Anterior Pituitary HormonesAnterior Pituitary Hormones

Dr. D. K. BrahmaDr. D. K. Brahma

Department of PharmacologyDepartment of Pharmacology

NEIGRIHMS, ShillongNEIGRIHMS, Shillong

Hypothalamus and anterior pituitaryHypothalamus and anterior pituitary

Hypothalamic HormonesHypothalamic Hormones– Thyrotropin-releasing hormone (TRH)Thyrotropin-releasing hormone (TRH)– Corticotropin-releasing hormone (CRH)Corticotropin-releasing hormone (CRH)– Gonadotropin-releasing hormone Gonadotropin-releasing hormone

(GnRH)(GnRH)– Growth hormone-releasing hormone Growth hormone-releasing hormone

(GHRH)(GHRH)– Growth hormone-inhibiting hormone Growth hormone-inhibiting hormone

(GHIH)(GHIH)– Prolactin-releasing factor (PRF)Prolactin-releasing factor (PRF)– Prolactin-inhibiting hormone (PIH)Prolactin-inhibiting hormone (PIH)

Hypothalamic Hormones – contd.Hypothalamic Hormones – contd.HYPOTHALAMIC HORMONEHYPOTHALAMIC HORMONEThyrotropin-releasing Thyrotropin-releasing

hormone (TRH)hormone (TRH)Corticotropin-releasing Corticotropin-releasing

hormone (CRH)hormone (CRH)Gonadrotropin-releasing Gonadrotropin-releasing

hormone (GnRH)hormone (GnRH)Growth hormone-releasing Growth hormone-releasing

hormone (GHRH)hormone (GHRH)Growth hormone-inhibiting Growth hormone-inhibiting

hormone (GHIH)hormone (GHIH)Prolactin releasing factor Prolactin releasing factor

(PRF)(PRF)Prolactin-inhibiting hormone Prolactin-inhibiting hormone

(PIH)(PIH)

EFFECTS ON THE EFFECTS ON THE ANTERIOR PITUITARYANTERIOR PITUITARY

Stimulates release of TSH Stimulates release of TSH (thyrotropin) and Prolactin(thyrotropin) and Prolactin

Stimulates release of ACTH Stimulates release of ACTH (corticotropin)(corticotropin)

Stimulates release of FSH and Stimulates release of FSH and LH (gonadotropins)LH (gonadotropins)

Stimulates release of growth Stimulates release of growth hormonehormone

Inhibits release of growth Inhibits release of growth hormone hormone

Stimulates release of Stimulates release of prolactinprolactin

Inhibits release of prolactinInhibits release of prolactin

Anterior Pituitary HormonesAnterior Pituitary Hormones

Growth HormoneGrowth Hormone

Human growth hormone is called hGH and Human growth hormone is called hGH and are peptide hormonesare peptide hormones

It is an 191 amino acid, single chain It is an 191 amino acid, single chain peptidepeptide

Gene encoding on chromosome 17Gene encoding on chromosome 17

Growth HormoneGrowth HormoneMost of the GH are Most of the GH are prohormonesprohormones

In liver it is converted In liver it is converted to to SomatomedinsSomatomedins,, also called also called Insulin like Insulin like growth factor growth factor (IGF 1, (IGF 1, also IGF 2)also IGF 2)

IGF 1 is structurally IGF 1 is structurally and functionally and functionally analogous to insulin analogous to insulin receptorsreceptors

GH – Physiological functionsGH – Physiological functions(Promotes Growth)(Promotes Growth)

