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Reproductive Hormones; Male
Reproductive Endocrinology
Chapters 16, 17
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
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)
• 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
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 106 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
Testes
• Fibrous outer layer; connective tissue;
lobules w/ seminiferous tubules
• Interstitium between seminiferous tubules
contain Leydig cells (interstitial
endocrinocytes)
Leydig Cells
• Testicular androgen production
• From cholesterol (liver)
– Cycopentanoperhydophenanthrene nucleus
• Signal = LH @ plasma membr receptor
– Heptahelical
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
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
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
• 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
• 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
• 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
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
• 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 b hydroxysteroid dehydrogenaseisomerase 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
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