Anterior pitutary hormones


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Physiology and pharmacology of anterior pitutary hormones

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  • 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,
  • 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
  • Anterior pitutary hormones

    1. 1. Anterior pitutary hormones <br />
    2. 2. Hormone<br />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 <br />
    3. 3. Types of cell-to-cell signaling<br />Endocrine Hormones: travel via bloodstream to target cells<br />Neurocrine hormones: released from nerve terminals<br />Paracrine hormones: act on adjacent cells <br />Autocrine hormones: Released and act on the cell that secreted them. <br />Intracrine Hormones: act within the cell that produces them. <br />
    4. 4. Classification of hormones <br /><ul><li>Depending upon chemical nature
    5. 5. Amines or amino acid derivatives
    6. 6. Catecholamines, thyroid hormones
    7. 7. Proteins & polypeptides
    8. 8. Posterior pitutary hormones: oxytocin, vasopressin
    9. 9. Insulin , glucagon, PTH, other anterior pitutary hormones
    10. 10. Steroid hormones
    11. 11. Glucocorticoids, mineralocorticoids, sex steroids, Vit D
    12. 12. Depending on Mechanism of action
    13. 13. Group I & Group II hormones </li></li></ul><li>Depending on MOA<br /><ul><li>Group I: bind to intracellular receptors
    14. 14. Group II: Involve second messenger
    15. 15. A: cyclic AMP: ACTH, ADH, CRH, FSH, LH,TSH, PTH
    16. 16. B: cyclic GMP: Atrial natriuretic factor, NO
    17. 17. C: calcium/PI: AcH, catecholamines 1, gastrin, oxytocin, TRH, GnRH
    18. 18. D:kinases/phosphatase: erythropoetin, GH, insulin, IGF, NGF, prolactin </li></li></ul><li>Regulation of hormone secretion <br /><ul><li>Feed back control
    19. 19. Negative feed back
    20. 20. Long loop feed back
    21. 21. Short loop feed back
    22. 22. Ultra short loop feed back
    23. 23. Positive feed back
    24. 24. Neural control
    25. 25. Chronotrophic control </li></li></ul><li>Negative feed back control <br /><br />Hypothalamus<br />Long loop <br /><br />Ultra Short loop <br />Hypophysiotrophic hormone <br /><br />Anterior pitutary<br />Pitutarytrophic hormone <br />Short loop <br />Target gland <br />Target gland hormone <br />
    26. 26. Negative feedback effects of cortisol<br />
    27. 27. Feedback control of insulin by glucose concentrations<br />
    28. 28. Neural control <br /><ul><li>Evokes or supresses hormone secretion in response to external & internal stimuli
    29. 29. External stimuli: visual, auditory, olfactory
    30. 30. Internal stimuli: pain, emotion, fright
    31. 31. Examples of neural control
    32. 32. Oxytocin : fills milk ducts in response to suckling
    33. 33. Aldosterone: augments circulatory volume in response to upright posture
    34. 34. Release of melatonin: in response to darkness</li></li></ul><li>Chronotropic control<br /><ul><li>Endogenous neuronal rhythmicity
    35. 35. Diurnal rhythms, circadian rhythms (growth hormone and cortisol), Sleep-wake cycle; seasonal rhythm</li></li></ul><li>Episodic secretion of hormones<br /><ul><li>frequency of about one hour—circhoral
    36. 36. An episode of release longer than an hour, but less than 24 hours: ultradian
    37. 37. If the periodicity is approximately 24 hours, the rhythm is referred to as circadian
    38. 38. usually referred to as diurnal because the increase in secretory activity happens at a defined period of the day. </li></li></ul><li>Circadian (chronotropic) control<br />
