Anterior pitutary hormones
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Physiology and pharmacology of anterior pitutary hormones
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Anterior pitutary hormones
- 2. Hormone Secretory products of endocrine glands released directly into circulation in small amounts and transported to specific target cells or organs where they exert physiological, morphological or biochemical responses
- 3. Types of cell-to-cell signaling Endocrine Hormones: travel via bloodstream to target cells Neurocrine hormones: released from nerve terminals Paracrine hormones: act on adjacent cells Autocrine hormones: Released and act on the cell that secreted them. Intracrine Hormones: act within the cell that produces them.
- 5. Amines or amino acid derivatives
- 8. Posterior pitutary hormones: oxytocin, vasopressin
- 9. Insulin , glucagon, PTH, other anterior pitutary hormones
- 10. Steroid hormones
- 11. Glucocorticoids, mineralocorticoids, sex steroids, Vit D
- 12. Depending on Mechanism of action
- 14. Group II: Involve second messenger
- 15. A: cyclic AMP: ACTH, ADH, CRH, FSH, LH,TSH, PTH
- 16. B: cyclic GMP: Atrial natriuretic factor, NO
- 17. C: calcium/PI: AcH, catecholamines 1, gastrin, oxytocin, TRH, GnRH
- 20. Long loop feed back
- 21. Short loop feed back
- 22. Ultra short loop feed back
- 24. Neural control
- 26. Negative feedback effects of cortisol
- 27. Feedback control of insulin by glucose concentrations
- 29. External stimuli: visual, auditory, olfactory
- 30. Internal stimuli: pain, emotion, fright
- 31. Examples of neural control
- 32. Oxytocin : fills milk ducts in response to suckling
- 33. Aldosterone: augments circulatory volume in response to upright posture
- 36. An episode of release longer than an hour, but less than 24 hours: ultradian
- 37. If the periodicity is approximately 24 hours, the rhythm is referred to as circadian
- 39. Circadian Clock
- 41. If given once hourly, gonadotropin secretion and gonadal function are maintained normally
- 42. A slower frequency won’t maintain gonad function
- 44. Role of hypothalamus Highest relay centre Integrates endocrine & ANS and ensures the smooth coordination by the cerebral cortex Hypothalamic regulatory hormones Releasing hormones TRH, GnRH, GHRH,CRH, MSH-RF, Prolactin Releasing factor Releasing inhibitory hormones GH-RIH, MSH-RIF, PIF
- 46. Pitutary gland
- 47. Anterior pitutary hormones Acidophils: Somatotrophes: Growth hormone Lactotrophes: Prolactin Basophils: Gonadotrophes: FSH & LH Thyrotropes: TSH Corticolipotrohes: ACTH
- 48. Growth hormone 191 amino acid 22000 molecular weight Physiological Functions: Growth of organs Positive nitrogen balance Direct and indirect actions
- 49. Regulation of secretion GHRH & GHIH secreted by hypothalamus GH Release stimulated by Dopamine 5 HT α2 Agonist GH Release inhibited by IGF-1 Free Fatty Acids Beta Agonist GH itself Amplitude of secretory pulses is maximal at night
- 50. Provocative stimuli for GH Arginine Glucagon L-Dopa Insulin Clonidine
- 51. Syndromes associated with GH Deficiency of GH Dwarfism Increased CVS Mortality Excess GH Gigantism Acromegaly
- 52. Dwarfism Shortness of stature Growth retardation in all parts of body proportionately Normal mental activity Immature faces Delicate extremities Sexual maturity does not occur if associated with gonadotropin deficiency
- 53. Gigantism Abnormal height Large hands and feet Coarse facial features Bilateral gynaecomastia Loss of libido Hyperglycemia