Growth is a very complex process, and requires the Growth is a very complex process, and requires the coordinated action of several hormonescoordinated action of several hormonesThe major role of growth hormone in stimulating body The major role of growth hormone in stimulating body growth is to stimulate the liver and other tissues to secrete growth is to stimulate the liver and other tissues to secrete IGF-I.IGF-I.IGF-I stimulates proliferation of chondrocytes (cartilage IGF-I stimulates proliferation of chondrocytes (cartilage cells), resulting in bone growth.cells), resulting in bone growth.Growth hormone does seem to have a direct effect on Growth hormone does seem to have a direct effect on bone growth in stimulating differentiation of chondrocytes.bone growth in stimulating differentiation of chondrocytes.IGF-I also appears to be the key player in muscle growth. It IGF-I also appears to be the key player in muscle growth. It stimulates both the differentiation and proliferation of stimulates both the differentiation and proliferation of myoblasts.myoblasts.It also stimulates amino acid uptake and protein synthesis It also stimulates amino acid uptake and protein synthesis in muscle and other tissuesin muscle and other tissues

Growth HormoneGrowth Hormone

(Direct effect)(Direct effect)Direct effects are the result of growth hormone binding its receptor on target cells. Fat cells (adipocytes), for example, have growth hormone receptors, and growth hormone stimulates them to break down triglyceride and suppresses their ability to take up and accumulate circulating lipids. Also cause glycogenolysis in liver and decrease glucose utilization by muscles.

(Indirect effect)Indirect effects are mediated primarily by a insulin-like growth factor-I (IGF-I), a hormone that is secreted from the liver and other tissues in response to growth hormone. A majority of the growth promoting effects of growth hormone is actually due to IGF-I acting on its target cells. IGF promotes lipogenesis nd glucose uptake by muscles

Physiological actionsPhysiological actionsProtein metabolism:Protein metabolism: In general, growth hormone stimulates In general, growth hormone stimulates protein anabolism in many tissues. This effect reflects protein anabolism in many tissues. This effect reflects increased amino acid uptake, increased protein synthesis increased amino acid uptake, increased protein synthesis and decreased oxidation of proteinsand decreased oxidation of proteinsFat metabolism:Fat metabolism: Growth hormone enhances the utilization Growth hormone enhances the utilization of fat by stimulating triglyceride breakdown and oxidation of fat by stimulating triglyceride breakdown and oxidation in adipocytesin adipocytesCarbohydrate metabolism:Carbohydrate metabolism: Growth hormone is one of a Growth hormone is one of a battery of hormones that serves to maintain blood glucose battery of hormones that serves to maintain blood glucose within a normal rangewithin a normal rangeGrowth hormone is often said to have anti-insulin activity, Growth hormone is often said to have anti-insulin activity, because it suppresses the abilities of insulin to stimulate because it suppresses the abilities of insulin to stimulate uptake of glucose in peripheral tissues and enhance uptake of glucose in peripheral tissues and enhance glucose synthesis in the liverglucose synthesis in the liverSomewhat paradoxically, administration of growth hormone Somewhat paradoxically, administration of growth hormone stimulates insulin secretion, leading to hyperinsulinemiastimulates insulin secretion, leading to hyperinsulinemia

Regulation of secretionRegulation of secretionThe hypothalamus is the primitive site of the brain that sends either stimulating or inhibiting hormones to the pituitary.Growth hormone stimulating hormone (GHRH) tells the pituitary gland to secrete more growth hormone (GH).On the other side, Growth Hormone Inhibiting Hormone (GHIH = Somatostatin) tells the pituitary gland to stop producing more

…….. contd... contd.

•Once the pituitary receives the positive Once the pituitary receives the positive stimulating signal it then secretes GH which in stimulating signal it then secretes GH which in turn stimulates the liver to produce IGF-1 turn stimulates the liver to produce IGF-1 (Insulin-like growth factor 1) .(Insulin-like growth factor 1) .• IGF-1 is also a more stable compound unlike IGF-1 is also a more stable compound unlike true GH which has up to 5 spurts a day – the true GH which has up to 5 spurts a day – the largest being just before sleep.largest being just before sleep.• If we were to measure GH directly it might If we were to measure GH directly it might show as too low or too high just because of the show as too low or too high just because of the timing. Measuring IGF-1 circumvents this timing. Measuring IGF-1 circumvents this problem because of its more constant blood problem because of its more constant blood levels. Interestingly, both have distinct levels. Interestingly, both have distinct biochemical properties.biochemical properties.• Once the IGF-1 levels are high enough, a Once the IGF-1 levels are high enough, a feedback message is sent back to the pituitary feedback message is sent back to the pituitary and the hypothalamus to modulate further GH and the hypothalamus to modulate further GH secretion. This is accomplished by secreting secretion. This is accomplished by secreting more Somatostatin which then slows down GH more Somatostatin which then slows down GH production.production.

