Reproductive Hormones; Male Reproductive Endocrinology Chapters 16, 17
 
Hypothalamus <ul><li>GnRH </li></ul><ul><ul><li>Peptide </li></ul></ul><ul><ul><li>Gonadotroph target  </li></ul></ul><ul>...
Anterior Pituitary <ul><li>FSH, LH </li></ul><ul><ul><li>Glycoprot’s sim to TSH, hCG </li></ul></ul><ul><ul><li>Share comm...
<ul><li>FSH    subunit </li></ul><ul><ul><li>Highest when low freq GnRH pulses </li></ul></ul><ul><ul><li>Stim’d w/  </li...
Gonads <ul><li>Gametogenesis, hormonogenesis  </li></ul><ul><li>Sex steroids </li></ul><ul><ul><li>Note:  also prod’d by a...
Male Reproductive Anatomy (Human) <ul><li>Organs </li></ul><ul><ul><li>Gonads:  prod gametes, secrete hormones </li></ul><...
<ul><li>Penis </li></ul><ul><ul><li>Root, body, glans </li></ul></ul><ul><ul><li>Dilation arteries w/ parasymp stim’n    ...
<ul><li>Accessory sex glands </li></ul><ul><ul><li>Seminal vesicles </li></ul></ul><ul><ul><ul><li>Secrete viscous, alkali...
<ul><li>Semen </li></ul><ul><ul><li>Sperm + secr’ns </li></ul></ul><ul><ul><ul><li>120 x 10 6  sperm/mL </li></ul></ul></u...
 
Ducts <ul><li>Urethra </li></ul><ul><li>Spermatic cord </li></ul><ul><ul><li>Testicular artery + autonomic nerves + veins ...
 
Testes <ul><li>Fibrous outer layer; connective tissue; lobules w/ seminiferous tubules </li></ul><ul><li>Interstitium betw...
 
 
 
Leydig Cells <ul><li>Testicular androgen production  </li></ul><ul><li>From cholesterol (liver) </li></ul><ul><ul><li>Cyco...
 
 
 
 
 
Sex Steroid Biosynthesis <ul><li>Cholesterol    pregnenolone  </li></ul><ul><ul><li>W/in Leydig cell mitoch matrix </li><...
 
Pregnenolone :  produced directly from cholesterol, the precusor molecule for all C-18, C-19 and C-21 steroids    Aldoster...
Testosterone :  an androgen, male sex hormone synthesized in the testes, responsible for secondary male sex characteristic...
<ul><li>Most cholesterol extracell </li></ul><ul><ul><li>Lipoproteins </li></ul></ul><ul><ul><li>Also de novo </li></ul></...
<ul><li>StAR=Steroidogenic Acute Regulator protein </li></ul><ul><ul><li>Synth induced w/ LH-receptor binding </li></ul></...
 
 
<ul><li>Major product=testosterone </li></ul><ul><ul><li>Other androgens (fig.17.2), also estrogens </li></ul></ul><ul><li...
 
<ul><li>Aromatase </li></ul><ul><ul><li>sER membrane anchored </li></ul></ul><ul><ul><li>CYPC19 gene </li></ul></ul><ul><u...
<ul><li>Aromatase – cont’d </li></ul><ul><ul><li>Steroids </li></ul></ul><ul><ul><ul><li>Effects ox’n, cleavage C19 Me  </...
Testosterone :  an androgen, male sex hormone synthesized in the testes, responsible for secondary male sex characteristic...
<ul><li>Plasma binding proteins nec in systemic circ’n </li></ul><ul><ul><li>40% bound to SHBG </li></ul></ul><ul><ul><li>...
<ul><li>SHBG – cont’d </li></ul><ul><ul><li>Glycosylation impt for recognition of cell surface receptors </li></ul></ul><u...
Seminiferous Tubules <ul><li>Formed from specialized epithelium </li></ul><ul><li>Epith = Sertoli cells (sustentacular cel...
 
<ul><li>FSH at Sertoli cells </li></ul><ul><ul><li>Cell proliferation </li></ul></ul><ul><ul><li>Secretion </li></ul></ul>...
Sperm Development in Seminiferous Tubule
Endocrinology of Seminiferous Tubules <ul><li>FSH binds Sertoli cells  </li></ul><ul><ul><li>Specific </li></ul></ul><ul><...
<ul><li>Still elucidating pathway </li></ul><ul><li>Model:  through cAMP    ABP to localize testosterone </li></ul><ul><u...
 
