Reproductive Hormones; Male Reproductive Endocrinology

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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
• 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

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Anterior Pituitary

• FSH, LH
• Glycoprots sim to TSH, hCG
• Share common a subunit
• Hormone specific b subunits
• LH b subunit
• Stimd w/ GnRH _at_ higher freqs, amps
• Suppressed w/
• Androgens, progesterone (inhib freq GnRH pulses)
• Estrogens (directly _at_ pit)
• Testosterone ? estradiol in pit (via aromatase)

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• FSH b subunit
• Highest when low freq GnRH pulses
• Stimd w/
• Activins ? incrd FSH b mRNA (autocrine)
• Suppressed w/
• Sertoli cell inhibin B
• Testosterone/DHT
• Receptors on gonads
• cAMP ? PKA actn ? actn enzs for steroid
  biosynth

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Gonads

• Gametogenesis, hormonogenesis
• Sex steroids
• Note also prodd by adrenal gland
• Prior to puberty, basal levels secrd
• Hypothal very sensitive
• Feedback inhibitory control of GnRH, LH/FSH
• Endocrine
• Testosterone major testes secretion
• Estradiol major ovarian secretion

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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 regn

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• Penis
• Root, body, glans
• Dilation arteries w/ parasymp stimn ? erection
• Incrd blood flow ? expansion blood sinuses
• Sinuses compress veins, trap entering blood
• Ejaculation symp reflex
• Peristalsis smooth muscle
• Propels semen from urethra to exterior

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• 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

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• Semen
• Sperm secrns
• 120 x 106 sperm/mL
• Alkaline, nutrient secrns
• Vol 2-6 mL
• Seminalplasminantibiotic

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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 _at_ plasma membr receptor
• Heptahelical

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Sex Steroid Biosynthesis

• Cholesterol ? pregnenolone
• W/in Leydig cell mitoch matrix
• Catd by P450scc
• Family of microsomal metab enzs
• CYP genes
• 17a-hydroxylase (P450C17) dominant in gonads ?
  sex steroids (fig.15.3)
• 3b hydroxylases/isomerases sensitive to FSH

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Pregnenolone produced directly from cholesterol,
the precusor molecule for all C-18, C-19 and C-21
steroids 
Cortisoldominant 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 
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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 
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• Most cholesterol extracell
• Lipoproteins
• Also de novo
• Pathway via cAMP ? actn PKA ? actn steroid
  synthesis enzyme(s)
• Rate limiting delivery cholesterol to P450scc
  in mitoch matrix
• PKA-mediated induction steroidogenic acute
  regulatory protein (StAR)

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• StARSteroidogenic Acute Regulator protein
• Synth induced w/ LH-receptor binding
• Transiently incd into outer mitoch membr
• Activates PBR
• PBRPeripheral-type Benzodiazepine Receptor
• Transmembr prot
• Mitochondrial porin
• Allows cholesterol ? mitoch matrix and exposure
  to P450scc

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• Major producttestosterone
• Other androgens (fig.17.2), also estrogens
• DHT
• Potent activator androgen receptor
• Intracrine
• 5a reductase cats synth
• Almost all in periph tissues
• Impt to male embryonic devt 2o sex chars
• Also endocrine

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• Aromatase
• sER membrane anchored
• CYPC19 gene
• Reld to CYP11A (mitoch P450scc)
• Reld to CYP1A1 (monooxygenase regd by aryl
  hydrocarbon receptor
• Diff tissues ? diff isozymes and/or diff
  promoters
• Assocd w/ cytP450 reductase

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• Aromatase contd
• Steroids
• Effects oxn, cleavage C19 Me
• ? Aromatization testosterone A ring
• ? Estradiol
• In males, adipose tissue has active aromatase
• Correlation BMI/gynecomastia
• Impt to feedback control _at_ hypothal, ant pit

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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 
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• Plasma binding proteins nec in systemic circn
• 40 bound to SHBG
• 40 bound to albumin
• 17 bound to other prots
• SHBG
• Prodd by liver
• Homodimeric w/ testicular ABP
• Chromosome 17p12-13
• Differ by oligosacchs
• Higher affinity for testosterone over estrogens
• Glycosylation incrd by estrogens
• ? more SHBG
• ? more bound T more free E2

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• SHBG contd
• 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 actn
• Others

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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

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• FSH at Sertoli cells
• Cell proliferation
• Secretion
• Secretory prods of Sertolis
• Inhibin
• At ant pit inhibits FSH-b secrn
• At Sertolis antagonizes FSH prolifn
• Transferrin (prot)
• Shuttles Fe through blood-testis barrier
• Fe needed in mitoch cytochromes

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Sperm Development in Seminiferous Tubule
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Endocrinology of Seminiferous Tubules

• FSH binds Sertoli cells
• Specific
• Stims prodn 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 _at_ puberty

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• Still elucidating pathway
• Model through cAMP ? ABP to localize
  testosterone
• ABPglycoprot 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 sepn androgenic vs. anabolic effects
• Receptor differences?
• Book skel muscle androgen competition for
  glucocort receptors
• Androgenic effects at muscle
• Incrd retention dietary N2 through prot synth
• ? Incrd skeletal muscle mass
• Anabolic steroids body mass effect, w/out
  masculinizing effects
• Book anabolic steroids ineffective w/ normal
  circng testosterone

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Androgen Receptor

• At target cells
• Nuclear protein family
• High sequence identity w/ progesterone receptor
• Eight exons ? 3 functions
• N-terminal transactivation transcrn regn
• DNA binding domain (zinc fingers) DNA
  recognition dimerization w/ DNA binding
• C-terminal androgen binding

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