GH-Modulators of secretionGH-Modulators of secretion

Dopamine, 5-HT, α2-receptor Dopamine, 5-HT, α2-receptor agonists increase GH secretionagonists increase GH secretion

β-receptor antagonists, FFA, IGF-1 β-receptor antagonists, FFA, IGF-1 and GH inhibit releaseand GH inhibit release

Hypoglycemia, exercise, stress, Hypoglycemia, exercise, stress, emotional excitement, ingestion of emotional excitement, ingestion of protein rich meals increase GHprotein rich meals increase GH

Growth Hormone - PharmacologyGrowth Hormone - PharmacologyNatural GH not used due to rise of Natural GH not used due to rise of transmission transmission Creutzfeldt Jacob diseaseCreutzfeldt Jacob disease – –lethal infectionlethal infectionSomatropinSomatropin (synthetic hGH) is biosynthesis (synthetic hGH) is biosynthesis form made by recombinant DNA form made by recombinant DNA technologytechnologySomatremSomatrem is similar is similarActs on many organs to produce Acts on many organs to produce somatomedin which causes muscle, bone somatomedin which causes muscle, bone and tissue to increase growth i.e. protein and tissue to increase growth i.e. protein synthesis, and size and number of cellssynthesis, and size and number of cells

Mechanism of action-GHMechanism 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 – Clinical UsesGH – Clinical Uses1.1. GHRH: Diagnostic useGHRH: Diagnostic use

To differentiate dwarfism – pituitary (defect of somatrophs) To differentiate dwarfism – pituitary (defect of somatrophs) or hypothalamic (no production of GHRH) originor hypothalamic (no production of GHRH) originSermorelinSermorelin (a synthetic material behaves like GHRH) is (a synthetic material behaves like GHRH) is injected in dwarfisminjected in dwarfism

Subsequently hGH level is estimatedSubsequently hGH level is estimatedIf hGH level rises fault lies in hypothalamusIf hGH level rises fault lies in hypothalamus

2.2. hGH: Pituitary dwarfismhGH: Pituitary dwarfismSomatremSomatrem and and somatropinsomatropin are biologically equivalent to hGH are biologically equivalent to hGH and obtained by recombinant DNA techniqueand obtained by recombinant DNA techniqueDose: 0.03 to 0.07 mg/kg IM or SC 3 times a weekDose: 0.03 to 0.07 mg/kg IM or SC 3 times a weekStart at the age of 3 and continued till 20-25 yearsStart at the age of 3 and continued till 20-25 yearsShould not administer to persons whose epiphyses are Should not administer to persons whose epiphyses are closedclosedIGF 1 appears in plasma following injection and remains IGF 1 appears in plasma following injection and remains detectable till 48 Hrdetectable till 48 Hr

Other Uses of GHOther Uses of GH

Turner's SyndromeRenal failure in childrenConstitutional short stature of ChildrenAdult GH deficitAIDS – wasting (100 μgm/ kg)Abuse: Athlete abuse (???)

