A Power point presentation on "Anterior pituitary hormones" suitable for reading by UG MBBS students

1. Anterior Pituitary HormonesAnterior Pituitary Hormones
Dr. D. K. Brahma
Associate Professor
Department of Pharmacology
NEIGRIHMS, Shillong

2. Background - Endocrine System
• The ENDOCRINE SYSTEM includes all the glands (ductless glands)
of the body and the Hormones produced by those glands – maintain
Homeostasis
• Hormone (Greek. Hormaein - to excite/stir up): is a substance of
intense biological activity that is produced by specific cells in the
body and is transported through circulation to act on its target cells
• The endocrine system function is more generalized - In contrast,
ANS homeostasis links to specific target organs - (Circulation,
respiration, digestion, temperature regulation and some endocrine
secretion)
• Glands: Pituitary (anterior and posterior), Thyroid, Parathyroid,
Pancreas, Gonads
• Sites of action: (1) Cell membrane receptors - cAMP, IP3/DAG
generation, direct transmembrane activation of Tyrosine kinase; (2)
Cytoplasmic receptors; and (3) Nuclear receptors

3. Hypothalamic Hormones – releasing or
release inhibitory
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-inhibiting hormone (PIH)
Vasopressin and
Oxytocin
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
Inhibits release of prolactin

4. The Anterior pituitary hormones
Acidophils:
Somatotropes – GH
Latotropes – Prolactin
Basophils:
Gonadotropes- FSH & LH
Thyrotropes – TSH
Corticotrope - ACTH

5. Growth Hormone –
Physiological Role
Promotes Growth - 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)
• Indirectly: Exerted mainly through Somatomedins or Insulin-like
growth factors (IGF-1 and IGF-2) – growth promoting, nitrogen
retaining and certain other metabolic events
• 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

6. Growth Hormone
• Receptors are JAK-STAT protein kinase type
• Regulation: 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
• Secretory Stimuli: fasting, hypoglycaemia, stress, exercise etc.
• Inhibitory stimuli: Corticosteroids, free fatty acid etc.
• Human growth hormone is called hGH and are peptide hormones

7. Acromegaly, Dwarfism and Gigantism
• GH deficiency produces dwarfism
• Excess GH before epiphysis closes – Gigantism
• Excess GH after 18 years – Acromegaly

8. GH – Clinical Uses
• Natural GH not used due to rise of transmission of Creutzfeldt Jacob
disease – lethal infection (degenerative neurological disorder)
• Preparations: Somatropin is biosynthesis form made by
recombinant DNA technology - Somatrem is similar
1. 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
1. hGH: 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.

9. Other Uses of GH
• 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 (???)
• ADRS: Pain in injection site - lipodystrophy
– In first 8 weeks – intracranial hypertension, papilledema, visual
changes, headache, nausea and/or vomiting - Fundoscopic examination
at initiation of therapy and at periodic intervals
– Hypothyroidism, salt and water retention, myalgia, hand stiffness
– Increase type 2 diabetes mellitus

10. Somatostatin
• Somatostatin:14 amino acid peptide
• Produce mainly by hypothalamus and also in GIT
• Inhibits secretion of GH, TSH and prolactin by pituitary and insulin
and glucagon by pancreas and all GIT secretions (Gastrin, HCl)
• 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

11. Octreotide
• Synthetic analogue of Somatostatin and 40 times more
potent
• Longer duration of action (t1/2 – 90 min)
• In acromegaly preferred - Injection octreotide (100 μg)
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 binds preferentially to receptors on GH
secreting tumors - 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

12. Octreotide
• Other Uses:
– Secretory diarrhoeas associated with carcinoid, AIDS,
cancer chemotherapy or diabetes (100 mcg SC twice
daily) – benefits due to suppression of hormones
which enhance intestinal mucosal secretion
– 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: abdominal pain,
steatorrhoea, diarrhoea and gall stones
• Lanreotide and Pegyisomant (acromegaly)

13. 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: CPZ, haloperidol, Metoclopramide (TRH & VIP –
releases PRL)
• NO CLINICAL USE

14. Prolactin secretion

15. Prolactin inhibitors - Bromocriptine
• Ergot derivative: 2-bromo-α-ergocryptine
– Potent dopamine agonist and also has weak alpha-adrenergic
blocking property
– Greater affinity for D2; partial agonist/antagonist at D1
• Pharmacological actions:
– Decrease in prolactin release – anti-galactopoietic
– Increases GH in normal persons but decreases in presence of
pituitary tumours (acromegally)
– Antiparkinsonian effects – like levodopa
– CTZ stimulation – nausea, vomiting
– Hypotension – postural reflex and alpha-blockade
– Decrease in GI motility
• Pharmcokinetics: Partially absorbed (1/3rd
), high first
pass
– reaches peak plasma concentration within 1-2 Hrs, crosses BBB,
metabolites are excreted in Bile, t1/2 - 3-6 Hrs

16. Bromocriptine – contd.
• Mechanism of action:
– Prolactin is under constant inhibitory control of PRIH (Dopamine) –
acts on Pituitary lactotropes via D2 receptors
– Dopamine, Bromocriptine, cabergoline - act as agonist in D2
receptors – inhibitory to prolactin secretion
• Therapeutic uses:
1. Hyperprolactinemia: Due to Microprolactinomas causing
galactorrhoea, ammenorrhoea, infertility in female and impotence
and sterility in male- lower dose of 2.5 to 10 mg/day, response occurs
within weeks
• Should be stopped during pregnancy
• Lifelong therapy is required
1. Acromegaly: inoperable cases of pituitary tumors (5 – 20 mg/day)
2. Parkinsonism
3. Suppression of breast engorgement: neonatal death ?
4. Diabetes mellitus (D2 in hypothalaumus), hepatic coma
 Side effects: similar to levodopa – nausea, vomiting, constipation
and postural hypotension - Lately, behavioral alterations,
hallucinations, psychosis, mental confusions etc. – abnormal movements

17. Cabergoline
• New D2 agonist
• More potent and more D2 selective
• Very long half life – 60 days or more
• Twice weekly dose
• Lesser nausea and vomiting
• Better patient compliance and tolerance
• Preferred for hyperprolactinemia and
acromegaly

18. 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

19. 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)
– Oedewma, headache, mood changes

20. 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
1. 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
1. 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
2. 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

21. 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

22. 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

23. 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 BD intranasal followed by 200
mcg BD when Menstrual bleeding occurs For suppression of
endogenous LH surge – matured oocyte can be harvested
– Uterine fibroid: symptomatic relief 200 mcg BD
– Endometriosis: 200 mcg for 6 months
– Precocious puberty: 800 mcg BD nasal spray – arrest of breast
and genital development
• Goserelin: Long acting – used as depot – Gn suppression, Ca
Prostate, 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

24. 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
TSH and ACTH – Read yourself

25. Remember !
• Bromocriptine
• Octreotide
• Clinically used GnRH – decreases
FSH and LH secretion (!) - after 2
weeks of administration -
Desensitization

26. Thank you/Khublei shibun