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  • Reproductive Hormones; Male Reproductive Endocrinology Chapters 16, 17
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  • Hypothalamus
    • GnRH
      • Peptide
      • Gonadotroph target
      • G-prot linked heptahelical transmembr
        • G  q  PLC pathway
        •  IP3-Ca, DAG-PKC-MAP kinase  expression of  subunit common to FSH/LH
      • Also  opening of voltage gated Ca channels  Ca influx
  • Anterior Pituitary
    • FSH, LH
      • Glycoprot’s sim to TSH, hCG
      • Share common  subunit
      • Hormone specific  subunits
    • LH  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)
    • FSH  subunit
      • Highest when low freq GnRH pulses
      • Stim’d w/
        • Activins  incr’d FSH  mRNA (autocrine)
      • Suppressed w/
        • Sertoli cell inhibin B
        • Testosterone/DHT
    • Receptors on gonads
      • cAMP  PKA act’n  act’n enz’s for steroid biosynth
  • 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
  • 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
    • 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
    • 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
    • Semen
      • Sperm + secr’ns
        • 120 x 10 6 sperm/mL
        • Alkaline, nutrient secr’ns
      • Vol: 2-6 mL
      • Seminalplasmin=antibiotic
  •  
  • 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
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  • Testes
    • Fibrous outer layer; connective tissue; lobules w/ seminiferous tubules
    • Interstitium between seminiferous tubules contain Leydig cells (interstitial endocrinocytes)
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  • Leydig Cells
    • Testicular androgen production
    • From cholesterol (liver)
      • Cycopentanoperhydophenanthrene nucleus
    • Signal = LH @ plasma membr receptor
      • Heptahelical
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  • Sex Steroid Biosynthesis
    • Cholesterol  pregnenolone
      • W/in Leydig cell mitoch matrix
      • Cat’d by P450scc
        • Family of microsomal metab enz’s
        • CYP genes
    • 17  -hydroxylase (P450C17) dominant in gonads  sex steroids (fig.15.3)
    • 3  hydroxylases/isomerases sensitive to FSH
  •  
  • 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  
  • 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
    • 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)
    • 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
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    • Major product=testosterone
      • Other androgens (fig.17.2), also estrogens
    • DHT
      • Potent activator androgen receptor
        • “ Intracrine”
      • 5  reductase cat’s synth
        • Almost all in periph tissues
        • Impt to male embryonic dev’t + 2 o sex char’s
      • Also endocrine
  •  
    • 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
    • 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
  • 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
    • 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
    • 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
  • 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
  •  
    • 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
  • Sperm Development in Seminiferous Tubule
  • 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  hydroxysteroid dehydrogenase- isomerase activity
    • With testosterone  spermatogenesis @ puberty
    • 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
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  • 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]
  • 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
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