- 54. Acromegaly Acromegalic face: thick lips, macroglossia, prominent eye brows Broad thick nose, thickened skin Prognathism Protrusion of lower jaw Spade like hands, thick wide fingers, large feet Kyphosis Organomegaly
- 55. Treatment of GH Deficiency Cadaveric pitutary growth hormone Human recombinant preparations Somatotropin Somatotrem Encapsulated somatotropin Sermorelin acetate
- 56. Somatropin Growth hormone preparation whose sequence matches native growth hormone
- 57. Somatrem Derivative of growth hormone with additional methionine at amino terminus Somatropin and somatrem have similar biological action and potencies Half life = 20 minutes but biological action lasts 9-17 hrs Once daily administration is sufficient
- 58. Encapsulated somatropin Injected IM once or twice per month
- 59. Sermorelin acetate A synthetic form of Human GHRH Peptide of 29 Aminoacids corresponds to first 29 AA of Human GHRH Has full biological activity Well tolerated , Less expensive But less effective will not work in defects of anterior pitutary
- 60. Uses of Growth hormone Replacement therapy 20-40 microgram/ kg Subcutaneously daily Turners syndrome 50 microgram/kg Aids associated wasting 3-4 microgram / kg
- 61. Adverse effects ↑ ICT with papilloedema Visual changes Headache, nausea Leukemia ↑ incidence of type 2 DM Adults: Edema, carpal tunnel syndrome, arthralgia, myalgia
- 62. Agents used in GH excess Somatostatin Somatostatin analogs Octreotide Lanreotide Vapreotide Sandostatin Dopamine receptor agonists: bromocriptine GH antagonist: Pegvisomant
- 63. Somatostatin GHIH Non specific TSH, insulin, gastrin Half life = 1-3 min Rebound increase in GH after its discontinuation Not preferred
- 64. Octreotide More specific for Growth hormone Less chances of hyperglycemia Uses Carcinoid syndrome VIP secreting tumors Gastrinoma Secretorydiarhoea: AIDS, DM IBS , Esophageal Varices , insulinoma Dose: 50 -200 µg TDS subcutaneously
- 65. Sandostatin Slow releasing form 20-40 mg IM 4 weekly Adverse effects of somatostatin analogs Abdominal pain Steathorrea GB stone Vit B12 deficiency
- 66. Prolactin 198 Amino acid peptide hormone Synthesis and secretion starts in fetal pitutary ↓ Secretion of prolactin by Hypothalamic regulation (D2 ↑ secretion of prolactin by Stress, exertion, hypoglycemia TRH, VIP, prolactin releasing peptide
- 69. Physiological effects Growth & development of breast Growth and development of ductal and lobular epithelium Induce lactation after birth of baby Increased prolactin levels supress normal menstrual cycle
- 70. Hyperprolactinemia Females: Galactorrhea and amenorrhoea Infertility Males: Loss of libido Infertility Drugs causing hyperprolactinemia Chlorpromazine, haloperidol, metoclopramide Reserpine , alpha methyl dopa
- 71. Treatment of hyperprolactinemia Dopaminergic agonists Bromocriptine Cabergoline Pergolide Quinagolide
- 72. Bromocriptine Uses Hyperprolactinemia Acromegaly Parkinsonism Hepatic coma Supression of lactation
- 73. Bromocriptine Pharmacokinetics Only 1/3rd absorbed orally First pass metabolism present Half life = 3 hours Dose: Start 1.25 mg HS After 1 week 1.25 mg can be added in morning Can be increased to 5 mg BD
- 74. Bromocriptine Adverse effects Nausea , vomiting Postural hypotension Nasal decongestion Digital vasospasm CNS effects: hallucinations, night mares, insomnia
- 75. Pergolide Ergot derivative Cheapest Dopamine agonist Dose= 0.025 mg increased to 0.25 mg gradually
