1 1 chapter: 37 hypothalamic & pituitary hormones

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ChapterChapter: 37: 37 Hypothalamic & pituitary hormonesHypothalamic & pituitary hormones

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Anterior pituitary hormones & Anterior pituitary hormones & their hypothalamic regulatorstheir hypothalamic regulators

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Anterior pituitary hormonesAnterior pituitary hormones

• Are essential for the regulation of growth and Are essential for the regulation of growth and development, reproduction, responses to stress, development, reproduction, responses to stress, and intermediary metabolismand intermediary metabolism

• Within this tissue are specialised cells such as Within this tissue are specialised cells such as corticotrophs, lactotrophs (mammotrophs), corticotrophs, lactotrophs (mammotrophs), somatotrophs, thyrotrophs and gonadotrophs, somatotrophs, thyrotrophs and gonadotrophs, which secrete hormones that regulate different which secrete hormones that regulate different endocrine organs of the body endocrine organs of the body

• Their synthesis and secretion are controlled by Their synthesis and secretion are controlled by hypothalamic hormones and by hormones from hypothalamic hormones and by hormones from the peripheral endocrine organs (negative the peripheral endocrine organs (negative feedback control)feedback control)

+

+-

-

-ve feedback

StimulusHypothalamus

Hypothalamic hormoneHypothalamic hormone

Anterior pitutary gland

Endocrine gland

Anterior pituitary hormoneAnterior pituitary hormone

Response

Target tissue

HormoneHormone

Feedback mechanisms

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• Hypothalamic hormones somatostatin and Hypothalamic hormones somatostatin and gonadotrophin-releasing hormone are used gonadotrophin-releasing hormone are used therapeutically, the rest being used for diagnostic therapeutically, the rest being used for diagnostic tests or as research toolstests or as research tools

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• A large number of disease states, as well as a A large number of disease states, as well as a diverse group of drugs, also affect their secretiondiverse group of drugs, also affect their secretion

• Knowledge of the levels of the pituitary signal Knowledge of the levels of the pituitary signal hormone and the target hormone allows the hormone and the target hormone allows the clinician to identify the site of the endocrine clinician to identify the site of the endocrine disorder.disorder.

• Endocrine deficiency states can be divided into: Endocrine deficiency states can be divided into: primary, secondary and tertiaryprimary, secondary and tertiary

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• In primary hypofunction, the production of the In primary hypofunction, the production of the target endocrine hormone will be impaired; target endocrine hormone will be impaired; however, the hypothalamus and pituitary will however, the hypothalamus and pituitary will sense the diminished feedback inhibition and the sense the diminished feedback inhibition and the anterior pituitary gland will secrete higher than anterior pituitary gland will secrete higher than normal levels of the signal hormonenormal levels of the signal hormone

• In secondary hypofunction, both the signal In secondary hypofunction, both the signal hormone and the target hormone will be below the hormone and the target hormone will be below the normal rangenormal range

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• Hormone excess similarly can result either from:Hormone excess similarly can result either from:1)1) Primary disorders Primary disorders at the level of the target at the level of the target

endocrine glands (e.g., a hyperfunctioning endocrine glands (e.g., a hyperfunctioning tumor of the adrenal cortex that oversecretes tumor of the adrenal cortex that oversecretes cortisol) cortisol)

2)2) Secondary disorders Secondary disorders at the level of the at the level of the pituitary gland (e.g., a pituitary corticotrope pituitary gland (e.g., a pituitary corticotrope adenoma that oversecretes corticotropin, the adenoma that oversecretes corticotropin, the predominant stimulator of adrenal predominant stimulator of adrenal glucocorticoid biosynthesis)glucocorticoid biosynthesis)

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I. Growth hormone (Somatotropin, GH)I. Growth hormone (Somatotropin, GH)

• The hypothalamus secretes two hormones that The hypothalamus secretes two hormones that regulate GH:regulate GH:I.I. GH-releasing hormone (GHRH)GH-releasing hormone (GHRH)II.II. Somatostatin (SST)Somatostatin (SST)

• GH is released in a pulsatile manner, with the GH is released in a pulsatile manner, with the highest levels occurring during sleephighest levels occurring during sleep

• GH is required during childhood and adolescence GH is required during childhood and adolescence for attainment of normal adult sizefor attainment of normal adult size

• It has an important role throughout life on lipid and It has an important role throughout life on lipid and CHO metabolismCHO metabolism

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Physiological Effects of Growth HormonePhysiological Effects of Growth Hormone

• Many physiologic effects of GH are exerted Many physiologic effects of GH are exerted directlydirectly at its target: GH acts directly on at its target: GH acts directly on adipocytes to increase lipolysis and on adipocytes to increase lipolysis and on hepatocytes to stimulate gluconeogenesishepatocytes to stimulate gluconeogenesis

