Hypothalamic hormones

Pituitary hormones
Hormones (from Greek hormao – to set in motion)
are chemical substances of intense biological activity.
They are secreted by specific endocrine glands and
are transported in the bloodstream to act on their
distant target organs. Hormones regulate body
functions and maintain homeostasis in the face of
markedly variable external and internal environment.
The natural hormones and their synthetic analogues
(which in many cases may be more effective), are
used as drugs for substitution therapy as well as
for pharmacotherapy.
In addition, hormone antagonists and hormone syn-
thesis release inhibitors have significant therapeutic
importance too.
 Hypothalamus and anterior pituitary

Acidophils:

Somatotropes – GH
Latotropes – Prolactin

Basophils:

Gonadotropes – FSH & LH

Thyrotropes – TSH
Corticotrope – ACTH
 Classification of hormones
1. Hypothalamic hormones
Thyrotropin releasing hormone (TRH) – peptide
Corticotropin releasing hormone (CRH) – peptide
Gonadotropin releasing hormone
(GnRH – Gonadorelin): LH-RH/FSH-RH – peptide
Growth hormone releasing hormone: (GHRH) – peptide
Prolactin releasing hormone (PRH): Unknown
Prolactin release inhibitory hormone (PRIH):
Dopamine (DA)
Growth hormone release inhibitory hormone:
(GHRIH): Somatostatin – peptide
2. Pituitary hormones
a) Anterior Pituitary hormones (-tropins/-trophins)
Growth hormone (GH) − Somatotropin
Prolactin
Adrenocorticotropic hormone (ACTH, Corticotropin)
Thyroid stimulating hormones (TSH, Thyrotropin)
Gonadotropins
- Follicle stimulating hormone (FSH)
- Luteinizing hormone (LH)
b) Posterior Pituitary hormones
Oxytocin
Antidiuretic hormone (ADH, Vasopressin)
2. Thyroid hormones
Thyroxine (T4), Triiodothyronine (T3)
Calcitonin
3. Parathyroid hormone: Parathormone (PTH)
4. Hormones of endocrine pancreas: Insulin, Amylin, Glucagon
5. Adrenal hormones
a) Hormones of Adrenal cortex (Steroids)
- Glucocorticoids (GCS): Hydrocortisone, Cortisone
- Mineralocorticoids: Aldosterone
- Sex steroids: Dehydroepiandrosterone
b) Hormone of Adrenal medulla: Adrenaline
6. Hormone of Gonads
a) Androgens: Testosterone
b) Estrogens: Estradiol
c) Progestins: Progesterone
7. Placental hormones
Estrogens, Progesterone,
Chorionic gonadotropin
8. Hormone of Adipocytes:
Leptin – acts on receptors in the
hypothalamus of the brain where
it inhibits appetite.
9. Ghrelin is a peptide hormone
that is produced mainly by
the fundus of the stomach and
epsilon cells of the pancreas.
It stimulates hunger. Ghrelin levels increase
before meals and decrease after meals.
Mechanisms of hormone action
1. Action on the cell membrane receptors
a) Through alteration of intracellular cAMP concentration

ACTH, Adrenaline, Calcitonin, Glucagon, FSH, LH, PTH,

some hypothalamic RH, TSH, Vasopressin (via V2-rec.)

Alteration of protein kinase A

Regulation of cell function: Ca2+ acting

as a third messenger in some situations
b) Through the IP3 and DAG generation

Oxytocin and Vasopressin (via V1-rec.)

Release of intracelullar Ca2+

and protein kinase C activation
c) Direct transmembrane activation
of tyrosine kinase

GH, Insulin, Prolactin

Phosphorylation cascade

Regulation of various enzymes

 2. Action on the intracellular
(steroid or thyroid) receptors
a) At cytoplasmic receptors:
• Steroid hormones, Calcitriol
b) Directly at nuclear receptors:
• Thyroid hormones (T3, T4)
T3 or T4 penetrates the nucleus