Adverse Effects of GH TherapyAdverse Effects of GH TherapyIn first 8 weeks – intracranial hypertension, In first 8 weeks – intracranial hypertension, papilledema, visual changes, headache, papilledema, visual changes, headache, nausea and/or vomiting - Fundoscopic nausea and/or vomiting - Fundoscopic examination at initiation of therapy and at examination at initiation of therapy and at periodic intervalsperiodic intervalsLeukemiaLeukemiaIncrease type 2 diabetes mellitusIncrease type 2 diabetes mellitusIn adults side effects on therapy initiation - In adults side effects on therapy initiation - Peripheral edema, Carpal tunnel Peripheral edema, Carpal tunnel syndrome, Arthralgia, Myalgiasyndrome, Arthralgia, MyalgiaSymptoms decrease with decrease in doseSymptoms decrease with decrease in dose

Pharmacologic and PhysiologicAgents That Affect hGH Production

Exercise stimulates endogenous GH secretion acutely

Agents used in excess of hGH Agents used in excess of hGH Acromegaly and GigantismAcromegaly and Gigantism

Somatostatin AnaloguesSomatostatin Analogues

1. Somatostatin – 281. Somatostatin – 28

(prosomatostatin)(prosomatostatin)

2. Somatostatin – 142. Somatostatin – 14

3. Octreotide3. Octreotide

4. Lanreotide4. Lanreotide

5. Vapreotide5. Vapreotide

GigantismGigantismGiantism 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

AcromegalyResults 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 IGF-I also lead to metabolic derangements, including glucose intoleranceProgresses slowly, delayed diagnosis, decreased life expectancyIncrease death rate due to CVS disorders, upper airway obstruction, gastrointestinal malignanciesIncreased circulating GH or IGF-1Overall clinically: Arthropathy, Carpal tunnel syndrome, Generalized visceromegally, Hypertension, Glucose intolerance, Headache, lethargy, excess perspiration, sleep apnoea

GH inhibitors – SomatostatinGH inhibitors – SomatostatinSomatostatin:14 amino acid peptideSomatostatin:14 amino acid peptide– Produce mainly by hypothalamus and also in GITProduce mainly by hypothalamus and also in GIT– Inhibits secretion of GH, TSH and prolactin by pituitary Inhibits secretion of GH, TSH and prolactin by pituitary

and insulin and glucagon by pancreasand insulin and glucagon by pancreas– All GIT secretions are inhibited including HCl - Diarrhoea, All GIT secretions are inhibited including HCl - Diarrhoea,

stetorrhoea, hypochlorhydria etc. occursstetorrhoea, hypochlorhydria etc. occurs– Constrict hepatic, splanchnic blood vesselsConstrict hepatic, splanchnic blood vessels– Uses:Uses:

Acromegally: limited use due to short half-life (2-3 min)Acromegally: limited use due to short half-life (2-3 min)GI haemorrhages (250 mcg slow IV, 3 mg infusion for 12 GI haemorrhages (250 mcg slow IV, 3 mg infusion for 12 Hrs)Hrs)Pancreatic, biliary and intestinal fistulaePancreatic, biliary and intestinal fistulaeAPUD tumours producing excess HClAPUD tumours producing excess HCl

OctreotideOctreotideSynthetic analogue of Somatostatin and 40 times more potentLonger duration of action (t1/2 – 90 min)But, weak inhibitor of insulinOctreotide binds preferentially to SSTR-2 and SSTR-5 receptors on GH secreting tumorsIn acromegally - Injection octreotide (100μg) s.c thrice dailyMonitor serum GH and IGF-1 levels to assess effectivenessGoal – decrease GH levels < 2ng/ml & IGF-1 levels within normal range for age and sexOctreotide decreases tumor sizeOctreotide inhibits TSH secretion and is treatment of choice in thyrotrope adenoma that over secrete TSH and not good candidate for surgery

OctreotideOctreotideOther Uses: Other Uses: – Secretory diarrhoeas associated with carcinoid, Secretory diarrhoeas associated with carcinoid,

AIDS, cancer chemotherapy or diabetes (100 AIDS, cancer chemotherapy or diabetes (100 mcg SC twice daily)mcg SC twice daily)

– Oesophageal bleeding (100 mcg followed by Oesophageal bleeding (100 mcg followed by 25-50 mcg/hr25-50 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, Adverse effects: abdominl pain, steatorrhoea, diarrhoea and gall stonessteatorrhoea, diarrhoea and gall stones