• The anabolic & growth-promoting effects are The anabolic & growth-promoting effects are mediated mediated indirectlyindirectly through an increase in the through an increase in the production of insulin-like growth factor 1 (IGF-1)production of insulin-like growth factor 1 (IGF-1) in in the liver, bone, cartilage, muscle, and the kidneythe liver, bone, cartilage, muscle, and the kidney

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-

+

Hypothalamus

GHRHGHRH

Anterior pitutary gland

Liver

GHGH

IGF-1

SomatostatinSomatostatin

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+

--

Lipolysis↓ glucose uptake by muscles

Growth prmoting actions:↑cell division↑protein synthesis↑bone growth

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Physiological Effects of Growth HormonePhysiological Effects of Growth Hormone

• The main effect of growth hormone (and its The main effect of growth hormone (and its analogues) is to stimulate normal growth in analogues) is to stimulate normal growth in conjunction with other hormones secreted from conjunction with other hormones secreted from the thyroid, the gonads and the adrenal cortexthe thyroid, the gonads and the adrenal cortex

• GH stimulates longitudinal bone growth until the GH stimulates longitudinal bone growth until the epiphyses close—near the end of pubertyepiphyses close—near the end of puberty

• In both children and adults, GH has anabolic In both children and adults, GH has anabolic effects in muscle and catabolic effects in lipid cells effects in muscle and catabolic effects in lipid cells that shift the balance of body mass to an increase that shift the balance of body mass to an increase in muscle mass and a reduction in central in muscle mass and a reduction in central adiposityadiposity

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Pathophysiology of Growth HormonePathophysiology of Growth Hormone

• Distinct endocrine disorders result from either Distinct endocrine disorders result from either excessive or deficient GH productionexcessive or deficient GH production

• Children with GH deficiency (pituitary dwarfism) Children with GH deficiency (pituitary dwarfism) present with short stature often with mild present with short stature often with mild adiposity, delayed bone age, and a low age-adiposity, delayed bone age, and a low age-adjusted growth velocityadjusted growth velocity

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• GH deficiency in adults is associated with GH deficiency in adults is associated with decreased muscle mass and exercise capacity, decreased muscle mass and exercise capacity, decreased bone density, impaired psychosocial decreased bone density, impaired psychosocial function, and increased mortality from CV causes, function, and increased mortality from CV causes, probably secondary to deleterious changes in fat probably secondary to deleterious changes in fat distribution, increases in circulating lipids, and distribution, increases in circulating lipids, and increased inflammationincreased inflammation

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• An excessive production of growth hormone in An excessive production of growth hormone in children results in gigantism. It occurs due to GH-children results in gigantism. It occurs due to GH-secreting adenoma before the long bone secreting adenoma before the long bone epiphyses closeepiphyses close

• An excessive production in adults, which is An excessive production in adults, which is usually the result of a benign pituitary tumour, usually the result of a benign pituitary tumour, results in acromegaly, which is characterized by results in acromegaly, which is characterized by abnormal growth of cartilage and bone tissue, and abnormal growth of cartilage and bone tissue, and many organs including skin, muscle, heart, liver, many organs including skin, muscle, heart, liver, and GITand GIT

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GH preparationsGH preparations

• Somatropin refers to the many GH preparations Somatropin refers to the many GH preparations whose sequences match that of native GH: whose sequences match that of native GH: accretropin, genotropin, humatrope, norditropin, accretropin, genotropin, humatrope, norditropin, nutropin, omnitrope, saizen, serostim, tevtropin, nutropin, omnitrope, saizen, serostim, tevtropin, valtropin, and zorbtivevaltropin, and zorbtive

• GH is administered subcutaneouslyGH is administered subcutaneously

• To match the usual pattern of secretion, GH To match the usual pattern of secretion, GH typically is administered at bedtimetypically is administered at bedtime

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Clinical usesClinical uses

1.1. Treatment of growth hormone deficiency Treatment of growth hormone deficiency (dwarfism)(dwarfism)

2.2. Children with other conditions associated Children with other conditions associated with short stature caused by factors other with short stature caused by factors other than GH deficiencythan GH deficiency: :

a)a) Turner's syndromeTurner's syndromeb)b) Noonan's syndromeNoonan's syndromec)c) Prader-Willi syndromePrader-Willi syndromed)d) Chronic renal insufficiency in pediatric patientsChronic renal insufficiency in pediatric patientse)e) Children born small for gestational ageChildren born small for gestational agef)f) Children with idiopathic short statureChildren with idiopathic short stature11

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Other uses of GHOther uses of GH

• GH affects many organ systems and also has a GH affects many organ systems and also has a net anabolic effect. It is approved for the net anabolic effect. It is approved for the treatment of:treatment of:

1.1. Wasting in patients with AIDSWasting in patients with AIDS2.2. Short bowel syndromeShort bowel syndrome

• GH is a popular component of anti-aging GH is a popular component of anti-aging programsprograms

• Used by athletes to increase lean body mass Used by athletes to increase lean body mass and athletic performance (banned by Olympic and athletic performance (banned by Olympic committee)committee)

