thyroid gland.

➢ Thyrotoxicosis is due to excessive secretion of thyroid hormones.

➢ The two main causes are Graves’ disease and toxic nodular goiter.
➢ Graves’ disease is an autoimmune disorder: IgG class of antibodies to the TSH
receptor are detected in blood. They bind to and stimulate thyroid cells, and
produce other TSH like effects.

➢ Due to feedback inhibition, TSH levels are low. The accompanying

exophthalmos is due to autoimmune inflammation of periorbital tissues.
➢ Toxic nodular goiter, which produces thyroid hormone independent of TSH. It
is more common in the elderly; ocular changes are generally absent.
 ❑ CLASSIFICATION OF DRUGS

➢ Inhibit hormone synthesis (Antithyroid drugs)

▪ Propylthiouracil, Methimazole, Carbimazole
➢ Inhibit iodide trapping (Ionic inhibitors)
▪ Thiocyanates (–SCN), Perchlorates (–ClO4), Nitrates (–NO3)
➢ Inhibit hormone release
▪ Iodine, Iodides of Na and K, Organic iodide
➢ Destroy thyroid tissue
▪ Radioactive iodine (131I, 125I, 123I)

Compounds in groups 1 and 2 may be collectively called goitrogens

because, if given in excess, they cause enlargement of thyroid by feedback
release of TSH.
 ➢ ANTITHYROID DRUGS (Thioamides)

Antithyroid drugs bind to the thyroid peroxidase and prevent oxidation of iodide/
iodotyrosyl residues, thereby;

(i) Inhibit iodination of tyrosine residues in thyroglobulin

(ii) Inhibit coupling of iodotyrosine residues to form T3 and T4.
▪ Action: 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.
▪ Propylthiouracil also inhibits peripheral conversion of T4 to T3 by D1 type of 5’DI, but
not by D2 type. Methimazole and carbimazole do not have this action
➢ Pharmacokinetics
▪ All antithyroid drugs are quickly absorbed orally, widely distributed in the body,
enter milk and cross placenta and are metabolized in liver and excreted in urine.

▪ All are concentrated in thyroid: intrathyroid t½ is longer: effect of a single dose

lasts longer than would be expected from the plasma t½.
▪ Carbimazole acts largely by getting converted to methimazole in the body and is
longer acting than propythiouracil.

➢ Adverse effects
▪ Hypothyroidism and goiter can occur due to overtreatment, but is reversible on
stopping the drug.
▪ Other side effects are: g.i. intolerance, skin rashes and joint pain.
▪ Loss or graying of hair, loss of taste, fever and liver damage are infrequent.
 ➢ IONIC INHIBITORS

▪ Certain monovalent anions inhibit iodide trapping by NIS into the thyroid
probably because of similar hydrated ionic size—T4/T3 cannot be
synthesized.
▪ Perchlorate is 10 times more potent than thiocyanate in blocking NIS,
while nitrate is very weak.

▪ They are toxic and not clinically used now.

▪ Thiocyanates: can cause liver, kidney, bone marrow and brain toxicity.
▪ Perchlorates: produce rashes, fever, aplastic anaemia, agranulocytosis.
 ➢ IODINE AND IODIDES

▪ It is the fastest acting thyroid inhibitor.

▪ 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.

▪ 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 resulting in reduced T3/T4 synthesis (Wolff-Chaikoff effect).
However, within a few days, the gland ‘escapes’ from this effect and hormone synthesis
resumes.

▪ Preparations and dose: Lugol’s solution (5% iodine in 10% Pot. iodide solution):
• Iodide (Sod./Pot.) 100–300 mg/day (therapeutic), 5–10 mg/day (prophylactic) for
endemic goiter.
➢ Adverse effects
[Link] reaction: It occurs only in individuals 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.
[Link] overdose (iodism): Inflammation of mucous membranes, salivation,
rhinorrhoea, sneezing, lacrimation, swelling of eyelids, burning sensation in mouth,
headache, rashes, g.i. symptoms, etc. Given to pregnant or nursing mothers, it may be
responsible for foetal/infantile goiter and hypothyroidism. Thyrotoxicosis may be
aggravated in multinodular goiter.
 ❑ RADIOACTIVE IODINE
➢ The stable isotope of iodine is 127I.
➢ Its radioactive isotope of medicinal importance is: 131I: physical half-life 8 days.
➢ The chemical behaviour of 131I is similar to the stable isotope.
➢ 131I emits X-rays as well as β particles.
➢ 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, incorporated in colloid - 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.
➢ Advantages and Disadvanteges
▪ Treatment with 131I is simple, conveniently given on outpatient basis and
inexpensive.

