Reproductive Hormones; Male Reproductive Endocrinology

1. Reproductive Hormones; Male Reproductive Endocrinology Chapters 16, 17

3. Hypothalamus • GnRH • Peptide • Gonadotroph target • G-prot linked heptahelical transmembr • Gaq  PLC pathway •  IP3-Ca, DAG-PKC-MAP kinase  expression of a subunit common to FSH/LH • Also  opening of voltage gated Ca channels  Ca influx

4. Anterior Pituitary • FSH, LH • Glycoprot’s sim to TSH, hCG • Share common a subunit • Hormone specific b subunits • LH b subunit • Stim’d w/ GnRH @ higher freq’s, amp’s • Suppressed w/ • Androgens, progesterone (inhib freq GnRH pulses) • Estrogens (directly @ pit) • Testosterone  estradiol in pit (via aromatase)

5. FSH b subunit • Highest when low freq GnRH pulses • Stim’d w/ • Activins  incr’d FSH b mRNA (autocrine) • Suppressed w/ • Sertoli cell inhibin B • Testosterone/DHT • Receptors on gonads • cAMP  PKA act’n  act’n enz’s for steroid biosynth

6. Gonads • Gametogenesis, hormonogenesis • Sex steroids • Note: also prod’d by adrenal gland • Prior to puberty, basal levels secr’d • Hypothal very sensitive • Feedback inhibitory control of GnRH, LH/FSH • Endocrine • Testosterone major testes secretion • Estradiol major ovarian secretion

7. Male Reproductive Anatomy (Human) • Organs • Gonads: prod gametes, secrete hormones • Ducts: transport, store gametes • Accessory sex glands: support gametes • Scrotum • Supports testes • Cremaster muscle • Temp reg’n

8. Penis • Root, body, glans • Dilation arteries w/ parasymp stim’n  erection • Incr’d blood flow  expansion blood sinuses • Sinuses compress veins, trap entering blood • Ejaculation: symp reflex • Peristalsis smooth muscle • Propels semen from urethra to exterior

9. Accessory sex glands • Seminal vesicles • Secrete viscous, alkaline fluid (60% semen vol) • Prostate gland • Secretes alkaline fluid (25% vol) • Impt to sperm viability, motility • Bulbourethral gland • Secretes mucus, alkaline fluid

10. Semen • Sperm + secr’ns • 120 x 106 sperm/mL • Alkaline, nutrient secr’ns • Vol: 2-6 mL • Seminalplasmin=antibiotic

12. Ducts • Urethra • Spermatic cord • Testicular artery + autonomic nerves + veins + lymph vessels + cremaster muscle + vas deferens • Vas deferens • Result of epidimi fusion • Stores mature sperm • Ductus epididymis • Sperm maturation, storage • Rete testis • Result of seminiferous tubule fusion • Gives rise to ducts

14. Testes • Fibrous outer layer; connective tissue; lobules w/ seminiferous tubules • Interstitium between seminiferous tubules contain Leydig cells (interstitial endocrinocytes)

18. Leydig Cells • Testicular androgen production • From cholesterol (liver) • Cycopentanoperhydophenanthrene nucleus • Signal = LH @ plasma membr receptor • Heptahelical

24. Sex Steroid Biosynthesis • Cholesterol  pregnenolone • W/in Leydig cell mitoch matrix • Cat’d by P450scc • Family of microsomal metab enz’s • CYP genes • 17a-hydroxylase (P450C17) dominant in gonads  sex steroids (fig.15.3) • 3b hydroxylases/isomerases sensitive to FSH

26. Pregnenolone: produced directly from cholesterol, the precusor molecule for all C-18, C-19 and C-21 steroids  Cortisol:dominant glucocorticoid in humans, synthesized from progesterone in the zona fasciculata of the adrenal cortex, involved in stress adaptation, elevates blood pressure and Na+ uptake, numerous effects on the immune system Aldosterone: the principal mineralocorticoid, produced from progesterone in the zona glomerulosa of adrenal cortex, raises blood pressure and fluid volume, increases Na+ uptake 

27. Progesterone: a progestin, produced directly from pregnenolone and secreted from the corpus luteum, responsible for changes associated with luteral phase of the menstral cycle, differentiation factor for mammary glands Testosterone: an androgen, male sex hormone synthesized in the testes, responsible for secondary male sex characteristics, produced from progesterone  Estradiol: an estrogen, principal female sex hormone, produced in the ovary, responsible for secondary female sex characteristics 