    39. 39. Circadian Clock<br />
    40. 40. Physiological importance of pulsatile hormone release <br /><ul><li>Demonstrated by GnRH infusion
    41. 41. If given once hourly, gonadotropin secretion and gonadal function are maintained normally
    42. 42. A slower frequency won’t maintain gonad function
    43. 43. Faster, or continuous infusion inhibits gonadotropin secretion and blocks gonadal steroid production</li></li></ul><li>Functions of the hormones <br />Growth & differentiation <br />Maintenance of homeostasis <br />Reproduction<br />Regulation of biochemical reactions <br />
    44. 44. Role of hypothalamus <br />Highest relay centre <br />Integrates endocrine & ANS and ensures the smooth coordination by the cerebral cortex <br />Hypothalamic regulatory hormones <br />Releasing hormones <br />TRH, GnRH, GHRH,CRH, MSH-RF, Prolactin Releasing factor <br />Releasing inhibitory hormones <br />GH-RIH, MSH-RIF, PIF <br />
    45. 45. Anterior pitutary hormones <br />
    46. 46. Pitutary gland <br />
    47. 47. Anterior pitutary hormones <br />Acidophils: <br />Somatotrophes: Growth hormone<br />Lactotrophes: Prolactin<br />Basophils:<br />Gonadotrophes: FSH & LH<br />Thyrotropes: TSH<br />Corticolipotrohes: ACTH <br />
    48. 48. Growth hormone <br />191 amino acid <br />22000 molecular weight <br />Physiological Functions:<br />Growth of organs <br />Positive nitrogen balance <br />Direct and indirect actions <br />
    49. 49. Regulation of secretion <br />GHRH & GHIH secreted by hypothalamus <br />GH Release stimulated by <br />Dopamine<br />5 HT <br />α2 Agonist <br />GH Release inhibited by <br />IGF-1<br />Free Fatty Acids<br />Beta Agonist <br />GH itself <br />Amplitude of secretory pulses is maximal at night <br />
    50. 50. Provocative stimuli for GH<br />Arginine<br />Glucagon <br />L-Dopa<br />Insulin <br />Clonidine<br />
    51. 51. Syndromes associated with GH <br />Deficiency of GH <br />Dwarfism <br />Increased CVS Mortality <br />Excess GH<br />Gigantism <br />Acromegaly<br />
    52. 52. Dwarfism <br />Shortness of stature <br />Growth retardation in all parts of body proportionately <br />Normal mental activity <br />Immature faces <br />Delicate extremities <br />Sexual maturity does not occur if associated with gonadotropin deficiency <br />
    53. 53. Gigantism <br />Abnormal height <br />Large hands and feet<br />Coarse facial features <br />Bilateral gynaecomastia<br />Loss of libido <br />Hyperglycemia <br />
    54. 54. Acromegaly<br />Acromegalic face:<br /> thick lips, macroglossia, prominent eye brows<br />Broad thick nose, thickened skin <br />Prognathism<br />Protrusion of lower jaw<br />Spade like hands, thick wide fingers, large feet<br />Kyphosis<br />Organomegaly<br />
    55. 55. Treatment of GH Deficiency <br />Cadaveric pitutary growth hormone <br />Human recombinant preparations <br />Somatotropin<br />Somatotrem<br />Encapsulated somatotropin<br />Sermorelin acetate <br />
    56. 56. Somatropin<br />Growth hormone preparation whose sequence matches native growth hormone <br />
    57. 57. Somatrem<br />Derivative of growth hormone with additional methionine at amino terminus <br />Somatropin and somatrem have similar biological action and potencies <br />Half life = 20 minutes but biological action lasts 9-17 hrs <br />Once daily administration is sufficient <br />
    58. 58. Encapsulated somatropin<br />Injected IM once or twice per month <br />