• Bovine growth hormone (rbGH) in dairy cattle to Bovine growth hormone (rbGH) in dairy cattle to increase milk productionincrease milk production

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Insulin-like growth factor 1 (IGF-1)Insulin-like growth factor 1 (IGF-1)

• Two preparations are FDA-approved: Two preparations are FDA-approved:

1)1) Mecasermin: Mecasermin: recombinant human IGF-1recombinant human IGF-1

2)2) Mecasermin rinfabate: Mecasermin rinfabate: is a complex is a complex hIGF-1 and recombinant human insulin-hIGF-1 and recombinant human insulin-like growth factor-binding protein-3 like growth factor-binding protein-3 (rhIGFBP-3)(rhIGFBP-3)

• Mecasermin is administered SCMecasermin is administered SC

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Insulin-like growth factor 1 (IGF-1)Insulin-like growth factor 1 (IGF-1)

• Mecasermin is FDA-approved for:Mecasermin is FDA-approved for:

1)1) Patients with impaired growth secondary to Patients with impaired growth secondary to mutations in the GH receptor or postreceptor mutations in the GH receptor or postreceptor signaling pathwaysignaling pathway

2)2) Patients with GH deficiency who develop Patients with GH deficiency who develop antibodies against GH that interfere with its antibodies against GH that interfere with its actionaction

3)3) Patients with IGF-1 gene defects that lead to Patients with IGF-1 gene defects that lead to primary IGF-1 deficiencyprimary IGF-1 deficiency

• Mecasermin rinfabate is currently approved for Mecasermin rinfabate is currently approved for ssevere insulin resistance, muscular dystrophy, evere insulin resistance, muscular dystrophy, and HIV-related adipose redistribution syndromeand HIV-related adipose redistribution syndrome

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Growth hormone antagonistsGrowth hormone antagonists

• Pegvisomant Pegvisomant is a GH receptor antagonist is a GH receptor antagonist

• It It binds to the GH receptor but does not activate binds to the GH receptor but does not activate or stimulate IGF-1 secretionor stimulate IGF-1 secretion

• Approved by the FDA for the treatment of Approved by the FDA for the treatment of acromegalyacromegaly

• Administered SCAdministered SC

• Based on serum IGF-1 levels, the dose is titrated Based on serum IGF-1 levels, the dose is titrated at 4- to 6-week intervalsat 4- to 6-week intervals

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II. Growth hormone-releasing hormone II. Growth hormone-releasing hormone (GHRH, somatorelin)(GHRH, somatorelin)

• It is a peptide with 40-44 amino acid It is a peptide with 40-44 amino acid residuesresidues

• It stimulates the synthesis & release of It stimulates the synthesis & release of growth hormone (GH) from the anterior growth hormone (GH) from the anterior pituitarypituitary

• Sermorelin, is a GHRH analogue, was Sermorelin, is a GHRH analogue, was withdrawn from the U.S. market in late withdrawn from the U.S. market in late 2008 2008

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III. Somatostatin (GHIH, SRIH)III. Somatostatin (GHIH, SRIH)

• Somatostatin is found in the hypothalamus, other Somatostatin is found in the hypothalamus, other parts of the CNS, the pancreas, and other sites in parts of the CNS, the pancreas, and other sites in the GITthe GIT

• In the pituitary, somatostatin binds to distinct In the pituitary, somatostatin binds to distinct receptors, SSTR2 and SSTR5, which suppress receptors, SSTR2 and SSTR5, which suppress GH & TSH releaseGH & TSH release

• It inhibits the release of GH, TSH, glucagon, It inhibits the release of GH, TSH, glucagon, insulin, and gastrininsulin, and gastrin

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Somatostatin (GHIH, SRIH)Somatostatin (GHIH, SRIH)

• Exogenous Somatostatin has limited therapeutics Exogenous Somatostatin has limited therapeutics usefulness:usefulness:

1.1. Short duration of action (t1/2 = 1-3 minutes) Short duration of action (t1/2 = 1-3 minutes) 2.2. Multiple effects on many secretory systemsMultiple effects on many secretory systems

• Longer-acting somatostatin analogs have been Longer-acting somatostatin analogs have been developed: developed: OctreotideOctreotide & & Lanreotide Lanreotide

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OctreotideOctreotide

• The most widely used somatostatin analogThe most widely used somatostatin analog

• It has a longer half-life (half-life ~ 90 mins), and It has a longer half-life (half-life ~ 90 mins), and duration of action ~ 12 hrsduration of action ~ 12 hrs

• It is 45 times more potent that somatostatin in It is 45 times more potent that somatostatin in inhibiting GH with reduced effect on pancreatic inhibiting GH with reduced effect on pancreatic ββ--cells (cells (hyperglycemia rarely occurs)hyperglycemia rarely occurs)

• Octreotide is administered SC three times dailyOctreotide is administered SC three times daily

