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Anterior pituitary hormones

Anterior pituitary hormones. Five secretory cells producing 6 different hormones Cortocotroph ACTH Gonadotroph LH and FSH Somatotroph GH Lactotroph Prolactin Thyrotroph TSH. ACTH. Part of larger protein Pro-opiomelanocortin One gene (8kb, three exons and two introns)

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Anterior pituitary hormones

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  1. Anterior pituitary hormones

  2. Five secretory cells producing 6 different hormones • Cortocotroph • ACTH • Gonadotroph • LH and FSH • Somatotroph • GH • Lactotroph • Prolactin • Thyrotroph • TSH

  3. ACTH • Part of larger protein • Pro-opiomelanocortin • One gene (8kb, three exons and two introns) • Codes for one large protein • Transcription of gene • Activated by CRH, arginine vasopressin, cytokines • Inhibted by glucocorticoids

  4. Transcription of POMC gene • CRH type 1 receptor • Production of cAMP and activation of protein kinase A pathway • Activation of CREB transcription factor • Activation of MAP-Kinase pathway • Cytokine receptor (LIF) • Activation of JAK/Stat pathway • Interaction with CRH signaling pathway

  5. Pro-opiomelanocortin • 266 amino acids • Proteolytically cleaved to produce corticotrophic, opioid, and melanotrophic peptides

  6. Secretion of ACTH • Complex regulation through HPA (hypothalamus-pituitary-adrenal) axis • Circadian and ultradian rhythm • Hypothalamic control (CRH) • Activity of nuclei regulated by glucocorticoids • Pulse amplitude rather than frequency determines circadian rhythm

  7. Regulation of ACTH secretion • Exercise (short and exhausting) • Increased secretion of ACTH • Hypercortisolism in athletes • Stress • Increased production of cortisol • Integration of information received by the CNS • Constrain the inflammation

  8. Action of ACTH • Primary function • Proper maintenance of adrenal gland • Adrenal steroidogenesis • Cholesterol transport • Conversion to pregnenolone • Inhibited by glucocorticoids

  9. Gonadotropins • Two hormones from one type of cells • LH and FSH • Glycoprotein hormones • Two subunits • Alpha • Universal among all glycoprotein hormones • Beta • Hormone specific • Combination of alpha and beta subunits • Essential for biological activity

  10. Synthesis of gonadotropins • Alpha subunit • Generated from different gene • Chromosome 6 • Increased synthesis by GnRH and TRH • Beta subunits • Determinant of biological activity • LH beta on chromosome 19 • FSH beta on chromosome 11

  11. Transcription of LH beta subunit mRNA • GnRH • SF-1 • Estrogen • Transcription of FSH beta • Role of GnRH and steroids • Unclear • Different promoter structure from LH

  12. Regulation of gonadotropin secretion • Pulsatile secretion • Mirror image of GnRH pulses • Frequency and amplitude • LH more sensitive to changes in GnRH • Gonadal steroid hormones • Testosterone • Inhibits secretion • Enhances FSH beta subunit mRNA transcription • Estrogens • Dual function (stimulatory/inhibitory) • Cyclic changes in female during reproductive cycle

  13. Gonadal peptides • Inhibins • Inhibits secretion of FSH • Activins • Stimulates FSH secretion and action • Follistatin • Inhibits FSH secretion and action

  14. Function of gonadotropins • Receptors for LH and FSH • Highly homologous • 50 % of extracellular domain • 80 % of transmembrane domain • Steroidogenesis in male and female • cAMP production • Increased cholesterol availability via increased production of steroidogenic acute regular protein (StAR) • Increased enzyme activity

  15. Function of gonadotropins • Receptors for LH and FSH • Steroidogenesis in male and female • cAMP production • Increased cholesterol availability via increased production of steroidogenic acute regular protein (StAR) • Increased enzyme activity • Development and function of gonadal cells and gametes • FSH

  16. Growth hormone • Human GH gene • Located in chromosome 17 • 66 kb in length • Cluster of genes that encode closely related genes • GH-V • Placental lactogen/chorionic somatotropins • Transcription of GH mRNA • POUF1 transcription factor • Pituitary specificity • Interacts with protein kinase A pathway

  17. Large polypeptide hormone • 191 amino acids • Four alpha helices looped together • Interacts with binding protein (GHBP) • Extends half-life of GH • Found in rodents, rabbits, and humans • Extracellular domain of GH receptor in human and rabbit • Product of alternative transcription in rodents

  18. Regulation of GH secretion • Major GH pulses (70 % of total daily output) • Slow sleep (deep sleep) • Age-related loss of GH • Decrease quality of sleep • Obesity and diabetes • Decreased GH release • Nutritional status • One of the major regulatory factor of GH secretion

  19. Hormones • Steroids • Acute elevation in glucocorticoids (+) • Chronic elevation in glucocorticoids (-) • Gonadal steroids (+) • Thyroid hormones • Inhibitory

  20. Action of GH • Growth and metabolism • Action mediated by IGF-I • Mediation of growth • Endocrine IGF-I • Liver • Local (autocrine/paracrine) IGF-I

  21. Gender-specific pattern of GH secretion • Affects amount of steroidogenic enzymes • Gender-specific pattern of steroidogenesis • Gender-specific pattern of liver enzyme expression • Gender-specific action of GH • Mediated by STAT 5b activity

  22. TSH • Glycoprotein hormone • Alpha and beta subunits • Alpha is identical to that of gonadotropins • Thyrotroph-specific expression • Different region of gene promoter • Gene for TSH beta subunit • Located on chromosome 1 • Transcription regulated by Pit-1

  23. Post-translational modification • Glycosylation • Affects proper molecular folding • Combination of alpha and beta subunits • Regulated by TRH (+) and T3 (-)

  24. Secretion of TSH • Bioactivity of TSH • Glycosylation • Clearance rate • Pulsatile secretion • Not as pronoused as gonadotropins or GH • Low variation in concentrations • Circadian pattern • Increased secretion during night • Independent of sleep

  25. Hormonal regulation • Major factor of TSH secretion • Thyroid hormone concentrations • Extremely important • TRH • Dopamine (-) • Glucocorticoids (-) • SS (-)

  26. Action of TSH • Thyroid hormone production • G-protein coupled receptor • Thyroid cell integrity maintenance

  27. Prolactin • Structurally similar to GH • Common ancestry • Chromosome 6 • Prolactin gene expression • Estrogen • Dopamine • TRH • Thyroid hormones

  28. Exits as monomer or polymer in circulation • 23 kDa (monomer) • Most bioactive • 48-56 kDa (dimer) • > 100 kDa (polymer) • Glycosylated • Less active • Binds to prolactin binding protein

  29. Regulation of prolactin secretion • Inhibitory • Hypothalamic • Dopamine • Calcitonin • Paracrine factors • Endothelin-1 • TGF-beta 1

  30. Stimulatory • Growth factors • bFGF • EGF • Gut hormone • VIP • Estrogen

  31. Function of prolactin • Essential for survival • Lactation • Prolactin surge during labor • Essential for initiation of lactation • Not required for maintenance of lactation • Immune function • Stimulates lymphocyte development • Reproduction • Essential for rodents

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