Combines with their receptors

Alters DNA-RNA mediated

protein synthesis
Hypothalamic and
Pituitary Hormones
Hypothalamic hormones
regulate anterior pituitary
trophic hormones that, in
turn, determine target
gland secretion.
There is a
peripheral hormones
feedback which regulates
hypothalamic and
pituitary hormones.
Feedback
regulation
of
endocrine
axes
Neurons that regulate the
anterior lobe cluster in the
mediobasal hypothalamus,
including the paraventricular
(PVN) and the arcuate
(ARC) nuclei secrete
hypothalamic releasing
hormones, which reach the
anterior pituitary via the
hypothalamic-adenohypo-
physeal portal system and
stimulate distinct populations
of pituitary cells. These cells,
in turn, secrete the trophic
hormones, which regulate
endocrine organs and other
tissues.
 Hypothalamic Hormones
HYPOTHALAMIC HORMONE
Thyrotropin-releasing hormone (TRH)
Corticotropin-releasing hormone (CRH)
Gonadrotropin-releasing hormone (GnRH)
Growth hormone-releasing hormone (GHRH)
Growth hormone-inhibiting hormone (GHIH)
Prolactin releasing factor (PRF)
Prolactin-inhibiting hormone (PIH)
EFFECTS ON THE ANTERIOR PITUITARY
Stimulates release of TSH (thyrotropin) and
Prolactin
Stimulates release of ACTH (corticotropin)
Stimulates release of FSH and LH
(gonadotropins)
Stimulates release of growth hormone
Inhibits release of growth hormone
Stimulates release of prolactin
Inhibits release of prolactin
Anterior Pituitary Hormones
Corticotropin releasing hormone (CRH) –
corticoliberin, is a hypothalamic polypeptide for
diagnostic use. It increases ACTH secretion in
Cushing's disease.

Natural corticotropin (ACTH) is a 39-amino-acid

polypeptide secreted by the anterior pituitary gland,
obtained from animal pituitaries. The physiological
activity resides in the first 24-amino acids (which
are common to many species) and most of the immu-
nological activity resides in the remaining 15 amino
acids. The pituitary output of corticotropin responds
rapidly to physiological requirements by the
familiar negative-feedback homeostatic mechanism.
 Adrenocorticotropic hormone
(ACTH , corticotropin)
• Anterior pituitary hormone
• 39 single chain amino acid
peptide and derived from
pro-opiomelanocortin
(POMC)
• Regulated by CRH from
hypothalumus and by
feedback levels of blood
concentrations
 ACTH
MOA: It promotes steroidogenesis in adrenal cortex – by
stimulating cAMP in adrenal cortical cells through specific G-
protein coupled receptors to make increase availability of
cholesterol for pregnelone synthesis – rate limiting step
• Influences production of steroids in two ways:
– Acute phase: occurs within seconds and reflects an increased
availability of cholesterol substrate for production of steroids
– Chronic phase: occurs over days and is because of increased
transcription of steroidogenic enzymes
• Also exerts trophic influence on adrenal cortex (cAMP): high
doses cause hypertrophy and hyperplasia – absence of
ACTH results in adrenal atrophy
Synthetic corticotropin tetracosactide has the advantage
that contains shorter amino acid chain (devoid of amino acids
25-39) and so are less likely to cause serious allergy.
In addition, they are not contaminated by animal
proteins which are potent allergens. It consists of the biologically
active first 24 amino acids of natural corticotropin (from man or
animals) and so it has similar properties, e.g. t1/2 10 min.
Corticotropin stimulates the synthesis of corticosteroids (of
which the most important is hydrocortisone) and to a lesser
extent of androgens, by the cells of the adrenal cortex. It has
only a minor effect on aldosterone production. The release of
natural corticotropin by the pituitary gland is controlled by the
hypothalamus via corticotropin
releasing hormone (corticoliberin),
production of which is influenced
by stress as well as by the level
of circulating hydrocortisone.
High plasma concentration of any steroid with glucocorticoid
effect prevents release of corticotropin releasing hormone as
well as of ACTH, the lack of which in turn results in
adrenocortical hypofunction.
This is the reason why catastrophe may follow the sudden
withdrawal of steroid therapy in the chronically treated patient
who has an atrophied cortex.
The effects of corticotropin are those of the steroids
(hydrocortisone, androgens) liberated by its action on the
adrenal cortex. Prolonged heavy dosage causes Cushing's
syndrome.
Tetracosactide (Synacthen®) is used as a test of the capacity
of the adrenal cortex to produce cortisol (hydrocortisone).
 Cushing syndrome
• It is a condition when there is high level of cortisol.
Causes include – iatrogenic, and spontaneous –
ACTH secreting pituitary adenoma, tumour in adrenl
cortex and ectopic origin (lung cancer secreting
ACTH)
• CRH is used for diagnostic purpose to differentiate
between Cushing syndrome of ectopic origin and
pituitary origin – if CRH injection do not increase
cortisol level then the syndrome is of ectopic origin
(ACTH secreting lung cancers do not respond to CRH
injection)
Thyrotropin releasing hormone (TRH) – protirelin, is a
tripeptide formed in the hypothalamus and controlled by free
plasma T4 and T3 concentration. It has been synthesized
and can be used in diagnosis to test the capacity of the pituitary
to release thyroid stimulating hormone, e.g. to determine
whether hypothyroidism is due to primary thyroid gland failure or
is secondary to pituitary disease or to a hypothalamic lesion. TRH
is also a potent prolactin-releasing factor.