• A long-acting, slow-release form is administered A long-acting, slow-release form is administered IM every 4 week, typically to patients who have IM every 4 week, typically to patients who have tolerated and responded to the shorter-acting tolerated and responded to the shorter-acting formulationformulation

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Octreotide- Clinical usesOctreotide- Clinical uses

1.1. TTreat/reduce symptoms of hormone-secreting reat/reduce symptoms of hormone-secreting tumors (e.g. acromegaly, tumors producing tumors (e.g. acromegaly, tumors producing vasoactive intestinal peptide (VIPomas))vasoactive intestinal peptide (VIPomas))

2.2. Acute control of bleeding from esophageal Acute control of bleeding from esophageal varicesvarices

3.3. Perioperative prophylaxis in pancreatic surgeryPerioperative prophylaxis in pancreatic surgery

4.4. Thyrotrope adenomas that oversecrete TSH who Thyrotrope adenomas that oversecrete TSH who are not good candidates for surgery (DOC): are not good candidates for surgery (DOC): Octreotide has significant inhibitory effects on Octreotide has significant inhibitory effects on TSH secretionTSH secretion

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Octreotide- Clinical usesOctreotide- Clinical uses

5.5. Modified forms of octreotide labeled with indium Modified forms of octreotide labeled with indium or technetium have been used for diagnostic or technetium have been used for diagnostic imaging of neuroendocrine tumors such as imaging of neuroendocrine tumors such as pituitary adenomas and carcinoids pituitary adenomas and carcinoids (OCTREOSCAN)(OCTREOSCAN)

6.6. Modified forms labeled with emitters such as 90Y Modified forms labeled with emitters such as 90Y have been used in selective destruction of SST2 have been used in selective destruction of SST2 receptor-positive tumorsreceptor-positive tumors

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LanreotideLanreotide

• Long-acting octapeptide analog of somatostatin Long-acting octapeptide analog of somatostatin that causes prolonged suppression of GH that causes prolonged suppression of GH secretion when administered IMsecretion when administered IM

• Efficacy comparable to that of the long-acting Efficacy comparable to that of the long-acting formulation of octreotide, but its duration of action formulation of octreotide, but its duration of action is shorter (it is administered either at 10- or 14-is shorter (it is administered either at 10- or 14-day intervals)day intervals)

• Lanreotide autogel is supplied in prefilled syringes Lanreotide autogel is supplied in prefilled syringes and administered by deep Sc injection once every and administered by deep Sc injection once every 4 weeks. It provides more uniform drug levels 4 weeks. It provides more uniform drug levels than the depot formulation of octreotidethan the depot formulation of octreotide

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II. The GonadotropinsII. The Gonadotropins

• Gonadotropins: Gonadotropins: I.I. Luteinizing hormone (LH)Luteinizing hormone (LH)II.II. follicle-stimulating hormone (FSH)follicle-stimulating hormone (FSH)III.III. chorionic gonadotropin (hCG)chorionic gonadotropin (hCG)

• LH and FSH are synthesized and secreted by LH and FSH are synthesized and secreted by gonadotropes cells in the anterior pituitarygonadotropes cells in the anterior pituitary

• hCG is produced by the human placenta and hCG is produced by the human placenta and excreted into the urineexcreted into the urine

• Production is stimulated by Production is stimulated by pulsespulses of GnRH of GnRH secreted by hypothalamus and by feedback secreted by hypothalamus and by feedback effects of the gonadal hormoneseffects of the gonadal hormones

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Mechanism of actionMechanism of action

• The actions of LH and hCG on target tissues are The actions of LH and hCG on target tissues are mediated by the LH receptor; those of FSH are mediated by the LH receptor; those of FSH are mediated by the FSH receptormediated by the FSH receptor

• The gonadotropins and hCG exert their effects The gonadotropins and hCG exert their effects through G protein-coupled receptorsthrough G protein-coupled receptors

• The FSH and LH receptors couple to Gs to The FSH and LH receptors couple to Gs to activate the adenylyl cyclase/cyclic AMP activate the adenylyl cyclase/cyclic AMP pathwaypathway

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Physiological effects of Physiological effects of GonadotropinGonadotropin

I.I. The male:The male:

• LH acts on testicular Leydig cells to stimulate the LH acts on testicular Leydig cells to stimulate the de novode novo synthesis of androgens, primarily synthesis of androgens, primarily testosteronetestosterone

• FSH is the primary regulator of FSH is the primary regulator of spermatogenesis. It acts on the Sertoli cells to spermatogenesis. It acts on the Sertoli cells to stimulate the production of proteins and nutrients stimulate the production of proteins and nutrients required for sperm maturationrequired for sperm maturation

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II.II. The female:The female:• The actions of FSH and LH are more The actions of FSH and LH are more

complicatedcomplicated

• A coordinated pattern of FSH and LH secretion A coordinated pattern of FSH and LH secretion during the menstrual cycle is required for normal during the menstrual cycle is required for normal follicle development, ovulation, and pregnancyfollicle development, ovulation, and pregnancy