Prolactin - ReviewProlactin - ReviewProlactin causes synthesis of milk by the breast Prolactin causes synthesis of milk by the breast alveolar epitheliumalveolar epithelium– Estrogen causes proliferation of ducts of the breastsEstrogen causes proliferation of ducts of the breasts– Progesterone causes proliferation of alveoliProgesterone causes proliferation of alveoli– Oxytocin causes milk ejectionOxytocin causes milk ejection– During pregnancy estrogen level is high along with PRL, During pregnancy estrogen level is high along with PRL,

no milk secretionno milk secretion– During parturition, estrogen level falls, milk secretion During parturition, estrogen level falls, milk secretion

occursoccurs

High PRL (hyperprolactinemia) level causes loss High PRL (hyperprolactinemia) level causes loss of libido, ammenorrhoea, lack of ovulation , and of libido, ammenorrhoea, lack of ovulation , and impotence in maleimpotence in male– Causes: disorders of hypothalumus, DA depleting drugs, Causes: disorders of hypothalumus, DA depleting drugs,

prolactin secreting tumours and hypothyroidismprolactin secreting tumours and hypothyroidism

Prolactin secretionProlactin secretion

Prolactin inhibitors - BromocriptineProlactin inhibitors - BromocriptineErgot derivative: 2-bromo-Ergot derivative: 2-bromo-αα-ergocryptine-ergocryptine– Potent dopamine antagonist and also has weak alpha-Potent dopamine antagonist and also has weak alpha-

adrenergic blocking propertyadrenergic blocking property

Pharmacological actions:Pharmacological actions:– Decrease in prolactin release Decrease in prolactin release – Increases GH in normal persons but decreases in Increases GH in normal persons but decreases in

presence of pituitary tumourspresence of pituitary tumours– Antiparkinsonian effects – like levodopaAntiparkinsonian effects – like levodopa– HypotensionHypotension– Decrease in GI motilityDecrease in GI motility

Pharmcokinetics:Pharmcokinetics:– Partially absorbed, reaches peak plasma concentration Partially absorbed, reaches peak plasma concentration

within 1-2 Hrs, crosses BBB, metabolites are excreted in within 1-2 Hrs, crosses BBB, metabolites are excreted in Bile, t1/2 - 3-6 HrsBile, t1/2 - 3-6 Hrs

Bromocriptine – contd.Bromocriptine – contd.Mechanism of action:Mechanism of action:

– Acts as agonist in D2 receptors in brain and outside, e.g. CVSActs as agonist in D2 receptors in brain and outside, e.g. CVS– Partial agonist of D1 receptorsPartial agonist of D1 receptors

Therapeutic uses:Therapeutic uses:1.1. Hyperprolactinemia: lower dose of 2.5 to 10 mg/day, Hyperprolactinemia: lower dose of 2.5 to 10 mg/day,

response occurs within weeksresponse occurs within weeksShould be stopped during pregnancyShould be stopped during pregnancyLifelong therapy is requiredLifelong therapy is required

2.2. Acromegally: inoperable cases of pituitary tumors (5 – 20 Acromegally: inoperable cases of pituitary tumors (5 – 20 mg/day)mg/day)

3.3. ParkinsonismParkinsonism4.4. Suppression of breast engorgement: neonatal death ?Suppression of breast engorgement: neonatal death ?

Side effects: similar to levodopa – nausea, vomiting, Side effects: similar to levodopa – nausea, vomiting, constipation and postural hypotensionconstipation and postural hypotension

– Lately, behavioral alterations, hallucinations, psychosis, Lately, behavioral alterations, hallucinations, psychosis, mental confusions etcmental confusions etc

CabergolineCabergoline

New D2 agonistNew D2 agonist

More potent and more D2 selectiveMore potent and more D2 selective

Very long half life – 60 days or moreVery long half life – 60 days or more

Twice weekly doseTwice weekly dose

Better patient compliance and Better patient compliance and tolerancetolerance

Preferred for hyperprolactinemia and Preferred for hyperprolactinemia and acromegallyacromegally