Thyroid stimulating hormone (TSH) thyrotropin, a glycoprotein

of the anterior pituitary, controls the synthesis and release of
thyroid hormone from the gland, and also the uptake of
iodide. There is a negative feedback of thyroid hormones on both
the hypothalamic secretion of TRH and pituitary secretion of TSH.
TSH has no therapeutic uses now
Sermorelin is an analogue of the hypothalamic
growth hormone releasing hormone (somatorelin).
It is used in a diagnostic test for growth hormone
secretion from the pituitary.
GHRH: Diagnostic use
To differentiate dwarfism – pituitary (defect of
somatrophs) or hypothalamic (no production of
GHRH) origin Sermorelin (a synthetic material
behaves like GHRH) is injected in dwarfism
Subsequently hGH level is estimated and If hGH level
rises fault lies in hypothalamus.
Two hypothalamic factors,
growth hormone-releasing
hormone (GHRH) and
somatostatin (SST),
act on the somatotropes in
the anterior pituitary to
regulate GH secretion. SST
also inhibits GHRH
release.
Ghrelin is a potent
stimulator
of GH release.
Growth hormone (GH), one of the peptide
hormones produced by the anterior pituitary, 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 body mass. Coordinated action of several
hormones GH promotes growth of all organs by
inducing hyperplasia – proportionate increase in the
size and mass of all parts – except brain and eye.
• Retention of Nitrogen and other tissue constituents – more
protoplasm formation
• Positive Nitrogen balance – due to increase uptake of amino
acids
• Promotes utilization of fats – spares glucose (muscles)
Growth hormone (GH)
Its effects are primarily mediated indirectly via
insulin-like growth factor 1 (IGF-1) and IGF-2.
Direct effect: Lipolysis in adipose tissue, glycogenolysis
in liver and decreased glucose utilization in muscles
and also direct effect on bone growth – stimulating
differentiation of chondrocytes.
IGF-I: produced by the liver and other tissues
(Receptors are like Insulin).
IGF-I also stimulates proliferation of chondrocytes
(cartilage cells), resulting in bone growth.
Individuals with congenital or acquired deficiency in GH during
childhood or adolescence fail to reach their predicted adult
height and have disproportionately increased body fat and
decreased muscle mass. Adults with GH deficiency also have
Disproportionately small body mass.
 Growth Hormone
• Most of the GH are
prohormones
• In liver it is converted to
Somatomedins, also called
Insulin like growth factor
(IGF-1, also IGF-2) – growth
promoting, nitrogen
retaining and certain other
metabolic events
• IGF-1 is structurally and
functionally analogous to
insulin receptors
 Physiological actions
• Protein metabolism: In general, growth hormone stimulates
protein anabolism in many tissues. This effect reflects increased
amino acid uptake, increased protein synthesis and decreased
oxidation of proteins
• Fat metabolism: Growth hormone enhances the utilization of fat
by stimulating triglyceride breakdown and oxidation in adipocytes
• Carbohydrate metabolism: Growth hormone is one of a battery of
hormones that serves to maintain blood glucose within a normal
range
• Growth hormone is often said to have anti-insulin activity, because
it suppresses the abilities of insulin to stimulate uptake of glucose
in peripheral tissues and enhance glucose synthesis in the liver
• Somewhat paradoxically, administration of growth hormone
stimulates insulin secretion, leading to hyperinsulinemia
 Regulation of secretion
• Hypothalamus – secretes GHRH and
also inhibitory GHIH (Somatostatin –
also in pancreas) – controls secretion
(increasing or decreasing cAMP) – all
are GPCR
• GH secretion – high in children,
reaches maximum level in adolescent
and decreases in age related manner –
Occurs in irregular pulse, falls between
these pulses
• Amplitude of secretory pulses is
maximum at night, shortly after onset
of deep sleep
• Once the pituitary receives the positive stimulating
signal it then secretes GH which in turn stimulates the
liver to produce IGF-1 (Insulin-like growth factor 1).
• IGF-1 is also a more stable compound unlike true GH
which has up to 5 spurts a day – the largest being just
before sleep.
• If we were to measure GH directly it might show as
too low or too high just because of the timing.
Measuring IGF-1 circumvents this problem because of
its more constant blood levels. Interestingly, both have
distinct biochemical properties.
• Once the IGF-1 levels are high enough, a feedback
message is sent back to the pituitary and the
hypothalamus to modulate further GH secretion. This is
accomplished by secreting more Somatostatin which
then slows down GH production.
 GH-Modulators of secretion
• Dopamine, 5-HT, α2-
receptor agonists increase
GH secretion
• β-receptor antagonists,
Corticosteroids, free fatty
acid, IGF-1 and GH inhibit
release
• Hypoglycemia, exercise,
stress, emotional
excitement, ingestion of
protein rich meals
increase GH
 Mechanism of action – GH