▪ No surgical risk
▪ Once hyperthyroidism is controlled, cure is permanent.
▪ It can cause Hypothyroidism
▪ It is Contraindiacted in pregnancy
▪ Not suitable for young patients.
❑ β ADRENERGIC BLOCKERS
Propranolol (and other nonselective β blockers) have emerged as an important form of
therapy to rapidly alleviate manifestations of thyrotoxicosis that are due to sympathetic
overactivity, viz. palpitation, tremor, nervousness, severe myopathy, sweating. They
have little effect on thyroid function and the hypermetabolic state.
❖ HORMONES REGULATING
PLASMA CALCIUM LEVEL
 ❑ CALCIUM

▪ Calcium is the most abundant body constituent, making up about 2% of

body weight, or 1–1.5 kg in an adult.
▪ Over 99% of this is stored in bones, the rest being distributed in plasma and
all tissues and cells. Calcium serves important physiological roles.
 ❑ Physiological roles

▪ Calcium controls excitability of nerves and muscles and regulates

permeability of cell membranes. It also maintains integrity of cell membranes
and regulates cell adhesion.
▪ Ca2+ ions are essential for excitation-contraction coupling in all types of
muscle and excitation secretion coupling in exocrine and endocrine glands,
release of transmitters from nerve ending and other release reactions.

▪ Ca2+ is an intracellular messenger for hormones, autacoids and transmitters.

▪ Ca2+ controls impulse generation in heart; determines level of automaticity and
A-V conduction.

▪ Ca2+ is essential for coagulation of blood.

▪ Calcium serves structural function in bone and teeth.
❑ Plasma calcium level
▪ It is precisely regulated by 3 hormones: Parathormone (PTH), Calcitonin and
Calcitriol (active form of vit D).
▪ These regulators control its intestinal absorption, exchange with bone and renal
excretion.
▪ In addition, several other hormones, metabolites and drugs influence calcium
homeostasis.

▪ Normal plasma calcium is 9–11 mg/dl. Of this about 40% is bound to plasma proteins
- chiefly to albumin; 10% is complexed with citrate, phosphate and carbonate in an
undissociable form; the remaining (about 50%) is ionized and physiologically
important. For example, in hypoalbuminemia, total plasma calcium may be low but
the concentration of Ca2+ ion is usually normal. Acidosis favours and alkalosis
disfavours ionization of calcium. As such, hyperventilation (by raising plasma pH)
precipitates tetany and laryngospasm in calcium deficiency by reducing ionization.
❑ Absorption and excretion
▪ Calcium is absorbed by facilitated diffusion from the entire small intestine as well as from
duodenum by a carrier mediated active transport under the influence of vit D.

▪ Phytates, phosphates, oxalates and tetracyclines complex with Ca2+ in an insoluble form
in the intestines and interfere with its absorption. Glucocorticoids and phenytoin also
reduce calcium absorption.

▪ Ionized calcium is totally filtered at the glomerulus and most of it is reabsorbed in the
tubules.
▪ Vit D and PTH increase, while calcitonin decreases tubular reabsorption of Ca2+.
▪ About 300 mg of endogenous calcium is excreted daily: half in urine and half in faeces.
▪ To maintain calcium balance, the same amount has to be absorbed in the small intestine
from the diet.
▪ Thiazide diuretics impede calcium excretion by facilitating tubular reabsorption.
❑ Preparations
▪ Calcium carbonate
▪ Calcium citrate
▪ Calcium gluconate
▪ Calcium lactate.
▪ Calcium dibasic phosphate
▪ Calcium chloride

❑ Side effects
▪ Calcium supplements are usually well tolerated; only g.i. side effects
like constipation, bloating and excess gas (especially with cal.
carbonate) have been reported.

❑ Uses: Tetany, Osteoporosis and as dietary supplement.

 ❖ PARATHYROID HORMONE
(Parathormone, PTH)

▪ PTH is a single chain 84 amino acid polypeptide, MW 9500.

▪ It is synthesized as prepro-PTH, the excess amino acids are split off in two steps
and it is then stored in intracellular vesicles.
▪ Secretion of PTH is regulated by plasma Ca2+ concentration through a calcium-
sensing receptor (CaSR), that is a G-protein coupled receptor on the surface of
parathyroid cells.
▪ There is no trophic hormone for it. Fall in plasma Ca2+ induces PTH release and
rise inhibits secretion by decreasing cAMP in the parathyroid cells.