Stimulates the gonads and promote gametogenesis and Stimulates the gonads and promote gametogenesis and secretion of gonadal hormonessecretion of gonadal hormonesFSH: induces follicular growth, development of ovum and FSH: induces follicular growth, development of ovum and secretion of Oestrogen. In male support spermatogenesissecretion of Oestrogen. In male support spermatogenesisLH: Ripe of graafian follicles, triggers ovulation, rupture of LH: Ripe of graafian follicles, triggers ovulation, rupture of follicles and sustaining of corpus luteum. In male stimulates follicles and sustaining of corpus luteum. In male stimulates testosterone secretiontestosterone secretion

Source of gonadotropins:Source of gonadotropins:– Urine of menopausal women (hMG) – Urine of menopausal women (hMG) – MenotropinsMenotropins (FSH + (FSH +

LH), pure menotropins (pure FSH)LH), pure menotropins (pure FSH)– Placenta: human chorionic gonadotropin (hCG) – only LH Placenta: human chorionic gonadotropin (hCG) – only LH

activityactivity– Recombinant: rFSH and rLHRecombinant: rFSH and rLH

Gonadotropins – Gonadotropins – FSH and LHFSH and LH

FSH and LH – contd.FSH and LH – contd.Therapeutic Uses: Therapeutic Uses:

1.1. Amenorrhoea and infertility: Menotropins (75 IU FSH +75 IU Amenorrhoea and infertility: Menotropins (75 IU FSH +75 IU LH) IM daily for 10 days and followed by 10,000 units of hCGLH) IM daily for 10 days and followed by 10,000 units of hCG

2.2. Hypogonadism in males: oligospermia, male sterilityHypogonadism in males: oligospermia, male sterility– Start with 1000-4000 IU hCG IM 2-3 times a week – testosterone Start with 1000-4000 IU hCG IM 2-3 times a week – testosterone

secretionsecretion– FSH+LH (75 IU) after 3-4 months – spermatogenesisFSH+LH (75 IU) after 3-4 months – spermatogenesis

3.3. Cryptorchism: undescended testes. Start between 1-7 years Cryptorchism: undescended testes. Start between 1-7 years of age with 1000-2000 IU 2-3 times a week. Stop if no result of age with 1000-2000 IU 2-3 times a week. Stop if no result in 2-6 weeksin 2-6 weeks

4.4. In vitro fertilization: FSH and LH is used to induce maturation In vitro fertilization: FSH and LH is used to induce maturation of several ova and to precisely time the ovulation such that of several ova and to precisely time the ovulation such that harvesting can be doneharvesting can be done

Adverse effects: Ovarian bleeding – hyperstimulation, Adverse effects: Ovarian bleeding – hyperstimulation, precocious puberty and allergic reactions (skin test)precocious puberty and allergic reactions (skin test)

GnRH analogsGnRH analogsGnRH analogs used clinically are GnRH analogs used clinically are Leuprolide, goserelin, histrelin, triptorelin Leuprolide, goserelin, histrelin, triptorelin and nafarelinand nafarelinMOA: down regulation of GnRH receptorsMOA: down regulation of GnRH receptorsNafarelin: long acting GnRH agonist and Nafarelin: long acting GnRH agonist and 150 times more potent than GnRH150 times more potent than GnRH– Uses:Uses:

Assisted reproduction: 400 mcg BD intranasalAssisted reproduction: 400 mcg BD intranasalUterine fibroid: symptomatic relief 200 mcg BDUterine fibroid: symptomatic relief 200 mcg BDEndometriosis: 200 mcg for 6 monthsEndometriosis: 200 mcg for 6 monthsPrecocious puberty: 800 mcg BD nasal spray – arrest Precocious puberty: 800 mcg BD nasal spray – arrest of breast and genital developmentof breast and genital development