• Acts on GH receptor – a widely distributed cell surface receptor,

belongs to cytokine receptor super family – similar to prolactin,
erythropoietin receptor
• Extracellular domain binds to GH – Intracellular domain mediates
signal transduction
• Single GH molecule binds to two identical receptor molecule
• GH- GHR-ligand occupied receptor dimer lacks inherent tyrosine
kinase activity, provides docking site for two molecules of Janus
Kinase 2(JAK-2) a cytoplasmic tyrosine of Janus Kinase family
• Juxtaposition of two JAK-2 molecules leads to trans-phosphorylation
and autoactivation of JAK-2 with phosphorylation of cytoplasmic
proteins that mediate downstream signaling events
GH is a 191-amino-acid peptide. Two types of
recombinant human growth hormone (rhGH)
are approved for clinical use: Somatropin (identical
with the native form of human GH) and Somatrem
(with an extra methionine residue at the amino
terminal end).
The drugs are used in children with growth hormone
deficiency, while the bone epiphyses are still open,
to prevent dwarfism (underdevelopment of the body)
and provide normal growth. Treatment improves
exercise performance and increases lean body
mass. It may improve overall quality of life.
 Uses of GH
Pituitary dwarfism
• Somatropin is available for clinical use (rhGH) and obtained by recombinant DNA
technique
• Dose: 0.03 to 0.07 mg/kg IM or SC 3 times a week Start at the age of 3 and continued till
20-25 years
• Should not administer to persons whose epiphyses are closed
• IGF-1 appears in plasma following injection and remains detectable till 48 Hrs.
Other:
• Constitutional short stature in children
• Adult GH deficit – 150-300 mcg/day SC – mortality and morbidity reduction
• Catabolic states – burns, renal failure, bed ridden patients and osteoporosis etc.
• Renal failure in children
• AIDS – wasting (100 μgm/ kg)
• Abuse: Athlete abuse (???)
Possibilities of abuse have also arisen, e.g. creation
of “super” sports people. Less dubious, but not yet
a licensed indication of GH, is the potential for
accelerated wound healing reported in children
with large cutaneous burns. GH is a popular compo-
nent of anti-aging programs. Serum levels of GH
normally decline with aging. GH is one of the drugs
banned by the Olympic Committee.
In acromegaly, excess GH causes diabetes, hyperten-
sion, and arthritis. Surgery is the treatment of choice.
GH secretion is reduced by octreotide and other
somatostatin analogues and to a lesser degree
by bromocriptine.
 Pharmacologic and Physiologic
Agents That Affect hGH Production
 Adverse Effects of GH Therapy
• In first 8 weeks – intracranial hypertension,
papilledema, visual changes, headache, nausea
and/or vomiting – Fundoscopic examination at
initiation of therapy and at periodic intervals
• Leukemia
• Increase type 2 diabetes mellitus
• In adults side effects on therapy initiation –
Peripheral edema, Carpal tunnel syndrome,
Arthralgia, Myalgia
• Symptoms decrease with decrease in dose
Somatostatin (growth hormone release inhibiting hormone)
occurs in other parts of the brain as well as in the hypothalamus,
and also in pancreas, stomach, and intestine. It inhibits
secretion of GH, TSH and prolactin, insulin, glucagon,
all GIT secretions: gastrin, CCK (cholecystokinine), secretin,
motilin, VIP (vasoactive Intestinal peptide),
GIP (gastric inhibitory peptide), 5-HT, etc.
All GIT secretions are inhibited including HCl – Diarrhoea, stetorrhoea, hypochlorhydria,
nausea, dyspepsia etc. occurs. Constrict hepatic, splanchnic and renal blood vessels.
Uses:
• Acromegaly: limited use due to short half-life (2-3 min)
• GI haemorrhages (250 mcg slow IV, 3 mg infusion for 12 Hrs)
• Pancreatic, biliary and intestinal fistulae – antisecretory effects
• APUD tumours producing excess HCl
• Diabetic ketoacidosis (inhibits glucagon and GH secretion)
Drawbacks: Short duration (2-3 min) and rebound GH secretion
Radiolabelled somatostatin is used to localize metastases
from neuroendocrine tumours which often bear
somatostatin receptors.
•Octreotide is a synthetic analogue of somatostatin
having a longer action (t1/2 1.5 h).
•Lanreotide is much longer acting, and is administered
only twice a month. Main indications:
acromegaly/gigantism,
carcinoid (serotonin secreting) tumours,
and other rare tumours of the GIT.
 Gigantism
• Giantism is the result
of excessive growth
hormone secretion that
begins in young
children or
adolescents.
• It is a very rare
disorder, usually
resulting from a tumor
of somatotropes
A 22-year-old man with gigantism due to excess growth hormone
is shown to the left of his identical twin. The increased height
and prognathism (A) and enlarged hand (B) and foot (C) of the