• FSH stimulates the growth of developing ovarian FSH stimulates the growth of developing ovarian follicles and induces the expression of LH follicles and induces the expression of LH receptors on theca and granulosa cellsreceptors on theca and granulosa cells

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II.II. The female:The female:

• LH acts on the theca cells to stimulate the LH acts on the theca cells to stimulate the de de novonovo synthesis of androgens, whereas FSH synthesis of androgens, whereas FSH stimulates the conversion by granulosa cells of stimulates the conversion by granulosa cells of androgens to estrogensandrogens to estrogens

• hcG is a placental protein that stimulates the hcG is a placental protein that stimulates the ovarian corpus luteum to produce progesterone ovarian corpus luteum to produce progesterone and maintain the placenta in females during and maintain the placenta in females during pregnancypregnancy

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Clinical UsesClinical Uses

I.I. Diagnostic Uses of GonadotropinsDiagnostic Uses of Gonadotropins

• Diagnosis of Pregnancy: Diagnosis of Pregnancy: • Commercial pregnancy kits (qualitative Commercial pregnancy kits (qualitative

assay) assay) which can be detected in maternal which can be detected in maternal urineurine

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I.I. Diagnostic Uses of GonadotropinsDiagnostic Uses of Gonadotropins

• Diagnosis of Pregnancy: Diagnosis of Pregnancy: • Quantitative measurements of plasma hCG Quantitative measurements of plasma hCG

concentration by immunoassay concentration by immunoassay can indicate can indicate whether pregnancy is proceeding normally whether pregnancy is proceeding normally and can help to detect the presence of an and can help to detect the presence of an ectopic pregnancy, hydatidiform mole, or ectopic pregnancy, hydatidiform mole, or choriocarcinomachoriocarcinoma

• Such assays also are used to follow the Such assays also are used to follow the therapeutic response of malignancies that therapeutic response of malignancies that secrete hCG, such as germ cell tumorssecrete hCG, such as germ cell tumors

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II.II. Therapeutic Uses of Gonadotropins Therapeutic Uses of Gonadotropins

A.A. Ovulation induction: Ovulation induction: in women with in women with anovulation that is secondary to anovulation that is secondary to hypogonadotropic hypogonadism, polycystic hypogonadotropic hypogonadism, polycystic ovary syndrome, obesity, and other causesovary syndrome, obesity, and other causes

B.B. Controlled ovarian hyperstimulationControlled ovarian hyperstimulation

C.C. Male infertilityMale infertility

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III. Gonadotropins releasing hormone (GnRH, III. Gonadotropins releasing hormone (GnRH, gonadorelin)gonadorelin)

• Decapeptide secreted by neurons in the Decapeptide secreted by neurons in the hypothalamus that control the release of hypothalamus that control the release of gonadotropins FSH & LHgonadotropins FSH & LH

• The intermittent/ The intermittent/ pulsatilepulsatile release of GnRH is release of GnRH is crucial for the proper synthesis and release of the crucial for the proper synthesis and release of the gonadotropinsgonadotropins

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III. Gonadotropins releasing hormone (GnRH, III. Gonadotropins releasing hormone (GnRH, gonadorelin)gonadorelin)

• The continuous/ sustained/ The continuous/ sustained/ nonpulsatilenonpulsatile administration of GnRH leads to desensitization administration of GnRH leads to desensitization and down-regulation of GnRH receptors on and down-regulation of GnRH receptors on pituitary gonadotropespituitary gonadotropes

• This inhibits the release of FSH and LH by the This inhibits the release of FSH and LH by the pituitary in both women and men, resulting in pituitary in both women and men, resulting in hypogonadismhypogonadism

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• Pulsatile intravenous administration of Pulsatile intravenous administration of gonadorelin every 1–4 hours gonadorelin every 1–4 hours stimulatesstimulates FSH and FSH and LH secretionLH secretion

• Continuous administration Continuous administration of gonadorelin or its of gonadorelin or its longer-acting analogs produces a biphasic longer-acting analogs produces a biphasic response:response:

• Flare (first 7–10 days): increase concentrations Flare (first 7–10 days): increase concentrations of gonadal hormonesof gonadal hormones

• The continued presence of GnRH results in an The continued presence of GnRH results in an inhibitory action (drop in the concentration of inhibitory action (drop in the concentration of gonadotropins and gonadal steroids)gonadotropins and gonadal steroids)

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11 . .StimulationStimulation

A.A. Female Infertility: Female Infertility: pulsatile GnRH is less likely pulsatile GnRH is less likely than gonadotropins to cause multiple than gonadotropins to cause multiple pregnancies and the ovarian hyperstimulation pregnancies and the ovarian hyperstimulation syndrome, the inconvenience and cost syndrome, the inconvenience and cost associated with continuous use of an associated with continuous use of an intravenous pump and difficulties obtaining intravenous pump and difficulties obtaining gonadorelin are barriers to pulsatile GnRHgonadorelin are barriers to pulsatile GnRH