Thyroid stimulating hormone (TSH)Thyroid stimulating hormone (TSH)Physiological Role:Physiological Role:– TSH stimulates thyroid gland to synthesize and TSH stimulates thyroid gland to synthesize and

secrete thyroxine (T4) and triiodothyronine secrete thyroxine (T4) and triiodothyronine (T3)(T3)

– Induces hyperplasia and hypertrophy of thyroid Induces hyperplasia and hypertrophy of thyroid follicles and increases blood supplyfollicles and increases blood supply

– Promotes iodide trappingPromotes iodide trapping– Promotes orgnification of trapped IodinePromotes orgnification of trapped Iodine– Helps in proteolysis of thyroglobulin to release Helps in proteolysis of thyroglobulin to release

T3 and T4T3 and T4

TSH has no therapeutic usesTSH has no therapeutic uses

Adrenocorticotropic hormone Adrenocorticotropic hormone (ACTH , corticotropin)(ACTH , corticotropin)

Anterior pituitary Anterior pituitary hormonehormone39 single chain amino 39 single chain amino acid peptide and acid peptide and derived from pro-derived from pro-opiomelanocortin opiomelanocortin (POMC)(POMC)Regulated by CRH Regulated by CRH from hypothalumus from hypothalumus and by feedback and by feedback levels of blood levels of blood concentrationsconcentrations

ACTHACTHMOA:MOA: It promotes steroidogenesis in adrenal It promotes steroidogenesis in adrenal cortex – by stimulating cAMP in adrenal cortical cortex – by stimulating cAMP in adrenal cortical cells through specific cells through specific G-proteinG-protein coupled receptors coupled receptors to make increase availability of cholesterol for to make increase availability of cholesterol for pregnelonepregnelone synthesis – rate limiting step synthesis – rate limiting stepInfluences production of steroids in two ways:Influences production of steroids in two ways:– Acute phase:Acute phase: occurs within seconds and reflects an occurs within seconds and reflects an

increased availability of cholesterol substrate for increased availability of cholesterol substrate for production of steroidsproduction of steroids

– Chronic phase:Chronic phase: occurs over days and is because of occurs over days and is because of increased transcription of steroidogenic enzymesincreased transcription of steroidogenic enzymes

Also exerts trophic influence on adrenal cortex Also exerts trophic influence on adrenal cortex (cAMP): high doses cause hypertrophy and (cAMP): high doses cause hypertrophy and hyperplasia – absence of ACTH results in adrenal hyperplasia – absence of ACTH results in adrenal atrophy atrophy

ACTH - UsesACTH - UsesMany therapeutic uses in the past, but now Many therapeutic uses in the past, but now obsoleteobsoleteLimited therapeutic uses – less predictable, less Limited therapeutic uses – less predictable, less convenient and stimulates mineralocorticoid and convenient and stimulates mineralocorticoid and adrenal androgen secretion – water retention and adrenal androgen secretion – water retention and virilizationvirilizationUsed in diagnostic purpose to differentiate Used in diagnostic purpose to differentiate between Addision`s disease and adrenocortical between Addision`s disease and adrenocortical insufficiency due to pituitary failureinsufficiency due to pituitary failureSynthetic human ACTH Synthetic human ACTH cosyntropincosyntropin is used – is used – injection of 250 mcg of it, if cortisol concentration injection of 250 mcg of it, if cortisol concentration rises in plasma, the adrenal cortex is intact and rises in plasma, the adrenal cortex is intact and symptoms are due to pituitary failure symptoms are due to pituitary failure