 
 
Other Physio Functions of Reproductive Hormones <ul><li>Some sep’n androgenic vs. anabolic effects </li></ul><ul><ul><li>R...
Androgen Receptor <ul><li>At target cells </li></ul><ul><li>Nuclear protein family </li></ul><ul><li>High sequence identit...
 
 
 
 
 
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  1. 1. Reproductive Hormones; Male Reproductive Endocrinology Chapters 16, 17
  2. 3. Hypothalamus <ul><li>GnRH </li></ul><ul><ul><li>Peptide </li></ul></ul><ul><ul><li>Gonadotroph target </li></ul></ul><ul><ul><li>G-prot linked heptahelical transmembr </li></ul></ul><ul><ul><ul><li>G  q  PLC pathway </li></ul></ul></ul><ul><ul><ul><li> IP3-Ca, DAG-PKC-MAP kinase  expression of  subunit common to FSH/LH </li></ul></ul></ul><ul><ul><li>Also  opening of voltage gated Ca channels  Ca influx </li></ul></ul>
  3. 4. Anterior Pituitary <ul><li>FSH, LH </li></ul><ul><ul><li>Glycoprot’s sim to TSH, hCG </li></ul></ul><ul><ul><li>Share common  subunit </li></ul></ul><ul><ul><li>Hormone specific  subunits </li></ul></ul><ul><li>LH  subunit </li></ul><ul><ul><li>Stim’d w/ GnRH @ higher freq’s, amp’s </li></ul></ul><ul><ul><li>Suppressed w/ </li></ul></ul><ul><ul><ul><li>Androgens, progesterone (inhib freq GnRH pulses) </li></ul></ul></ul><ul><ul><ul><li>Estrogens (directly @ pit) </li></ul></ul></ul><ul><ul><ul><li>Testosterone  estradiol in pit (via aromatase) </li></ul></ul></ul>
  4. 5. <ul><li>FSH  subunit </li></ul><ul><ul><li>Highest when low freq GnRH pulses </li></ul></ul><ul><ul><li>Stim’d w/ </li></ul></ul><ul><ul><ul><li>Activins  incr’d FSH  mRNA (autocrine) </li></ul></ul></ul><ul><ul><li>Suppressed w/ </li></ul></ul><ul><ul><ul><li>Sertoli cell inhibin B </li></ul></ul></ul><ul><ul><ul><li>Testosterone/DHT </li></ul></ul></ul><ul><li>Receptors on gonads </li></ul><ul><ul><li>cAMP  PKA act’n  act’n enz’s for steroid biosynth </li></ul></ul>
  5. 6. Gonads <ul><li>Gametogenesis, hormonogenesis </li></ul><ul><li>Sex steroids </li></ul><ul><ul><li>Note: also prod’d by adrenal gland </li></ul></ul><ul><ul><li>Prior to puberty, basal levels secr’d </li></ul></ul><ul><ul><ul><li>Hypothal very sensitive </li></ul></ul></ul><ul><ul><ul><li>Feedback inhibitory control of GnRH, LH/FSH </li></ul></ul></ul><ul><li>Endocrine </li></ul><ul><li>Testosterone major testes secretion </li></ul><ul><li>Estradiol major ovarian secretion </li></ul>
  6. 7. Male Reproductive Anatomy (Human) <ul><li>Organs </li></ul><ul><ul><li>Gonads: prod gametes, secrete hormones </li></ul></ul><ul><ul><li>Ducts: transport, store gametes </li></ul></ul><ul><ul><li>Accessory sex glands: support gametes </li></ul></ul><ul><li>Scrotum </li></ul><ul><ul><li>Supports testes </li></ul></ul><ul><ul><li>Cremaster muscle </li></ul></ul><ul><ul><li>Temp reg’n </li></ul></ul>
  7. 8. <ul><li>Penis </li></ul><ul><ul><li>Root, body, glans </li></ul></ul><ul><ul><li>Dilation arteries w/ parasymp stim’n  erection </li></ul></ul><ul><ul><ul><li>Incr’d blood flow  expansion blood sinuses </li></ul></ul></ul><ul><ul><ul><li>Sinuses compress veins, trap entering blood </li></ul></ul></ul><ul><ul><li>Ejaculation: symp reflex </li></ul></ul><ul><ul><ul><li>Peristalsis smooth muscle </li></ul></ul></ul><ul><ul><ul><li>Propels semen from urethra to exterior </li></ul></ul></ul>
