Pituitary and hypothalamus
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Ref Book 1.KG Tripathi,2.HL Sharma & KK Sharma,3 .Sparsh Gupta
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Pituitary and hypothalamus
- 1. Anterior Pituitary and Hormones and Related Drugs Dr Lokendra Sharma Professor Pharmacology SMS Medical College Jaipur
- 3. 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 Hormones???
- 4. 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. Cell to cell signaling ???
- 5. • Growth & Differentiation • Maintenance of homeostasis • Reproduction • Regulation of biochemical reactions Functions of Hormones
- 6. • 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 Role of Hypothalamus ?
- 7. Anterior Pituitary Hormones • Acidophils: • Somatotrophes: Growth hormone – Lactotrophes: Prolactin • Basophils: – Gonadotrophes: FSH & LH – Thyrotropes: TSH – Corticolipotrohes: ACTH
- 8. • 191 amino acid • 22000 molecular weight • Physiological Functions: – Growth of organs – Positive nitrogen balance – Direct and indirect actions Growth Hormones
- 9. • GH Release stimulated by – Dopamine – 5 HT – α2 Agonist • GH Release inhibited by – IGF-1 – Free Fatty Acids – Beta Agonist – GH itself GHRH & GHIH secreted by hypothalamus Amplitude of secretory pulses is maximal at night Regulation of Secretion?
- 10. Provocative stimuli for GH? • Arginine • Glucagon • L-Dopa • Insulin • Clonidine
- 11. Syndromes associated with GH? • Deficiency of GH –Dwarfism –Increased CVS Mortality • Excess GH –Gigantism –Acromegaly
- 12. Dwarfism • Shortness of stature • Growth retardation in all parts of body proportionately Q.Normal mental activity • Immature faces • Delicate extremities Q Sexual maturity does not occur if associated with gonadotropin deficiency
- 13. Gigantism • Abnormal height • Large hands and feet Q.Coarse facial features Q.Bilateral gynaecomastia • Loss of libido • Hyperglycemia
- 14. Acromegaly • Acromegalic face: • Thick lips, macroglossia, • Prominent eye brows – Broad thick nose, thickened skin Q.Prognathism – Protrusion of lower jaw • Spade like hands, thick wide fingers, large feet • Kyphosis
- 15. Treatment of GH Deficiency? • Cadaveric pitutary growth hormone • Human recombinant preparations –Somatotropin –Somatotrem –Encapsulated somatotropin –Sermorelin acetate
- 16. Somatropin • Growth hormone preparation whose sequence matches native growth hormone
- 17. Somatrem • Derivative of growth hormone with additional methionine at amino terminus Q.Somatropin and somatrem have similar biological action and potencies Q.Half life = 20 minutes but biological action lasts 9-17 hrs • Once daily administration is sufficient
- 18. Encapsulated somatropin • Injected IM once or twice per month
- 19. Sermorelin acetate? • A synthetic form of Human GHRH • Peptide of 29 Aminoacids corresponds to first 29 AA of Human GHRH Q.Has full biological activity • Well tolerated , Less expensive Q.But less effective will not work in defects of anterior pitutary
- 20. Uses of Growth hormone • Replacement therapy 20-40 microgram/ kgS.C. daily • Turners syndrome – 50 microgram/kg • Aids associated wasting – 3-4 microgram / kg
- 21. Adverse effects Q.↑ ICT with papilloedema • Visual changes • Headache, nausea • Leukemia Q.↑ incidence of type 2 DM • Adults: – Edema, Carpal tunnel syndrome, arthralgia, myalgia
- 22. Agents used in GH excess • Somatostatin • Somatostatin analogs – Octreotide – Lanreotide – Vapreotide – Sandostatin • Dopamine receptor agonists: Bromocriptine • GH antagonist: Pegvisomant
- 23. Somatostatin • GHIH • Non specific – TSH, insulin, gastrin • Half life = 1-3 min • Rebound increase in GH after its discontinuation • Not preferred