28. Most cholesterol extracell • Lipoproteins • Also de novo • Pathway: via cAMP  act’n PKA  act’n steroid synthesis enzyme(s) • Rate limiting: delivery cholesterol to P450scc in mitoch matrix • PKA-mediated induction steroidogenic acute regulatory protein (StAR)

29. StAR=Steroidogenic Acute Regulator protein • Synth induced w/ LH-receptor binding • Transiently inc’d into outer mitoch membr • Activates PBR • PBR=Peripheral-type Benzodiazepine Receptor • Transmembr prot • “Mitochondrial porin” • Allows cholesterol  mitoch matrix and exposure to P450scc

32. Major product=testosterone • Other androgens (fig.17.2), also estrogens • DHT • Potent activator androgen receptor • “Intracrine” • 5a reductase cat’s synth • Almost all in periph tissues • Impt to male embryonic dev’t + 2o sex char’s • Also endocrine

34. Aromatase • sER membrane anchored • CYPC19 gene • Rel’d to CYP11A (mitoch P450scc) • Rel’d to CYP1A1 (monooxygenase reg’d by aryl hydrocarbon receptor • Diff tissues  diff isozymes and/or diff promoters • Assoc’d w/ cytP450 reductase

35. Aromatase – cont’d • Steroids • Effects ox’n, cleavage C19 Me •  Aromatization testosterone A ring •  Estradiol • In males, adipose tissue has active aromatase • Correlation BMI/gynecomastia • Impt to feedback control @ hypothal, ant pit

36. Progesterone: a progestin, produced directly from pregnenolone and secreted from the corpus luteum, responsible for changes associated with luteral phase of the menstral cycle, differentiation factor for mammary glands Testosterone: an androgen, male sex hormone synthesized in the testes, responsible for secondary male sex characteristics, produced from progesterone  Estradiol: an estrogen, principal female sex hormone, produced in the ovary, responsible for secondary female sex characteristics 

37. Plasma binding proteins nec in systemic circ’n • 40% bound to SHBG • 40% bound to albumin • 17% bound to other prot’s • SHBG • Prod’d by liver • Homodimeric w/ testicular ABP • Chromosome 17p12-13 • Differ by oligosacch’s • Higher affinity for testosterone over estrogens • Glycosylation incr’d by estrogens •  more SHBG •  more bound T; more free E2

38. SHBG – cont’d • Glycosylation impt for recognition of cell surface receptors • Can bind target tissues if not bound to ligand • SHBG receptor • Presumed heptahelical transmembr • Known cAMP/PKA mediation • Binding SHBG  enhancement cAMP effects w/ subsequent steroid binding • Androgen receptor act’n • Others

39. Seminiferous Tubules • Formed from specialized epithelium • Epith = Sertoli cells (sustentacular cells) • Support, nourish • Mediate hormonal effects • Control sperm movement • Secrete • Fluid • Inhibin B • Form blood-testis barrier

41. FSH at Sertoli cells • Cell proliferation • Secretion • Secretory prod’s of Sertoli’s • Inhibin • At ant pit: inhibits FSH-b secr’n • At Sertoli’s: antagonizes FSH prolif’n • Transferrin (prot) • Shuttles Fe through blood-testis barrier • Fe needed in mitoch cytochromes

42. Sperm Development in Seminiferous Tubule

43. Endocrinology of Seminiferous Tubules • FSH binds Sertoli cells • Specific • Stim’s prod’n cyclic nucleotides • Does NOT stim synth, conversion of steroid hormones • BUT enhances LH receptors in Leydig cells • Book: w/ LH  3 b hydroxysteroid dehydrogenase- isomerase activity • With testosterone  spermatogenesis @ puberty

44. Still elucidating pathway • Model: through cAMP  ABP to localize testosterone • ABP=glycoprot sim to SHBG • ABP testosterone complex impt • Androgen avail to developing sperm • Exocytosis  lumen  epididymis  assist maturation

48. Other Physio Functions of Reproductive Hormones • Some sep’n androgenic vs. anabolic effects • Receptor differences? • Book: skel muscle androgen competition for glucocort receptors • Androgenic effects at muscle • Incr’d retention dietary N2 through prot synth •  Incr’d skeletal muscle mass • Anabolic steroids: body mass effect, w/out masculinizing effects • Book: anabolic steroids ineffective w/ normal circ’ng [testosterone]

49. Androgen Receptor • At target cells • Nuclear protein family • High sequence identity w/ progesterone receptor • Eight exons  3 functions • N-terminal: transactivation + transcr’n reg’n • DNA binding domain (zinc fingers): DNA recognition + dimerization w/ DNA binding • C-terminal: androgen binding