affected twin are apparent. Their clinical features began to
diverge at the age of approximately 13 years.
 Acromegaly
• Results from excessive secretion of growth hormone in adult. The onset
of this disorder is typically insidious.
• Clinically, an overgrowth of bone and connective tissue leads to a change
in appearance that might be described as having "coarse features".
• The excessive growth hormone and Insulin-like growth factor 1 (IGF-1)
also lead to metabolic derangements, including glucose intolerance
• Progresses slowly, delayed diagnosis, decreased life expectancy
• Increase death rate due to CVS disorders, upper airway obstruction,
gastrointestinal malignancies
• Increased circulating GH or IGF-1
• Overall clinically: Arthropathy, Carpal tunnel syndrome, Generalized
visceromegally, Hypertension, Glucose intolerance, Headache, lethargy,
excess perspiration, sleep apnoea
 Octreotide
• Synthetic analogue of Somatostatin and 40 times more potent
• Longer duration of action (t1/2 – 90 min)
• But, weak inhibitor of insulin
• Octreotide binds preferentially to SSTR-2 and SSTR-5 receptors on
GH secreting tumors
• In acromegally – Injection octreotide (100μg) s.c thrice daily
• Monitor serum GH and IGF-1 levels to assess effectiveness
• Goal – decrease GH levels < 2ng/ml & IGF-1 levels within normal
range for age and sex
• Octreotide decreases tumor size
• Octreotide inhibits TSH secretion and is treatment of choice in
thyrotrope adenoma that over secrete TSH and not good candidate
for surgery
 Octreotide
• Other Uses:
– Secretory diarrhoeas associated with carcinoid, AIDS,
cancer chemotherapy or diabetes (100 mcg SC twice
daily)
– Oesophageal bleeding (100 mcg followed by 25-50
mcg/hr
– Octreotide labeled with indium or technetium used for
diagnostic imaging of neuroendocrine tumors such as
pituitary adenoma and carcinoids
• Adverse effects: abdominl pain, steatorrhoea,
diarrhoea and gall stones
Lanreotide and Pegyisomant (acromegaly)
Pituitary adenoma
•Lacotrophic – secrete
prolactin (galactorrhea,
infertility, impotence)
•Somatotrophic – secrete GH
(acromegaly)
•Corticotrophic – secrete
ACTH (Cushing’s disease)
•Gonadotrophic – secrete
LH and FSH (no symptoms)
•Thyrotrophic – secrete TSH
(occasionally hyperthyroidism)
Transsphenoidal resection
of pituitary tumour mass
via the endonasal approach
Gonadorelin (gonadotropin releasing hormone –
GnRH) releases luteinizing hormone (LH) and
follicle-stimulating hormone (FSH). It has
use in the assessment of pituitary function. Intermittent
pulsatile administration evokes secretion of
gonadotropins (LH and FSH) and is used to treat
infertility. But continuous use evokes tachyphylaxis
due to down-regulation of its receptors, i.e.
gonadotropin release and therefore gonadal
secretions are reduced.
Longer-acting analogues – agonists of GnRH
(buserelin, goserelin, nafarelin, deslorelin, and leuprorelin)
are used to suppress androgen secretion
in prostatic carcinoma.
Gonadotropin Releasing Hormone (GnRH)
• Synthetic GnRH – 100 mg IV – causes release of
FSH and LH
• Short plasma half-life: 4-8 minutes (rapid enzymatic
degradation)
• Used for testing pituitary gonadal axis in male and female
hypogonadism
• Pulsatile exposure to GnRH releases FSH/LH
– Desensitization of pituitary gonadotropes – loss of Gn release – not
used in treatment of hypogonadism
Other uses may include endometriosis, precocious puberty, and
contraception. All these drugs need to be administered by a
parenteral route, by i.m. injection or intranasally.
 Superactive/long-acting GnRH agonists
GnRH analogs used clinically are Leuprolide, goserelin,
histrelin, triptorelin and nafarelin – Superactive GnRH
15-150 times more potent than natural GnRH – longer
acting (2-6 Hours) – high affinity to receptors and lack of
enzymatic hydrolysis
MOA: Physiological release is pulsatile – but agonists act
continuously down regulation of GnRH receptors after 1-2
weeks (desensitization)
– Inhibition of FSH and LH – suppression of gonadal function –
suppression of ovulation and spermatogenesis
– Testosterone and oestrogen level falls to castration level
– Pharmacological Oophorectomy/orchiectomy
 Nafarelin
• Long acting GnRH agonist and 150 times more potent than GnRH –
Plasma half-life 2-3 hrs
• Peak down regulation of pituitary GnRH receptors – 1 month
• Uses:
– Assisted reproduction: 400 mcg intranasal followed by 200
• when Menstrual bleeding occurs For suppression of endogenous LH
surge – matured oocyte can be harvested
– Uterine fibroid: symptomatic relief 200 mcg
– Endometriosis: 200 mcg for 6 months
– Precocious puberty: 800 mcg nasal spray – arrest of breast and genital development