    59. 59. Sermorelin acetate <br />A synthetic form of Human GHRH <br />Peptide of 29 Aminoacids corresponds to first 29 AA of Human GHRH <br />Has full biological activity <br />Well tolerated , Less expensive <br />But less effective will not work in defects of anterior pitutary<br />
    60. 60. Uses of Growth hormone <br />Replacement therapy <br />20-40 microgram/ kg Subcutaneously daily <br />Turners syndrome <br />50 microgram/kg <br />Aids associated wasting <br />3-4 microgram / kg <br />
    61. 61. Adverse effects<br />↑ ICT with papilloedema<br />Visual changes<br />Headache, nausea<br />Leukemia <br />↑ incidence of type 2 DM<br />Adults:<br /> Edema, carpal tunnel syndrome, arthralgia, myalgia<br />
    62. 62. Agents used in GH excess<br />Somatostatin<br />Somatostatin analogs <br />Octreotide<br />Lanreotide<br />Vapreotide<br />Sandostatin<br />Dopamine receptor agonists: bromocriptine<br />GH antagonist: Pegvisomant<br />
    63. 63. Somatostatin<br />GHIH<br />Non specific<br />TSH, insulin, gastrin<br />Half life = 1-3 min<br />Rebound increase in GH after its discontinuation <br />Not preferred <br />
    64. 64. Octreotide<br />More specific for Growth hormone <br />Less chances of hyperglycemia <br />Uses<br />Carcinoid syndrome <br />VIP secreting tumors <br />Gastrinoma<br />Secretorydiarhoea: AIDS, DM<br />IBS , Esophageal Varices , insulinoma<br />Dose: 50 -200 µg TDS subcutaneously <br />
    65. 65. Sandostatin<br />Slow releasing form <br />20-40 mg IM 4 weekly <br />Adverse effects of somatostatin analogs <br />Abdominal pain <br />Steathorrea<br />GB stone <br />Vit B12 deficiency <br />
    66. 66. Prolactin<br />198 Amino acid peptide hormone <br />Synthesis and secretion starts in fetal pitutary<br />↓ Secretion of prolactin by <br />Hypothalamic regulation (D2<br />↑ secretion of prolactin by <br />Stress, exertion, hypoglycemia<br />TRH, VIP, prolactin releasing peptide <br />
    67. 67. Regulation of prolactin<br />
    68. 68. Mechanism of action <br />
    69. 69. Physiological effects <br />Growth & development of breast <br />Growth and development of ductal and lobular epithelium <br />Induce lactation after birth of baby <br />Increased prolactin levels supress normal menstrual cycle <br />
    70. 70. Hyperprolactinemia<br />Females: <br />Galactorrhea and amenorrhoea<br />Infertility <br />Males:<br />Loss of libido <br />Infertility <br />Drugs causing hyperprolactinemia<br />Chlorpromazine, haloperidol, metoclopramide<br />Reserpine , alpha methyl dopa<br />
    71. 71. Treatment of hyperprolactinemia<br />Dopaminergic agonists <br />Bromocriptine<br />Cabergoline<br />Pergolide<br />Quinagolide<br />
    72. 72. Bromocriptine<br />Uses <br />Hyperprolactinemia<br />Acromegaly<br />Parkinsonism <br />Hepatic coma <br />Supression of lactation <br />
    73. 73. Bromocriptine<br />Pharmacokinetics<br />Only 1/3rd absorbed orally <br />First pass metabolism present <br />Half life = 3 hours <br />Dose: <br />Start 1.25 mg HS <br />After 1 week 1.25 mg can be added in morning <br />Can be increased to 5 mg BD <br />
    74. 74. Bromocriptine<br />Adverse effects<br />Nausea , vomiting <br />Postural hypotension <br />Nasal decongestion<br />Digital vasospasm <br />CNS effects: hallucinations, night mares, insomnia <br />
    75. 75. Pergolide<br />Ergot derivative <br />Cheapest Dopamine agonist <br />Dose= 0.025 mg increased to 0.25 mg gradually <br />
    76. 76. Cabergoline<br />Ergot derivative with longer hlaf life <br />T ½ = 65 hours <br />Higher affinity and selectivity to D2 receptors<br />More effective less toxic <br />Dose= 0.25 mg twice weekly <br />