B.B. Male Infertility: Male Infertility: pulsatile gonadorelin for pulsatile gonadorelin for infertility in men with hypothalamic infertility in men with hypothalamic hypogonadotropic hypogonadismhypogonadotropic hypogonadism

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11 . .StimulationStimulation

C.C. Diagnosis of LH responsivness (delayed Diagnosis of LH responsivness (delayed puberty): puberty): to determine whether delayed to determine whether delayed puberty in a is due to constitutional delay or puberty in a is due to constitutional delay or to hypogonadotropic hypogonadismto hypogonadotropic hypogonadism

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22 . .SuppressionSuppression

A.A. Controlled ovarian hyperstimulation, such as Controlled ovarian hyperstimulation, such as IVF, to suppress an endogenous LH surgeIVF, to suppress an endogenous LH surge

B.B. Palliative therapy of hormonally responsive Palliative therapy of hormonally responsive tumors (tumors (e.g.,e.g., prostate cancer) prostate cancer)

C.C. Suppress steroid-responsive conditions such as Suppress steroid-responsive conditions such as endometriosis and uterine Fibroidsendometriosis and uterine Fibroids

D.D. Treatment of central precocious pubertyTreatment of central precocious puberty

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GnRH receptor antagonistsGnRH receptor antagonists

• Agents: Agents: Ganirelix, cetrorelix, Ganirelix, cetrorelix, andand degarelix degarelix

• Competitive antagonists of GnRH receptors Competitive antagonists of GnRH receptors that inhibit the secretion of FSH and LH in a that inhibit the secretion of FSH and LH in a dose-dependent mannerdose-dependent manner

• They do not induce an initial hypersecretion of They do not induce an initial hypersecretion of gonadotropins but instead cause an gonadotropins but instead cause an immediate and rapid, reversible suppression immediate and rapid, reversible suppression of gonadotropin secretionof gonadotropin secretion

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A.A. Suppression of Gonadotropin Suppression of Gonadotropin Production: Production: preventing the LH surge preventing the LH surge during controlled ovarian hyperstimulationduring controlled ovarian hyperstimulation

B.B. Advanced Prostate Cancer Advanced Prostate Cancer (Degarelix)(Degarelix)

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IV. Prolactin • Prolactin is a peptide hormone secreted from the Prolactin is a peptide hormone secreted from the

anterior pituitary by anterior pituitary by lactotrophlactotroph (mammotroph) cells (mammotroph) cells

• Its structure resembles that of GHIts structure resembles that of GH

• Prolactin is unique among the anterior pituitary Prolactin is unique among the anterior pituitary hormones in that hypothalamic regulation of its hormones in that hypothalamic regulation of its secretion is predominantly inhibitorysecretion is predominantly inhibitory

• Prolactin production is inhibited by the Prolactin production is inhibited by the catecholamine catecholamine dopaminedopamine acting through the D acting through the D22

subtype of dopamine receptorsubtype of dopamine receptor

Prolactin secretion and actions. Prolactin is the only anterior pituitary hormone for which a unique stimulatory releasing factor has not been identified. Thyrotropin-releasing hormone (TRH), however, can stimulate prolactin release and dopamine can inhibit it. Suckling induces prolactin secretion, and prolactin affects lactation and reproductive functions but also has varied effects on many other tissues. Prolactin is not under feedback control by peripheral hormones

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IV. Prolactin • Prolactin primary function is to stimulate and Prolactin primary function is to stimulate and

maintain of lactation: it plays an important role in maintain of lactation: it plays an important role in inducing growth and differentiation of the ductal inducing growth and differentiation of the ductal and lobuloalveolar epitheliumand lobuloalveolar epithelium

• It decreases sexual drive and reproductive It decreases sexual drive and reproductive functionfunction

• No preparation of prolactin is available for use in No preparation of prolactin is available for use in prolactin-deficient patientsprolactin-deficient patients

• Dopamine agonists are used to inhibit prolactin Dopamine agonists are used to inhibit prolactin secretion in patients with symptomatic secretion in patients with symptomatic hyperprolactinemiahyperprolactinemia

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IV. Prolactin • Prolactin receptors are widely distributed cell Prolactin receptors are widely distributed cell

surface receptors that belong to the cytokine surface receptors that belong to the cytokine receptor superfamily and thus share structural receptor superfamily and thus share structural similarity with the receptors for GHsimilarity with the receptors for GH

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Dopamin agonistsDopamin agonists

• Dopamine agonists suppress prolactin release Dopamine agonists suppress prolactin release viavia activation of Dactivation of D22 dopamine receptors dopamine receptors

• Agents: Agents: o Ergot derivatives: Ergot derivatives: bromocriptinebromocriptine, , cabergolinecabergoline, & , &

pergolidepergolideo Non-ergot derivative:Non-ergot derivative: Quinagolide Quinagolide