Goserelin: Long acting – used as depot – Gn suppression, Prostate

cancer, endometriosis etc. – 1-3 weeks earlier before ovulation
Triptorelin – long acting (once a month): For regular release – daily
• SC injection (female infertility). For long-term use – IM injection monthly
Leuprolide: Long acting IM/SC
 GnRH antagonists
Inhibits Gn without initial stimulation
Older ones – Reactions due to histamine release
Newer – Ganirelix, cetrorelix
Used in in vitro fertilization for suppression
of LH surge
Advantages:
• Quick – competitive antagonist
• Lower risk of ovarian hyperstimulation
• Complete suppression
Follicle stimulating hormone (FSH) stimulates
the development of ova and of spermatozoa.
It is prepared from the urine of postmenopausal
women.
Urofollitropin (Metrodin®) contains FSH.
Menotropins (Pergonal®) contains FSH and LH.
These drugs are used in female and male
hypopituitary infertility.
Chorionic gonadotropin (human chorionic
gonadotropin – hCG) is secreted by the
placenta and is obtained from the urine of
pregnant women.
The predominant action of hCG is that of LH.
It induces progesterone production by the corpus
luteum and, in the male – gonadal testosterone
production. It is used in hypopituitary anovular and
other infertility in both sexes. It is also used
for cryptorchidism in prepubertal boys (6 years of
age; if it fails to induce testicular descent, there is
time for surgery before puberty to provide maximal
possibility of a full functional testis). It may also
precipitate puberty in men where this is delayed.
 Gonadotropins – FSH and LH
Stimulates the gonads and promote gametogenesis and secretion of
gonadal hormones
FSH: induces follicular growth, development of ovum and secretion of
Oestrogen. In male – spermatogenesis and trophic to seminiferous tubules.
Atrophy of ovary and testes in absence
LH: Ripening of graafian follicles, triggers ovulation, rupture of follicles and
sustaining of corpus luteum. In male stimulates testosterone secretion
Receptors: GPCR – cAMP – gametogenesis – cholesterol to
pregnelone
Regulation: GnRH (FSH/LH-RH) – single releasing factor for both
• Secretes in pulses – high frequency, low amplitude and low frequency,
high amplitude
• Oestrogen and progesteron are feedback inhibitors
• Also Testosterone – weak inhibitor of FSH and LH secretion
• Inhibin – inhibits FSH and Dopamine inhibits LH
 Therapeutic Source of gonadotropins
Preparations
• Urine of menopausal women (hMG) – Menotropin (FSH +
LH)
• Urofollitropin or pure menotropins (pure FSH)
• Placenta: human chorionic gonadotropin (hCG) – only
LH activity – urine of pregnant women
• Recombinant: rFSH and rLH
Adverse effects: Ovarian bleeding, polycystic ovary, pain
in lower abdomen – due to hyper stimulation
• precocious puberty
• allergic reactions (skin test)
• oedema, headache, mood changes
 FSH and LH
Therapeutic Uses:
1. Amenorrhoea and infertility in low Gns patients (decreased secretion
from pituitary) to induce ovulation: Clomiphene citrate failed cases.
Menotropins (75 IU FSH +75 IU LH) IM daily for 10 days and followed by
10,000 units of hCG – OVULATION
• Controlled ovarian hyperstimulation – suppression of endogenous
FSH/LH – by superactive GnRH/GnRH antagonist
2. Hypogonadism in males: oligospermia, male sterility.
• Sexual Maturation by Androgens – then Start with 1000-4000 IU hCG IM
2-3 times a week – to stimulate testosterone secretion
• FSH+LH (75 IU) after 3-4 months – spermatogenesis
3. Cryptorchism: undescended testes. Start between 1-7 years of age with
1000-2000 IU 2-3 times a week. Stop if no result in 2-6 weeks.
4. In vitro fertilization: FSH and LH is used to induce maturation of several
ova and to precisely time the ovulation such that harvesting can be done.
Prolactin is secreted by the lactotroph cells of the
anterior pituitary gland. Its control is by tonic
hypothalamic inhibition through prolactin inhibitory
factor (PIF), probably dopamine, opposed by a
prolactin releasing factor (PRF) in both women and
men and, despite its name, it influences numerous
biological functions. Prolactin secretion is
controlled by an inhibitory dopaminergic path. Hyper-
prolactinaemia may be caused by drugs (with anti-
dopaminergic actions, e.g. metoclopramide), hypo-
thyroidism, or prolactin secreting adenomas. Medical
treatment is with bromocriptine, cabergoline, or
quinagolide at bedtime.
 Prolactin – Review
Prolactin (PRL) causes synthesis of milk proteins and lactose by the breast alveolar
epithelium – proliferation of ductal and acinar cells
• After parturition – PRL induces milk secretion: inhibitory influence of high
Oestrogen and Progesterone withdrawn
• Oxytocin causes milk ejection
Secretion: Very low in childhood, increases in girls at puberty, high in adult females,
progressive increase in pregnancy and peak at term
PRL suppresses – hypothalamo-pituitary-gonadal axis: Inhibits