▪ Agents that increase cAMP cause PTH release, but direct activation of protein
kinase C by fall in Ca2+ concentration is more important physiologically.
▪ Prolonged hypocalcaemia causes hypertrophy and hyperplasia of parathyroids,
while sustained hypercalcaemia has the opposite effect.
▪ Changes in phosphate concentration in plasma affect PTH secretion indirectly
by altering Ca2+ concentration.
▪ The active form of vit. D calcitriol inhibits expression of PTH gene in
parathyroid cells reducing PTH production.

▪ PTH is rapidly degraded in liver and kidney; its plasma t½ is 2–5 min.
❖ Actions
➢ PTH increases plasma calcium levels by:
1. Bone: PTH promptly increases resorption of calcium from bone. This is the most
prominent action of PTH—exerted by increasing the number of bone remodeling units
and activating osteoclasts when high concentrations are present continuously. Since bone
resorption is followed by new bone deposition, this is also promoted by PTH: increased
bone formation occurs when PTH is given intermittently and in low doses.
2. Kidney: PTH increases calcium reabsorption in the distal tubule and provides moment
to moment regulation of calcium excretion. It also promotes phosphate excretion which
tends to supplement the hypercalcaemic effect.

3. Intestines: PTH has no direct effect on calcium absorption but increases it indirectly by
enhancing the formation of calcitriol (active form of vit D) in the kidney by activating
1α-hydroxylase. Calcitriol then promotes intestinal absorption of calcium.
4. PTH: decreases calcium levels in milk, saliva and ocular lens. This may be responsible
for development of cataract in hypoparathyroidism.
 ❖ Mechanism of action
➢ The PTH receptor is a G protein coupled receptor which on activation increases
cAMP formation and intracellular Ca2+ in target cells.
➢ In bone, the target cell is the osteoblast because PTH receptors are not expressed on the
surface of osteoclasts.
➢ Acting on the osteoblast, PTH induces a factor ‘Receptor for activation of nuclear factor-
κB-ligand’ (RANKL) which diffuses and combines with RANK on osteoclast precursors
and transforms them into osteoclasts as well as activates osteoclasts (matured, fused
multinucleated with ruffled surface)
➢ In addition, birth rate of bone remodeling units into which osteoclasts are recruited is
enhanced. Formation of the remodeling pit is followed by osteoblastic deposition of new
bone into it.
➢ PTH enhances proliferation and differentiation of preosteoblasts and deposition of osteoid
as well. Bone resorption predominates when high concentrations of PTH are present
continuously, but intermittent exposure to low concentrations has the opposite effect.
 PTH

Bind with receptor on osteoblast

Osteoblast release RANKL

RANKL attach on the RANK receptor over osteoclast

Now osteoclast get matured and fused to gather to form multinucleated osteoclast
having ruffled surface

A bone resorption pit is dug out by secretion of acid and proteolytic acid
hydrolases
Osteoblasts produce another protein Osteoprotegerin (OPG) as well, which can bind
RANKL and prevent it from combining with RANK to activate osteoclasts. Thus,
osteoblasts by producing RANKL and OPG regulate bone resorption.
▪ Hypoparathyroidism: Low plasma calcium levels, tetany, convulsions, laryngospasm,
paresthesias, cataract and psychiatric changes. Pseudohypoparathyroidism occurs due to
reduced sensitivity of target cells to PTH caused by a mutant G protein that couples PTH
receptor activation to cAMP generation in target cells.
▪ Hyperparathyroidism: It is mostly due to parathyroid tumour. It produces -
Hypercalcaemia, decalcification of bone - deformities and fractures (osteitis fibrosa
generalisata), metastatic calcification, renal stones, muscle weakness, constipation and
anorexia.
• Treatment is surgical removal of the parathyroid tumour. When this is not
possible—low calcium, high phosphate diet with plenty of fluids is advised.
➢ Cinacalcet: It activates the Ca2+ sensing receptor (CaSR) in the parathyroids and
blocks PTH secretion. It is indicated in secondary hyperparathyroidism due to renal
disease and in parathyroid tumour.
➢ Use: PTH is not used in hypoparathyroidism because plasma calcium can be
elevated and kept in the normal range more conveniently by vit D therapy.
▪ PTH has to be given parenterally, while vit D can be given orally. Vit D is
cheap. However, recombinant human PTH (1–84 amino acid) has been
produced and is being clinically evaluated for use in hypoparathyroidism.
➢ Teriparatide
▪ This recombinant preparation of of human PTH has been recently introduced for the
treatment of severe osteoporosis.
▪ Side effects include dizziness and leg cramps. Pagets disease and hypercalcaemia are the
contraindications.
✓ Diagnostic use: To differentiate pseudo from true hypo-parathyroidism: teriparatide is
given i.v.: if plasma calcium level fails to rise, then it is pseudo-hypoparathyroidism.
 ❖ CALCITONIN
➢ Calcitonin is the hypocalcaemic hormone discovered by Copp in 1962. It is a 32 amino
acid single chain polypeptide (MW 3600) produced by parafollicular ‘C’ cells of
thyroid gland.
➢ Parathyroids, thymus and cells of medullary carcinoma of thyroid also contain
calcitonin.
➢ Synthesis and secretion of calcitonin is regulated by plasma Ca2+ concentration itself:
rise in plasma Ca2+ increases, while fall in plasma Ca2+ decreases calcitonin release.