    77. 77. Quinagolide<br />Non ergot D2 agonist <br />T ½ = 22 hours dose= 0.1 -0.5 mg /day <br />
    78. 78. Gonadotropins (FSH & LH)<br />Hypothalamus releases GnRH in pulses 1-2 hrly<br />GnRh regulates FSH & LH <br />Feed back inhibition of LH>FSH<br />Estrogen & Progesterone inhibit both FSH & LH <br />Inhibin inhibits only FSH <br />Dopamine Inhibits only LH <br />
    79. 79. Physiological functions <br />FSH<br />Females:<br />Gametogenesis<br />Follicular development <br />Estrogen and progesterone production <br />Imp role in Menstrual cycle <br />Males<br />Stimulation & maintainence of spermatogenesis <br />LH <br />Females<br />Ovulation <br />Corpus luteumMaintainence<br />Estrogen & progesterone production <br />Imp role in menstrual cycle<br />Males:<br />Testesterone & androgen biosynthesis <br />
    80. 80. Disturbances of gonadotropin secretion <br />Excess<br />Precocious puberty <br />Deficiency <br />Amenorrhoea, infertility<br />oligospermia<br />
    81. 81. Preparations of gonadotropins<br />Menotropin: FSH + LH<br />Obtained from urine of postmenopausal women<br />Urofollitropin: Pure FSH <br />Preferred in PCOD <br />HCG<br />Obtained From Urine Of Pregnant Females<br />DNA recombinant FSH <br />
    82. 82. Uses of gonadotropins<br />Infertility in females <br />When clomiphene fails <br />Menotropin for 10 days then HCG 10000 IU, IM<br />Infertility in males <br />HCG 1000-2500 IU, IM 3 times in a week <br />Then menotropin after 3-4 months <br />Cryptorchism<br />To aid Invitro fertilization<br />Regress AIDS related Kaposis Sarcoma <br />
    83. 83. Adverse effects <br />Ovarian hyperstimulation, multiple pregnancies <br />Polycystic ovarian disease <br />Pain in lower abdomen <br />Edema, headache, depression<br />Allergic reactions <br />
    84. 84. GnRH & GnRH analogs <br />
    85. 85. Gonadorelin<br />Synthetic GnRH<br />T ½ = 4-6 min <br />Used for testing pitutarygonadal axis in male or female hypogonadism<br />Pulsatile administration IV every 90 min <br />Infertility, cryptorchism. & delayed puberty <br />
    86. 86. GnRH agonists <br />Goserelin<br />Buserilin<br />Leuprolide<br />Naferiline<br />Triptoreline<br />
    87. 87. GnRH agonists <br />Longer acting 6-12 hours <br />Initial increase in LH & FSH <br />But after 1-2 weeks cause desensitization and decrease FSH & LH secretion <br />Decrease estrogen and testesterone<br />They cause pharmacological oopherectomy and orchiectomy<br />
    88. 88. Uses of GnRH analogs <br />Precocious puberty <br />Prostatic carcinoma <br />Breast cancer <br />Contraception: under investigation <br />
    89. 89. Adverse effects <br />Hot flushes <br />Loss of libido <br />Vaginal dryness <br />Osteoporosis <br />Emotional liability<br />
    90. 90. GnRH antagonists Cetrorelix , Granirelix<br />Competitive antagonists <br />Advantage<br />No initial increase in gonadotropins<br />Do not cause histamine release <br />Used in endometriosis 3 mg Cetrorelix SC weekly for 2 months<br />Uterine Fibroids: cetrorelix twice weekly for 1 month before surgery <br />
    91. 91. Thyroid stimulating hormone <br />Stimulates T3 & T4 secretion<br />Induces hyperplasia and hypertrophy of thyroid <br />Promotes oxidation of trapped iodide <br />
    92. 92. ACTH<br />Stimulate cortisol synthesis from adrenal cortex<br />Corticotropin Regulating Hormone (CRH): secreted by hypothalamus regulates it.<br />USES<br />Diagnosis of pitutary –adrenal axis disorders <br />Like corticosteroids but unpredictable action <br />