- 24. Octreotide • More specific for Growth hormone • Less chances of hyperglycemia • Uses – Carcinoid syndrome – VIP secreting tumors – Gastrinoma – Secretory diarhoea: AIDS, DM – IBS , Esophageal Varices , insulinoma • Dose: 50 -200 µg TDS subcutaneously
- 25. Sandostatin • Slow releasing form • 20-40 mg IM 4 weekly • Adverse effects of somatostatin analogs – Abdominal pain – Steathorrea – GB stone – Vit B12 deficiency
- 26. Prolactin • 198 Amino acid peptide hormone • Synthesis and secretion starts in fetal pitutary • ↓ Secretion of prolactin by – Hypothalamic regulation • ↑ secretion of prolactin by – Stress, exertion, hypoglycemia – TRH, VIP, prolactin releasing peptide
- 29. Hyperprolactinemia ? • Females: – Galactorrhea and amenorrhoea – Infertility • Males: – Loss of libido – Infertility • Drugs causing hyperprolactinemia – Chlorpromazine, haloperidol, metoclopramide – Reserpine , alpha methyl dopa
- 30. Treatment of hyperprolactinemia • Dopaminergic agonists – Bromocriptine – Cabergoline – Pergolide – Quinagolide
- 31. Bromocriptine • Uses – Hyperprolactinemia – Acromegaly – Parkinsonism – Hepatic coma – Supression of lactation
- 32. 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
- 33. Bromocriptine • Adverse effects – Nausea , vomiting – Postural hypotension – Nasal decongestion – Digital vasospasm – CNS effects: hallucinations, night mares, insomnia
- 34. Pergolide • Ergot derivative Q.Cheapest Dopamine agonist • Dose= 0.025 mg increased to 0.25 mg gradually
- 35. Cabergoline • Ergot derivative with longer half life • T ½ = 65 hours • Higher affinity and selectivity to D2 receptors • More effective less toxic • Dose= 0.25 mg twice weekly
- 36. Quinagolide • Non ergot D2 agonist • T ½ = 22 hours dose= 0.1 -0.5 mg /day
- 37. 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
- 38. Physiological functions • Females: – Gametogenesis – Follicular development – Estrogen and progesterone production – Imp role in Menstrual cycle • Males – Stimulation & maintainence of spermatogenesis FSH LH Females –Ovulation –Corpus luteum Maintainence –Estrogen & progesterone production –Imp role in menstrual cycle Males: –Testesterone & androgen biosynthesis
- 39. Disturbances of gonadotropin secretion • Excess – Precocious puberty • Deficiency – Amenorrhoea, infertility – oligospermia
- 40. 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
- 41. 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
- 42. Adverse effects • Ovarian hyperstimulation, multiple pregnancies • Polycystic ovarian disease • Pain in lower abdomen • Edema, headache, depression • Allergic reactions
- 43. GnRH & GnRH analogs
- 44. Gonadorelin • Synthetic GnRH • T ½ = 4-6 min • Used for testing pitutary gonadal axis in male or female hypogonadism • Pulsatile administration IV every 90 min – Infertility, cryptorchism. & delayed puberty
- 45. GnRH agonists • Goserelin • Buserilin • Leuprolide • Naferiline • Triptorelin e
- 46. 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
- 47. Uses of GnRH analogs • Precocious puberty • Prostatic carcinoma • Breast cancer • Contraception: under investigation
- 48. Adverse effects • Hot flushes • Loss of libido • Vaginal dryness • Osteoporosis • Emotional liability
- 49. 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
- 50. Pegvisomant It is a new GH- receptor antagonist. Mechanism: prevent GH- Binding to its receptor & Suppression of serum IGF-1 levels Uses : Acromegaly( patients resistant to other therapies) ADRs: Pain, Abnormal liver function tests
- 51. Mecasermin It is combination of recombinant human IGF-1 with recombinant human IGFBP-3. This combination maintain desired half life of IGF-1. Uses: 1.Growth failure in children due to deficiency of IGF-1. 2.Treatment of patients with GH gene deletion ADRs: Cardiac murmur, hypoglycemia, iron deficiency anaemia.