• All available dopamine agonists are active as oral All available dopamine agonists are active as oral preparationspreparations

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Dopamin agonists- Clinical UsesDopamin agonists- Clinical Uses

1.1. HyperprlactinemiaHyperprlactinemia

2.2. Acromegaly:Acromegaly: alone or in combination with alone or in combination with pituitary surgery, irradiation, or octreotidepituitary surgery, irradiation, or octreotide

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Hormones of the posterior Hormones of the posterior pituitary glandpituitary gland

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IntroductionIntroduction

• Two posterior pitutary hormones: oxytocin & Two posterior pitutary hormones: oxytocin & arginine vasopressinarginine vasopressin

• Are synthesized in neuronal cell bodies in the Are synthesized in neuronal cell bodies in the hypothalamus and transported to the posterior hypothalamus and transported to the posterior pituitary, where they are stored and then released pituitary, where they are stored and then released into the circulation into the circulation

• Vasopressin & oxytocin are not regulated by Vasopressin & oxytocin are not regulated by releasing hormonesreleasing hormones

• They are released in response to specific They are released in response to specific physiologic signalsphysiologic signals

Synthesis, storage, and release of posterior pituitary hormones

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I. OxytocinI. Oxytocin

• Oxytocin is a peptide hormone secreted by the Oxytocin is a peptide hormone secreted by the posterior pituitary that participates in labor and posterior pituitary that participates in labor and delivery and elicits milk ejection in lactating delivery and elicits milk ejection in lactating womenwomen

• Stimuli for oxytocin secretion include sensory Stimuli for oxytocin secretion include sensory stimuli arising from dilation of the cervix and stimuli arising from dilation of the cervix and vagina and from suckling at the breastvagina and from suckling at the breast

• Has weak antidiuretic & pressor activityHas weak antidiuretic & pressor activity

• Oxytocin acts through G protein-coupled Oxytocin acts through G protein-coupled receptors and the phosphoinositide-calcium receptors and the phosphoinositide-calcium second-messenger system to contract uterine second-messenger system to contract uterine smooth musclesmooth muscle

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Physiological rolePhysiological role

A.A. The uterus: The uterus: • During the third trimester, estrogen induces During the third trimester, estrogen induces

oxytocin receptor synthesisoxytocin receptor synthesis• Uterine smooth muscle becomes Uterine smooth muscle becomes

increasingly sensitive to the stimulant action increasingly sensitive to the stimulant action of endogenous oxytocinof endogenous oxytocin

• Oxytocin stimulates the frequency and force Oxytocin stimulates the frequency and force of uterine contractionsof uterine contractions

• Oxytocin also stimulates the release of Oxytocin also stimulates the release of prostaglandins and leukotrienes that prostaglandins and leukotrienes that augment uterine contractionaugment uterine contraction

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Physiological rolePhysiological role

B.B. The breast: The breast: • Oxytocin secretion causes contraction of the Oxytocin secretion causes contraction of the

myoepithelium that surrounds alveolar myoepithelium that surrounds alveolar channels in the mammary glandchannels in the mammary gland

• This action forces milk from the alveolar This action forces milk from the alveolar channels into large collecting sinuses, channels into large collecting sinuses, where it is available to the suckling infantwhere it is available to the suckling infant

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A.A. Oxytocin challenge test (OCT): Oxytocin challenge test (OCT): used to used to assess fetal well-beingassess fetal well-being

B.B. Induction of Labor Induction of Labor for conditions requiring for conditions requiring early vaginal delivery such as Rh problems, early vaginal delivery such as Rh problems, maternal diabetes, preeclampsia, or ruptured maternal diabetes, preeclampsia, or ruptured membranesmembranes

C.C. Augment abnormal labor Augment abnormal labor that is protracted or that is protracted or displays an arrest disorderdisplays an arrest disorder

D.D. Control of uterine hemorrhage Control of uterine hemorrhage after vaginal or after vaginal or cesarean delivery cesarean delivery

E.E. Impaired milk ejection (intranasally)Impaired milk ejection (intranasally)

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CCcontraindicationscontraindications

1.1. Fetal distressFetal distress

2.2. PrematurityPrematurity

3.3. Abnormal fetal presentationAbnormal fetal presentation

4.4. Cephalopelvic disproportion Cephalopelvic disproportion

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Oxytocin antagonist (Atosiban)Oxytocin antagonist (Atosiban)

• Peptide analogs that competitively inhibit the Peptide analogs that competitively inhibit the interaction of oxytocin with its receptorinteraction of oxytocin with its receptor

• Administered by IV infusion for 2–48 hoursAdministered by IV infusion for 2–48 hours

• Indicated to halt premature/preterm labour Indicated to halt premature/preterm labour (tocolysis) (not approved by the US FDA)(tocolysis) (not approved by the US FDA)