  8. 9. <ul><li>Accessory sex glands </li></ul><ul><ul><li>Seminal vesicles </li></ul></ul><ul><ul><ul><li>Secrete viscous, alkaline fluid (60% semen vol) </li></ul></ul></ul><ul><ul><li>Prostate gland </li></ul></ul><ul><ul><ul><li>Secretes alkaline fluid (25% vol) </li></ul></ul></ul><ul><ul><ul><li>Impt to sperm viability, motility </li></ul></ul></ul><ul><ul><li>Bulbourethral gland </li></ul></ul><ul><ul><ul><li>Secretes mucus, alkaline fluid </li></ul></ul></ul>
  9. 10. <ul><li>Semen </li></ul><ul><ul><li>Sperm + secr’ns </li></ul></ul><ul><ul><ul><li>120 x 10 6 sperm/mL </li></ul></ul></ul><ul><ul><ul><li>Alkaline, nutrient secr’ns </li></ul></ul></ul><ul><ul><li>Vol: 2-6 mL </li></ul></ul><ul><ul><li>Seminalplasmin=antibiotic </li></ul></ul>
  10. 12. Ducts <ul><li>Urethra </li></ul><ul><li>Spermatic cord </li></ul><ul><ul><li>Testicular artery + autonomic nerves + veins + lymph vessels + cremaster muscle + vas deferens </li></ul></ul><ul><li>Vas deferens </li></ul><ul><ul><li>Result of epidimi fusion </li></ul></ul><ul><ul><li>Stores mature sperm </li></ul></ul><ul><li>Ductus epididymis </li></ul><ul><ul><li>Sperm maturation, storage </li></ul></ul><ul><li>Rete testis </li></ul><ul><ul><li>Result of seminiferous tubule fusion </li></ul></ul><ul><ul><li>Gives rise to ducts </li></ul></ul>
  11. 14. Testes <ul><li>Fibrous outer layer; connective tissue; lobules w/ seminiferous tubules </li></ul><ul><li>Interstitium between seminiferous tubules contain Leydig cells (interstitial endocrinocytes) </li></ul>
  12. 18. Leydig Cells <ul><li>Testicular androgen production </li></ul><ul><li>From cholesterol (liver) </li></ul><ul><ul><li>Cycopentanoperhydophenanthrene nucleus </li></ul></ul><ul><li>Signal = LH @ plasma membr receptor </li></ul><ul><ul><li>Heptahelical </li></ul></ul>
  13. 24. Sex Steroid Biosynthesis <ul><li>Cholesterol  pregnenolone </li></ul><ul><ul><li>W/in Leydig cell mitoch matrix </li></ul></ul><ul><ul><li>Cat’d by P450scc </li></ul></ul><ul><ul><ul><li>Family of microsomal metab enz’s </li></ul></ul></ul><ul><ul><ul><li>CYP genes </li></ul></ul></ul><ul><li>17  -hydroxylase (P450C17) dominant in gonads  sex steroids (fig.15.3) </li></ul><ul><li>3  hydroxylases/isomerases sensitive to FSH </li></ul>
  14. 26. Pregnenolone : produced directly from cholesterol, the precusor molecule for all C-18, C-19 and C-21 steroids  Aldosterone : the principal mineralocorticoid, produced from progesterone in the zona glomerulosa of adrenal cortex, raises blood pressure and fluid volume, increases Na + uptake  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  
  15. 27. 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  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
  16. 28. <ul><li>Most cholesterol extracell </li></ul><ul><ul><li>Lipoproteins </li></ul></ul><ul><ul><li>Also de novo </li></ul></ul><ul><li>Pathway: via cAMP  act’n PKA  act’n steroid synthesis enzyme(s) </li></ul><ul><ul><li>Rate limiting: delivery cholesterol to P450scc in mitoch matrix </li></ul></ul><ul><ul><li>PKA-mediated induction steroidogenic acute regulatory protein (StAR) </li></ul></ul>