- 52. Sermorelin Synthetic peptide analogue of GHRH, given by S.C. Uses: As a diagnostic agent to assess GH secretion for the purpose of diagnosing GH deficiency. Off label uses : Acute or age-related growth hormone insufficiency Side effects: injection site reactions (such as pain, swelling, or redness), headache, flushing,difficulty swallowing,dizziness,,sleepiness,nausea,vomiting
- 53. Hexarelin Potent synthetic, orally-active, centrally- penetrant & highly selective agonist of GHRH. Uses: growth hormone deficiency
- 54. Somatrem It is first recombinant human GH Sequence was identical to human GH except extra methionine at N- terminal Uses: GH deficiency in children but due to short half life require subcutaneous injection once a day Side effects: Precipitation of type 2 diabetes, pain at injection site, fluid retention & headache
- 55. Somatostatin Analogue Vapreotide: Synthetic somatostatin analogue Use: Esophageal variceal bleeding in patients with cirrhotic liver disease, AIDS related diarrhea. Pasireotide: new somatostatin analogue with higher affinity for receptors. Uses: orphan drug for cushing disease Seglitide: is another potent somatostatin analogue
- 56. Quinagoline • It is oral selective D-2 receptor agonist. • Racemic mixture of two enantiomers • Uses: • Hyperprolactinemia, breast pain, acromegaly • Side effects: • nausea, headache, orthostatic hypotension.
- 57. MCQ
- 58. Which of the following is not an adverse effect of growth hormone therapy? a.Carpal tunnel syndrome b.Hypoglycemia c. Intracranial hypertension d.Slipped femoral epiphysis (b)
- 59. Which of the following is used in the treatment of hyperprolactinemia? a. Cimetidine b. Methysergide c. Bromocriptine d. Ondanesetron (c)
- 60. Octerotide is used in all except a. Glucagonoma b. Insulinoma c. Carcinoids syndrome d. Glioma (d)
- 61. All of the following statements about octerotide are true except a. It is effective orally b. It is used for the treatment of acromegaly c. It can be used for the management of secretory diarrhea d. It can be used in portal hypertension (a)
- 62. Octreotide is useful in esophageal varices. It is a synthetic analogue of somatostatin. The true statement regarding this drug is a.It can be given orally b.It is longer acting than somatostatin c. Its major adverse effects is secretary diarrhea d.All of the above (b)
- 63. All of the following agents are useful in acromegaly except a. Bromocriptine b. Somatostatin c. Octreotide d. Nafarelin (d)
- 64. Mechanism of action of bromocriptine is via a. Agonism at D2 receptors b. Antagonism at D2 receptors c. Antagonism at D1 receptors d. Antagonism at α receptors (a)
- 65. Important difference between leuprolide and ganirelix is that ganirelix a. Can be given orally b. Immediately reduces gonadotropin secretion c. Must be given in a pulsatile fashion d. Initially stimulates release of LH and FSH (b)
- 66. Long acting dopamine agonist is a. Bromocriptine b. Lisuride c. Cabergoline d. Apomorphine (c)
- 67. Bromocriptine is useful in all except a. Parkinsonism b. Prolactinoma c. Endogenous depression d. Infertility (c)
- 68. Drugs used for treatment of acute variceal bleeding are all except a. Octreotide b. Somatostatin c. Desmopressin d. Terlipressin (c)
- 69. GnRH analogue used in hormonal treatment of carcinoma prostate is? a. Goserelin b. Nilutamide c. Cyproterone acetate d. Finasteride (a)
- 70. Which of the following is given at intervals as a pulsatile therapy? a. GnRH b. GH c. FSH d. Estrogen (a)
- 71. True regarding use of bromocriptine for suppression of lactation includes a. It can cause deep vein thrombosis b. It can cause hypotension c. Metoclopramide potentiates the action of bromocriptine d. It is given for 1 week only (b)
- 72. The clinical use of leuprolide include all the following EXCEPT a. Endometriosis b. Osteoporosis c. Prostate cancer d. Precocious puberty (b)
- 73. Thanks