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II. Vasopressin (Antidiuretic Hormone, ADH)II. Vasopressin (Antidiuretic Hormone, ADH) • Peptide hormone released by the posterior Peptide hormone released by the posterior

pituitary in response to rising plasma tonicity pituitary in response to rising plasma tonicity or falling blood pressureor falling blood pressure

• It possesses antidiuretic & vasopressor It possesses antidiuretic & vasopressor properties properties

• Deficiency results in diabetes insipidusDeficiency results in diabetes insipidus

• Vasopressin is administered by IV or IM Vasopressin is administered by IV or IM injectioninjection

• The half-life of circulating vasopressin is The half-life of circulating vasopressin is approximately 15 minutesapproximately 15 minutes

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Desmopressin acetate (DDAVP)Desmopressin acetate (DDAVP)

• Long-acting synthetic analog with Long-acting synthetic analog with minimal Vminimal V11 activity and an antidiuresis/ activity and an antidiuresis/

vaspressor ratio 4000x that of vaspressor ratio 4000x that of vasopressinvasopressin

• Can be administered IV, SC, intranasally, Can be administered IV, SC, intranasally, or orallyor orally

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Mechanism of actionMechanism of action

• Vasopressin activates two subtypes of G-protein Vasopressin activates two subtypes of G-protein coupled receptors:coupled receptors:

– VV11 (or V (or V1a1a) receptors) receptors are found on vascular are found on vascular

smooth muscle cells and mediate vasoconstriction smooth muscle cells and mediate vasoconstriction via the coupling protein Gvia the coupling protein Gqq

– VV22 receptors receptors are found on renal tubule cells and are found on renal tubule cells and

reduce diuresis through increased water reduce diuresis through increased water permeability and water resorption in the collecting permeability and water resorption in the collecting tubules via Gtubules via Gss

• Extrarenal VExtrarenal V22-like receptors mediate release of -like receptors mediate release of

coagulation factor VIII & von Willebrand factorcoagulation factor VIII & von Willebrand factor

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1.1. Pituitary diabetes insipidus: Vasopressin and Pituitary diabetes insipidus: Vasopressin and desmopressindesmopressin

2.2. Control bleeding in some cases of esophageal Control bleeding in some cases of esophageal variceal & colonic diverticular bleeding: variceal & colonic diverticular bleeding: VasopressinVasopressin

3.3. Nocturnal enuresis: Nocturnal enuresis: bedtime desmopressin bedtime desmopressin therapy, by intranasal or oral administration, therapy, by intranasal or oral administration, ameliorates nocturnal enuresis by decreasing ameliorates nocturnal enuresis by decreasing nocturnal urine productionnocturnal urine production

4.4. treatment of coagulopathy in hemophilia A and treatment of coagulopathy in hemophilia A and von Willebrand's disease: Desmopressinvon Willebrand's disease: Desmopressin

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Vasopressin receptors agonists & Vasopressin receptors agonists & antagonistsantagonists

• Many vasopressin analogues were Many vasopressin analogues were synthesized to:synthesized to:

1)1) Increase the duration of action Increase the duration of action

2)2) Improve selectivity for vasopressin Improve selectivity for vasopressin receptor subtypes (V1 vs. V2 receptor subtypes (V1 vs. V2 vasopressin receptors)vasopressin receptors)

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Vasopressin antagonists (Vaptans)Vasopressin antagonists (Vaptans)

• Agents: Agents: convivaptanconvivaptan and and tolvaptan tolvaptan

• Non-peptide ADH receptor antagonistsNon-peptide ADH receptor antagonists

• ADH antagonists inhibit the effect of ADH in ADH antagonists inhibit the effect of ADH in the collecting tubulesthe collecting tubules

• Conivaptan has high affinity for both VConivaptan has high affinity for both V1a1a and and

VV22 receptors (non-selective) receptors (non-selective)

• Tolvaptan has a 30-fold higher affinity for VTolvaptan has a 30-fold higher affinity for V22

than for Vthan for V11 receptors receptors

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• Clinical uses:Clinical uses:oConivaptan is approved by the FDA for Conivaptan is approved by the FDA for

intravenous administration in hyponatremiaintravenous administration in hyponatremia

o Tolvaptan is approved by the FDA for Tolvaptan is approved by the FDA for treatment of patients with clinically treatment of patients with clinically significant hypervolemic and euvolemic significant hypervolemic and euvolemic hyponatremia, including patients with heart hyponatremia, including patients with heart failure, cirrhosis, and the syndrome of failure, cirrhosis, and the syndrome of inappropriate antidiuretic hormone inappropriate antidiuretic hormone secretionsecretion

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• ADEs:ADEs:1)1) Nephrogenic diabetes inspidus Nephrogenic diabetes inspidus

2)2) Severe hyponatermia is serum Na+ is not Severe hyponatermia is serum Na+ is not monitored closelymonitored closely

1 1 chapter: 37 hypothalamic & pituitary hormones

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