- 76. Cabergoline Ergot derivative with longer hlaf life T ½ = 65 hours Higher affinity and selectivity to D2 receptors More effective less toxic Dose= 0.25 mg twice weekly
- 77. Quinagolide Non ergot D2 agonist T ½ = 22 hours dose= 0.1 -0.5 mg /day
- 78. Gonadotropins (FSH & LH) Hypothalamus releases GnRH in pulses 1-2 hrly GnRh regulates FSH & LH Feed back inhibition of LH>FSH Estrogen & Progesterone inhibit both FSH & LH Inhibin inhibits only FSH Dopamine Inhibits only LH
- 79. Physiological functions FSH Females: Gametogenesis Follicular development Estrogen and progesterone production Imp role in Menstrual cycle Males Stimulation & maintainence of spermatogenesis LH Females Ovulation Corpus luteumMaintainence Estrogen & progesterone production Imp role in menstrual cycle Males: Testesterone & androgen biosynthesis
- 80. Disturbances of gonadotropin secretion Excess Precocious puberty Deficiency Amenorrhoea, infertility oligospermia
- 81. Preparations of gonadotropins Menotropin: FSH + LH Obtained from urine of postmenopausal women Urofollitropin: Pure FSH Preferred in PCOD HCG Obtained From Urine Of Pregnant Females DNA recombinant FSH
- 82. Uses of gonadotropins Infertility in females When clomiphene fails Menotropin for 10 days then HCG 10000 IU, IM Infertility in males HCG 1000-2500 IU, IM 3 times in a week Then menotropin after 3-4 months Cryptorchism To aid Invitro fertilization Regress AIDS related Kaposis Sarcoma
- 83. Adverse effects Ovarian hyperstimulation, multiple pregnancies Polycystic ovarian disease Pain in lower abdomen Edema, headache, depression Allergic reactions
- 84. GnRH & GnRH analogs
- 85. Gonadorelin Synthetic GnRH T ½ = 4-6 min Used for testing pitutarygonadal axis in male or female hypogonadism Pulsatile administration IV every 90 min Infertility, cryptorchism. & delayed puberty
- 86. GnRH agonists Goserelin Buserilin Leuprolide Naferiline Triptoreline
- 87. GnRH agonists Longer acting 6-12 hours Initial increase in LH & FSH But after 1-2 weeks cause desensitization and decrease FSH & LH secretion Decrease estrogen and testesterone They cause pharmacological oopherectomy and orchiectomy
- 88. Uses of GnRH analogs Precocious puberty Prostatic carcinoma Breast cancer Contraception: under investigation
- 89. Adverse effects Hot flushes Loss of libido Vaginal dryness Osteoporosis Emotional liability
- 90. GnRH antagonists Cetrorelix , Granirelix Competitive antagonists Advantage No initial increase in gonadotropins Do not cause histamine release Used in endometriosis 3 mg Cetrorelix SC weekly for 2 months Uterine Fibroids: cetrorelix twice weekly for 1 month before surgery
- 91. Thyroid stimulating hormone Stimulates T3 & T4 secretion Induces hyperplasia and hypertrophy of thyroid Promotes oxidation of trapped iodide
- 92. ACTH Stimulate cortisol synthesis from adrenal cortex Corticotropin Regulating Hormone (CRH): secreted by hypothalamus regulates it. USES Diagnosis of pitutary –adrenal axis disorders Like corticosteroids but unpredictable action
Editor's Notes
- Ductless endocrine glands released directly into circulation in catalytic amounts Hormaein: To execute, or to arouse
- Trophic hormones: hormones of anterior pitutary stimulate the synthesis and release of hormones of the target glands (thyroid , adrenal, gonads ) in absence of these hormones the target glands not only stop functioning but also undergo atrophy these hormones are called as trophic hormones.