GnRH release – lactational ammenorrhoea, infertility etc. and loss of libido,
impotence in male
Regulation of secretion: Under constant inhibition by PRIH (dopamine) via D2
receptors
• DA agonists: DA, Bromocriptine, cabergoline
• DA antagonists: chlorpromazine, haloperidol, Metoclopramide (TRH & VIP –
releases PRL)
No clinical use
Prolactin secretion
 Prolactin inhibitors – Bromocriptine
Ergot derivative: 2-bromo-α-ergocryptine
– Potent dopamine antagonist and also has weak alpha-adrenergic
blocking property
Pharmacological actions:
– Decrease in prolactin release
– Increases GH in normal persons but decreases in presence of
pituitary tumours
– Antiparkinsonian effects – like levodopa
– Hypotension
– Decrease in GI motility
Pharmacokinetics:
– Partially absorbed, reaches peak plasma concentration within 1-2
Hrs, crosses BBB, metabolites are excreted in Bile, t1/2 - 3-6 Hrs
 Bromocriptine
Mechanism of action:
– Acts as agonist in D2 receptors in brain and outside, e.g. CVS
– Partial agonist of D1 receptors
Therapeutic uses:
1. Hyperprolactinemia: lower dose of 2.5 to 10 mg/day, response
occurs within weeks
• Should be stopped during pregnancy
• Lifelong therapy is required
2. Acromegaly: inoperable cases of pituitary tumors (5 – 20 mg/day)
3. Parkinsonism
4. Suppression of breast engorgement: neonatal death ?
Side effects: similar to levodopa – nausea, vomiting, constipation
and postural hypotension
– Lately, behavioral alterations, hallucinations, psychosis, mental confusions etc.
 Cabergoline
• New D2 agonist
• More potent and more D2 selective
• Very long half life – 60 days or more
• Twice weekly dose
• Better patient compliance and tolerance
• Preferred for hyperprolactinemia and
acromegaly
In hypopituitarism there is a partial or complete
deficiency of hormones secreted by the anterior
lobe of the pituitary. The posterior lobe hormones
may also be deficient in a few cases, e.g.
when a tumour has destroyed the pituitary.
Patients suffering from hypopituitarism
may present in coma, in which case
treatment is for a severe acute
adrenal insufficiency. Maintenance
therapy is required, using
hydrocortisone, thyroxine,
estradiol, and progesterone
(in women) and testosterone (in
men), or GH analogues (somatropin
or somatrem).
Hypothalamic neurons
in the supraoptic (SON)
and paraventricular (PVN)
nuclei synthesize arginine
vasopressin (AVP) or
oxytocin (OXY).
Most of their axons project
directly to the posterior
pituitary, from which AVP
and OXY are secreted into
the systemic circulation to
regulate their target tissues.
Vasopressin is a nonapeptide (t1/2 20 min) with
two separate G-protein coupled target receptors
responsible for its two roles. The V1 receptor on
vascular smooth muscle is coupled to calcium
entry. This receptor is not usually stimulated by
physiological concentrations of the hormone.
The V2 receptor is coupled to adenylyl cyclase, and
regulates opening of the water channel, aquaporin,
in cells of the renal collecting duct.
Secretion of the antidiuretic hormone is stimulated
by any increase in the osmotic pressure of the blood
supplying the hypothalamus and by a variety of
drugs, notably nicotine. Secretion is inhibited by a fall
in blood osmotic pressure and by alcohol.
In large nonphysiological doses (pharmacotherapy)
vasopressin causes contraction of all smooth
muscle, raising the blood pressure and causing
intestinal colic. The smooth-muscle stimulant effect
provides an example of tachyphylaxis (frequently
repeated doses give progressively less effect). It is
not only inefficient when used to raise the blood
pressure, but is also dangerous, since it causes
constriction of the coronary arteries and sudden
death has occurred following its use.
For replacement therapy of pituitary diabetes
insipidus the longer acting analogue desmopressin
is used.
Desmopressin (des-amino-D-arginine vasopressin)
(DDAVP) has two major advantages: the vasocon-
strictor effect has been reduced to near insignificance
and the duration of action with nasal instillation,
spray or s.c. injection, is 8-20 h (t1/2 75 min) so that,
using it once to twice daily, patients are not incon-
venienced by frequent recurrence of polyuria during
their waking hours and can also expect to spend the
night continuously in bed. The adult dose for
intranasal administration is 10-20 micrograms daily.
The dose for children is about half that for adults.
The bioavailability of intranasal DDAVP is 10%. It is
also the only peptide for which an oral formulation
is available, with a bioavailability of only 1%.
The main complication of DDAVP is hyponatraemia
which can be prevented by allowing the patient
to develop some polyuria for a short period
during each week. The requirement for DDAVP
may decrease during intercurrent illness.
Terlipressin is an analogue of vasopressin
used in NA-resistant septic shock and
esophageal varices.