  17. 29. <ul><li>StAR=Steroidogenic Acute Regulator protein </li></ul><ul><ul><li>Synth induced w/ LH-receptor binding </li></ul></ul><ul><ul><li>Transiently inc’d into outer mitoch membr </li></ul></ul><ul><ul><li>Activates PBR </li></ul></ul><ul><li>PBR=Peripheral-type Benzodiazepine Receptor </li></ul><ul><ul><li>Transmembr prot </li></ul></ul><ul><ul><li>“ Mitochondrial porin” </li></ul></ul><ul><ul><li>Allows cholesterol  mitoch matrix and exposure to P450scc </li></ul></ul>
  18. 32. <ul><li>Major product=testosterone </li></ul><ul><ul><li>Other androgens (fig.17.2), also estrogens </li></ul></ul><ul><li>DHT </li></ul><ul><ul><li>Potent activator androgen receptor </li></ul></ul><ul><ul><ul><li>“ Intracrine” </li></ul></ul></ul><ul><ul><li>5  reductase cat’s synth </li></ul></ul><ul><ul><ul><li>Almost all in periph tissues </li></ul></ul></ul><ul><ul><ul><li>Impt to male embryonic dev’t + 2 o sex char’s </li></ul></ul></ul><ul><ul><li>Also endocrine </li></ul></ul>
  19. 34. <ul><li>Aromatase </li></ul><ul><ul><li>sER membrane anchored </li></ul></ul><ul><ul><li>CYPC19 gene </li></ul></ul><ul><ul><ul><li>Rel’d to CYP11A (mitoch P450scc) </li></ul></ul></ul><ul><ul><ul><li>Rel’d to CYP1A1 (monooxygenase reg’d by aryl hydrocarbon receptor </li></ul></ul></ul><ul><ul><ul><li>Diff tissues  diff isozymes and/or diff promoters </li></ul></ul></ul><ul><ul><li>Assoc’d w/ cytP450 reductase </li></ul></ul>
  20. 35. <ul><li>Aromatase – cont’d </li></ul><ul><ul><li>Steroids </li></ul></ul><ul><ul><ul><li>Effects ox’n, cleavage C19 Me </li></ul></ul></ul><ul><ul><ul><li> Aromatization testosterone A ring </li></ul></ul></ul><ul><ul><ul><li> Estradiol </li></ul></ul></ul><ul><ul><li>In males, adipose tissue has active aromatase </li></ul></ul><ul><ul><ul><li>Correlation BMI/gynecomastia </li></ul></ul></ul><ul><ul><li>Impt to feedback control @ hypothal, ant pit </li></ul></ul>
  21. 36. 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  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
  22. 37. <ul><li>Plasma binding proteins nec in systemic circ’n </li></ul><ul><ul><li>40% bound to SHBG </li></ul></ul><ul><ul><li>40% bound to albumin </li></ul></ul><ul><ul><li>17% bound to other prot’s </li></ul></ul><ul><li>SHBG </li></ul><ul><ul><li>Prod’d by liver </li></ul></ul><ul><ul><li>Homodimeric w/ testicular ABP </li></ul></ul><ul><ul><ul><li>Chromosome 17p12-13 </li></ul></ul></ul><ul><ul><ul><li>Differ by oligosacch’s </li></ul></ul></ul><ul><ul><li>Higher affinity for testosterone over estrogens </li></ul></ul><ul><ul><ul><li>Glycosylation incr’d by estrogens </li></ul></ul></ul><ul><ul><ul><li> more SHBG </li></ul></ul></ul><ul><ul><ul><li> more bound T; more free E2 </li></ul></ul></ul>
  23. 38. <ul><li>SHBG – cont’d </li></ul><ul><ul><li>Glycosylation impt for recognition of cell surface receptors </li></ul></ul><ul><ul><ul><li>Can bind target tissues if not bound to ligand </li></ul></ul></ul><ul><ul><li>SHBG receptor </li></ul></ul><ul><ul><ul><li>Presumed heptahelical transmembr </li></ul></ul></ul><ul><ul><ul><li>Known cAMP/PKA mediation </li></ul></ul></ul><ul><ul><li>Binding SHBG  enhancement cAMP effects w/ subsequent steroid binding </li></ul></ul><ul><ul><ul><li>Androgen receptor act’n </li></ul></ul></ul><ul><ul><ul><li>Others </li></ul></ul></ul>