➢ However, circulating level of calcitonin is low and its physiological role in regulating
plasma Ca2+ appears to be minor.
➢ The plasma t½ of calcitonin is 10 min, but its action lasts for several hours.
Actions
➢ The actions of calcitonin are generally opposite to that of PTH.
➢ It inhibits bone resorption by direct action on osteoclasts—decreasing their
ruffled surface which forms contact with the resorptive pit.
➢ The actions of calcitonin are mediated through a G-protein coupled calcitonin
receptor (CTR) and increase in cAMP formation, but its target cells are different
from that of PTH.

➢ The hypocalcaemic action of calcitonin lasts ~8 hours.

➢ Calcitonin inhibits proximal tubular reabsorption of calcium and phosphate by direct
action on the kidney.
❖ Preparation
▪ Synthetic salmon calcitonin is used clinically, because it is more potent and longer acting
due to slower metabolism.
▪ Human calcitonin has also been produced. 1 IU = 4 μg of the standard preparation.
CALSYNAR, ZYCALCIT: Synthetic salmon calcitonin 100 IU/ml amp. for i.m. or s.c.
injection.
▪ Nausea, flushing and tingling of fingers is frequent after calcitonin injection. Bad taste,
flu-like symptoms, allergic reactions and joint pain are the other adverse effects.

❖ Uses
▪ Hypercalcaemic states
▪ Postmenopausal osteoporosis
▪ Paget disease
▪ Diagnosis of medullary carcinoma of thyroid
 ❖ VITAMIN D
Vitamin D is the collective name given to antirachitic substances synthesized in the
body and found in foods activated by UV radiation.

D3 : cholecalciferol - synthesized in the skin under the influence of UV rays.

D2 : calciferol—present in irradiated food - yeasts, fungi, bread, milk.
D1 : mixture of antirachitic substances found in food.

▪ In 1919 it was established that rickets was due to deficiency of a dietary factor as
well as lack of exposure to sunlight.
▪ McCollum (1922) showed that this fat soluble dietary factor was different from vit
A and its structure was determined in 1935.
▪ The interrelation between calciferol and cholecalciferol and their activation in the
body has been fully understood only in the 1970s.
 ▪ Activation of vit D
➢ It takes place in the following manner - Ergosterol differs from 7-
dehydrocholesterol in having an extra double bond between C22–23 and a methyl
group at C24.
➢ In man vit D2 and D3 are equally active and calcitriol (active form of D3) is more
important physiologically; 25-OH D3 is released in blood from the liver and binds
loosely to a specific vit D binding globulin.
➢ The final 1α-hydroxylation in kidney is rate limiting and is controlled by many
factors. This step is activated or induced by calcium/vit D deficiency as well as by
PTH, estrogens and prolactin, while calcitriol inhibits it in a feedback manner.
❑ Thus, vit D should be considered a hormone because:
➢ It is synthesized in the body (skin); under ideal conditions it is not required in the diet.
➢ It is transported by blood, activated and then acts on specific receptors in the target
tissues.
➢ Feedback regulation of vit D activation occurs by plasma Ca2+ level and by the active
form of vit D itself.
❖ Actions
1. Calcitriol enhances absorption of calcium and phosphate from intestine. This is
brought about by increasing the synthesis of calcium channels and a carrier protein for
Ca2+ called ‘calcium binding protein’ (Ca BP) or Calbindin.