- Group 1 hormones act through affecting gene expression at cellular level Group 2 hormones act through intermediary molecules called messenger Group1 HORMONES ARE LIPOPHILIC IN NATURE AsecondaryD CAN EASILY PASS ACROSS CELL MMB,
- INTERMEDIATE LOBE : 2 MSH AND 2 LIPOTROPINSPOSTERIOR PITUTARY: OXYTOCIN AZND VASOPRESSIN BUT BOTH THESE HORMONES ARE SYNTESIZED IN HYPOTHALAMUS AND SIMPLY TRANSPORTED VIA NEUROSECRETORY FIBRES OF HYPOTHALAMIC STALK TO POSTERIOR PITUTARY WHERE THEY ARE MAINLY STORED AND RELEASED
- GHIH is also called as somatostatin , also produced by d cells of islets of langerhansMost consistent period of GH SECRETION IS SHORTLY AFTER HE ONSET OF DEEP SLEEP
- Because of episodic release of hormone random estimation is not of value These agents increase the secretion within 45 to 90 min At present insulin induced hypoglycemia is the test advocated by GH RESEARCH SOCIETY
- Mechanisms of growth hormone and prolactin action and of GH receptor antagonism. Left (A): The binding of GH to a homodimer of the growth hormone receptor (GHR) induces autophosphorylation of JAK2. JAK2 then phosphorylatescytoplasmic proteins that activate downstream signaling pathways, including STAT5 and mediators upstream of MAPK, which ultimately modulate gene expression. The structurally related prolactin receptor also is a ligand activated homodimer that recruits the JAK-STAT signaling pathway (see text for further details). The GHR also activates IRS-1, which may mediate the increased expression of glucose transporters on the plasma membrane. The diagram does not reflect the localization of the intracellular molecules, which presumably exist in multicomponentsignaling complexes. JAK2, januskinase 2; IRS-1, insulin receptor substrate-1; PI3K, phosphatidyl inositol-3 kinase; STAT, signal transducer and activator of transcription; MAPK, mitogen-activated protein kinase; SHC, Src homology containing. Right (B): Pegvisomant, a recombinant pegylated variant of human GH, contains amino acid substitutions that increase the affinity for one site of the GHR but do not activate its downstream signaling cascade. It thus interferes with GH signaling in target tissues.The effects of prolactin on target cells also result from interactions with a cytokine receptor that is widely distributed and signals through many of the same pathways as the GH receptor. Alternative splicing of the prolactin receptor gene on chromosome 5 gives rise to multiple forms of the receptor that are identical in the extracellular domain but differ in their cytoplasmic domains. In addition, soluble forms that correspond to the extracellular domain of the receptor are found in circulation. Unlike human GH and placental lactogen, which also bind to the prolactin receptor and thus are lactogenic, prolactin binds specifically to the prolactin receptor and has no somatotropic (GH-like) activity.
- Unlike GH, prolactin does not induce the synthesis of a second hormone that then mediates many of its effects in an indirect manner. Rather, prolactin effects are limited to tissues that express the prolactin receptor, particularly the mammary gland. A number of hormones—including estrogens, progesterone, placental lactogen, and GH—stimulate development of the breast and prepare it for lactation. Prolactin, acting via prolactin receptors, plays an important role in inducing growth and differentiation of the ductal and lobuloalveolar epithelia and is essential for lactation. Target genes, by which prolactin induces mammary development, include those encoding milk proteins (e.g., caseins), genes important for intracellular structure (e.g., keratins), genes important for cell-cell communication (e.g., amphiregulin and Wnt4), and components of the extracellular matrix (e.g., laminin and collagen).Prolactin receptors are present in many other sites, including the hypothalamus, liver, adrenal, testes, ovaries, prostate, and immune system, suggesting that prolactin may play multiple roles outside of the breast. The physiological effects of prolactin at these sites remain poorly characterized, and specific defects in their function that result from prolactin deficiency have not been defined.
- Causes: disorders of hypothalamus reducing contol over pitutaryantidopaminergic or dopamine depleting drugs prolactin secreting tumors hypothyroidism with high TRH values Currently therapeutic options include: transphenoidal surgery for prolactinoma, radiation therapy or dopaminergic agonist
- Synthetic ergot derivative , is a potent dopaminergic agonist, greater action on d2 receptors
- 4 times more potent
- Neural pulse generator is arcuate nucleus
- Given IM,SC OR nasal spray
- Recovery in 2 monyhs
- Used in endometriosis because decrease FSH and thus decrease estrogen