Cushing syndromeCushing syndromeIt is a condition when there is high level of It is a condition when there is high level of cortisol. Causes include – iatrogenic, and cortisol. Causes include – iatrogenic, and spontaneous – ACTH secreting pituitary adenoma, spontaneous – ACTH secreting pituitary adenoma, tumour in adrenl cortex and ectopic origin (lung tumour in adrenl cortex and ectopic origin (lung cancer secreting ACTH)cancer secreting ACTH)CRHCRH is used for diagnostic purpose to is used for diagnostic purpose to differentiate between Cushing syndrome of differentiate between Cushing syndrome of ectopic origin and pituitary origin – if CRH ectopic origin and pituitary origin – if CRH injection do not increase cortisol level then the injection do not increase cortisol level then the syndrome is of ectopic origin (ACTH secreting syndrome is of ectopic origin (ACTH secreting lung cancers do not respond to CRH injection)lung cancers do not respond to CRH injection)

SummarySummaryRemember Physiological Roles of GH and Remember Physiological Roles of GH and therapeutic uses of inhibitors - therapeutic uses of inhibitors - Somatostatin and octreotideSomatostatin and octreotide

Remember also Physiological Roles of Remember also Physiological Roles of prolactin and therapeutic roles of its prolactin and therapeutic roles of its inhibitors -Bromocriptine and cabergolineinhibitors -Bromocriptine and cabergoline

Physiological Roles of FSH and LH and Physiological Roles of FSH and LH and their therapeutic uses - menotropinstheir therapeutic uses - menotropins

Thank You

GH- Regulation of secretionGH- Regulation of secretionSynthesized and secreted by somatotropes of anterior Synthesized and secreted by somatotropes of anterior pituitarypituitaryGH secretion –high in children, reaches maximum level in GH secretion –high in children, reaches maximum level in adolescent and decreases in age related manneradolescent and decreases in age related mannerOccurs in irregular pulse, falls between these pulsesOccurs in irregular pulse, falls between these pulsesAmplitude of secretory pulses is maximum at night, shortly Amplitude of secretory pulses is maximum at night, shortly after onset of deep sleepafter onset of deep sleep

GHRH-hypothalamic neurons in arcute nucleus increase GH GHRH-hypothalamic neurons in arcute nucleus increase GH secretion by binding to GPCRs on somatotropes increase secretion by binding to GPCRs on somatotropes increase intracellular cAMP & Ca++intracellular cAMP & Ca++Somatostatin(SST) synthesized by neurons, neuroendocrine Somatostatin(SST) synthesized by neurons, neuroendocrine cells of GIT, pancreas, decrease GH secretion by family of cells of GIT, pancreas, decrease GH secretion by family of GPCRs, cAMP accumulation, activation of K+ channels, GPCRs, cAMP accumulation, activation of K+ channels, activation of tyrosine phosphataseactivation of tyrosine phosphatase

GH – Pharmacological actionsGH – Pharmacological actionsEffects on Growth: Complex processEffects on Growth: Complex process– Stimulates liver to secrete IGFStimulates liver to secrete IGF– IGF stimulates proliferation of chondrocytes (cartilage cells) IGF stimulates proliferation of chondrocytes (cartilage cells)

resulting in bone growthresulting in bone growth– GH has also direct effect on bone in stimulating differentiation GH has also direct effect on bone in stimulating differentiation

of chondrocytesof chondrocytes– IGF acts on muscles also – stimulates differentiation and IGF acts on muscles also – stimulates differentiation and

proliferation of myoblasts, stimulates amino acid uptake proliferation of myoblasts, stimulates amino acid uptake protein synthesis in muscle and other tissuesprotein synthesis in muscle and other tissues

Metabolic effects: both direct and indirectMetabolic effects: both direct and indirect– Protein metabolism: increased amino acid uptake, increased Protein metabolism: increased amino acid uptake, increased

protein synthesis and decreased oxidation of proteinsprotein synthesis and decreased oxidation of proteins– Fat Metabolism: enhances utilization of fats by stimulating Fat Metabolism: enhances utilization of fats by stimulating

breakdown of triglyceridesbreakdown of triglycerides– Carbohydrate metabolism: glycogenolysis in liver, increased Carbohydrate metabolism: glycogenolysis in liver, increased

hepatic glucose output, decreased glucose utilization in hepatic glucose output, decreased glucose utilization in muscles muscles

Growth HormoneGrowth Hormone