  24. 39. Seminiferous Tubules <ul><li>Formed from specialized epithelium </li></ul><ul><li>Epith = Sertoli cells (sustentacular cells) </li></ul><ul><ul><li>Support, nourish </li></ul></ul><ul><ul><li>Mediate hormonal effects </li></ul></ul><ul><ul><li>Control sperm movement </li></ul></ul><ul><ul><li>Secrete </li></ul></ul><ul><ul><ul><li>Fluid </li></ul></ul></ul><ul><ul><ul><li>Inhibin B </li></ul></ul></ul><ul><ul><li>Form blood-testis barrier </li></ul></ul>
  25. 41. <ul><li>FSH at Sertoli cells </li></ul><ul><ul><li>Cell proliferation </li></ul></ul><ul><ul><li>Secretion </li></ul></ul><ul><li>Secretory prod’s of Sertoli’s </li></ul><ul><ul><li>Inhibin </li></ul></ul><ul><ul><ul><li>At ant pit: inhibits FSH-b secr’n </li></ul></ul></ul><ul><ul><ul><li>At Sertoli’s: antagonizes FSH prolif’n </li></ul></ul></ul><ul><ul><li>Transferrin (prot) </li></ul></ul><ul><ul><ul><li>Shuttles Fe through blood-testis barrier </li></ul></ul></ul><ul><ul><ul><li>Fe needed in mitoch cytochromes </li></ul></ul></ul>
  26. 42. Sperm Development in Seminiferous Tubule
  27. 43. Endocrinology of Seminiferous Tubules <ul><li>FSH binds Sertoli cells </li></ul><ul><ul><li>Specific </li></ul></ul><ul><ul><li>Stim’s prod’n cyclic nucleotides </li></ul></ul><ul><ul><li>Does NOT stim synth, conversion of steroid hormones </li></ul></ul><ul><ul><li>BUT enhances LH receptors in Leydig cells </li></ul></ul><ul><ul><ul><li>Book: w/ LH  3  hydroxysteroid dehydrogenase- isomerase activity </li></ul></ul></ul><ul><li>With testosterone  spermatogenesis @ puberty </li></ul>
  28. 44. <ul><li>Still elucidating pathway </li></ul><ul><li>Model: through cAMP  ABP to localize testosterone </li></ul><ul><ul><li>ABP=glycoprot sim to SHBG </li></ul></ul><ul><li>ABP testosterone complex impt </li></ul><ul><ul><li>Androgen avail to developing sperm </li></ul></ul><ul><ul><li>Exocytosis  lumen  epididymis  assist maturation </li></ul></ul>
  29. 48. Other Physio Functions of Reproductive Hormones <ul><li>Some sep’n androgenic vs. anabolic effects </li></ul><ul><ul><li>Receptor differences? </li></ul></ul><ul><ul><li>Book: skel muscle androgen competition for glucocort receptors </li></ul></ul><ul><li>Androgenic effects at muscle </li></ul><ul><ul><li>Incr’d retention dietary N2 through prot synth </li></ul></ul><ul><ul><li> Incr’d skeletal muscle mass </li></ul></ul><ul><li>Anabolic steroids: body mass effect, w/out masculinizing effects </li></ul><ul><ul><li>Book: anabolic steroids ineffective w/ normal circ’ng [testosterone] </li></ul></ul>
  30. 49. Androgen Receptor <ul><li>At target cells </li></ul><ul><li>Nuclear protein family </li></ul><ul><li>High sequence identity w/ progesterone receptor </li></ul><ul><li>Eight exons  3 functions </li></ul><ul><ul><li>N-terminal: transactivation + transcr’n reg’n </li></ul></ul><ul><ul><li>DNA binding domain (zinc fingers): DNA recognition + dimerization w/ DNA binding </li></ul></ul><ul><ul><li>C-terminal: androgen binding </li></ul></ul>

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