Oxytocin is a peptide hormone of the posterior

pituitary gland. It stimulates the contractions of the
pregnant uterus, which becomes much more sensitive
to it at term. Patients with posterior pituitary disease
(diabetes insipidus) can, however, go into labour normally.
Oxytocin is structurally close to vasopressin
and it is no surprise that it also has antidiuretic
activity. Serious water intoxication can
occur with prolonged i.v. infusions, especially
where accompanied by large volumes of fluid.
The association of oxytocin with neonatal
jaundice appears to be due to increased
erythrocyte fragility causing haemolysis.
Oxytocin has been supplanted by the
Methylergometrine (Methergin®), as the prime
treatment of postpartum haemorrhage.

Neonatal jaundice
Oxytocin is reflexly released from the pituitary
following suckling (also by manual stimulation of
the nipple) and causes almost immediate contraction
of the myoepithelium of the breast; it can be used to
enhance milk ejection (nasal spray).
Oxytocin is used i.v. in the induction of labour. It
produces, almost immediately, rhythmic contractions
with relaxation between, i.e. it mimics normal uterine
activity. The decision to use oxytocin requires special
skill. It has a t1/2 of 6 min and is given by i.v. infusion
using a pump; it must be closely supervised; the dose
is adjusted by the results; overdose can cause uterine
tetany and even rupture.
Atosiban is a modified form of oxytocin that inhibits
the action of this hormone on the uterus, leading to
a cessation of contractions. It is used i.v. as a
tocolytic to halt premature labor.
Barusiban is three to four times more potent
antagonist than atosiban with higher affinity and
selectivity for the oxytocin receptor.