▪ The action of calcitriol is analogous to that of steroid hormones. It binds to a

cytoplasmic vitamin D receptor (VDR) → translocate to the nucleus → increase
synthesis of specific mRNA → regulation of protein synthesis.
▪ Another line of evidence suggests that activation of VDR promotes endocytotic
capture of calcium, its transport across the duodenal mucosal cell and finally its
active extrusion through the serosal membrane.
▪ At least part of vit D action is quick (within minutes) and, therefore, appears to
be exerted by mechanisms not involving gene regulation.
2. Calcitriol enhances resorption of calcium and phosphate from bone by promoting
recruitment and differentiation of osteoclast precursors in the bone remodeling units,
but mature osteoclasts lack VDR.
▪ Like PTH, calcitriol induces RANKL in osteoblasts which may then activate the
osteoclasts.
▪ Osteoblastic cells express VDR and respond to calcitriol by laying down osteoid,
but it mainly appears to help bone mineralization indirectly by maintaining normal
plasma calcium and phosphate concentration.
▪ Its action is independent of but facilitated by PTH.
3. Calcitriol enhances tubular reabsorption of calcium and phosphate in the kidney,
but the action is less marked than that of PTH. However, in hypervitaminosis D,
influence of hypercalcaemia overrides the direct action and more calcium is
excreted in urine.
4. Other actions: Actions of calcitriol on immunological cells, lymphokine
production, proliferation and differentiation of epidermal and certain malignant
cells, neuronal and skeletal muscle function have also been demonstrated.
 ❑ Vit D deficiency
▪ Plasma calcium and phosphate tend to fall due to inadequate intestinal absorption.
As a consequence, PTH is secreted → calcium is mobilized from bone in order to
restore plasma Ca2+.

▪ The bone fails to mineralize normally in the newly laid area, becomes soft →
rickets in children and osteomalacia in adults.
▪ However, in contrast to osteoporosis, the organic matrix (osteoid) is normal in
these conditions.
 ❑ Hypervitaminosis D
▪ It may occur due to chronic ingestion of large doses (~50,000 IU/day) or due to
increased sensitivity of tissues to vit D.
▪ Manifestations are due to elevated plasma calcium and its ectopic deposition. These
are: hypercalcaemia, weakness, fatigue, vomiting, diarrhoea, sluggishness, polyuria,
albuminuria, ectopic Ca2+ deposition (in soft tissues, blood vessels, parenchymal
organs), renal stones or nephrocalcinosis, hypertension, growth retardation in children.
Even coma has been reported.
▪ Treatment: consists of withholding the vitamin, low calcium diet, plenty of fluids and
corticosteroids. Recovery may be incomplete in many cases.
 ❑ Pharmacokinetics
▪ Vit D is well absorbed from the intestines in the presence of bile salts, mainly through
lymphatics.

▪ Absorption of the D3 form is somewhat better than that of D2.

▪ Malabsorption and steatorrhoea interfere with its absorption.
▪ In the circulation, it is bound to a specific α globulin and is stored in the body, mostly
in adipose tissues, for many months.

▪ It is hydroxylated in the liver to active and inactive metabolites.

▪ The t½ of different forms varies from 1–18 days: 25-OHD3, having the longest t½ ,
constitutes the primary circulating form.

▪ Calcitriol is cleared rapidly. Metabolites of vit D are excreted mainly in bile.

1 μg of cholecalciferol = 40 IU of vit D. The daily requirement varies, depending on exposure
to sunlight. It is estimated that if no vit D3 is synthesized in the body, a dietary allowance of
400 IU/day will prevent deficiency symptoms. However, higher amounts (upto 1000 IU/day)
are also recommended.

❑ Formulations of Vit D:
1. Calciferol (Ergocalciferol, vit D2)
2. Cholecalciferol (vit D3)
3. Calcitriol
4. Alfacalcidol: It is 1 α-OHD3—a prodrug that is rapidly hydroxylated in the liver to 1,25
(OH)2 D3 or calcitriol.
5. Dihydrotachysterol A synthetic analogue of vit D2

❑ Use: Prophylaxis of nutritional vit D deficiency, Metabolic rickets, Senile or

postmenopausal osteoporosis, Hypoparathyroidism, Fanconi syndrome.
❑ Interactions: Cholestyramine and chronic use of liquid paraffine can reduce vit D
absorption. Phenytoin and phenobarbitone reduce the responsiveness of target tissues to
calcitriol; their prolonged use (for epilepsy) can cause rickets/ osteomalacia. It was
believed earlier that these drugs enhance degradation of vit D. However, now it has been
shown that plasma level of calcitriol is normal, but its effect on intestine and bone is
diminished.