Reproductive Biology BI399

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Reproductive BiologyBI-399

• Lecture 11
• Endocrinology of reproduction

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Two-cell mechanism of steroid function

• Gonadal steroidogenesis works as the result of
  functional cooperation between two cell types
• Male
• Leydig cells
• Described by Franz von Leydig (1850)
• Bouin and Ancel (1903) attribute masculine
  potential to these
• Produce testosterone (T)
• Sertoli cells
• Described by Enrico Sertoli (1865)
• Produces inhibin (more on this later)
• Female
• Theca cells
• Produce androstenedione (A) and testosterone (T)
• Granulosa cells
• Produce estradiol (E2)

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Feedback

• Homeostasis
• Regulation of hormone levels
• Control of basal levels
• Control of pulsatile release
• Set Point
• Level around which hormone concentrations are
  regulated
• Two mechanisms
• Negative feedback
• Positive feedback

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Negative feedback

• Acts like a thermostat
• Long-loop feedback
• Gonad is an intermediate
• Feed back at locus ceruleus, hypothalamus and
  pituitary
• site of feedback
• Short-loop feedback
• Direct feedback by tropic hormones
• LH FSH inhibit GnRH (at the hypothalamus and
  brain)
• Ultrashort feedback
• Releasing hormones and tropic hormones feedback
  on themselves
• negatively (and positively for GnRH)

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Feedback
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Positive feedback

• Females
• Controls LH surge and therefore ovulation
• Anterior Hypothalamic Preoptic
  Suprachiasmatic Center APS
• Regulated by estrogen levels
• a positive count of how much E2 is in the blood
• Threshold E2 levels trigger APS stimulation of
  ARC PON GnRH neurosecretory neurons
• NE glutamate activate GnRH surge (probably
  inhibited by endorphins, too)
• GnRH stimulates surge of LH
• Superultrashort Paracrine GnRH feedback
• GnRH feedback on ARC GnRH cells plays a role in
  regulating pulsatile release

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Gonadal axis regulation

• GnRH (pulsatile) LH (pulsatile) T E2
• GnRH stimulates the release of both LH and FSH
• Pulsatile GnRH release necessary for gonadotropin
  secretion
• Pulsatility maintains GnRH-R
• Autopriming
• LH/FSH release 4-6x higher on 2nd dose (pulse) of
  GnRH
• T or E2 feed back to regulate GnRH and LH levels
• Carried by binding proteins (SBP) in the blood
• Manner of feedback determines manner of release
• Positive () vs negative (-) modified by activin,
  inhibin, leptin, galanin

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Feedback

• Inhibin/Activin
• Small polypeptides
• Made in Sertoli cells
• Feeds back to regulate FSH levels
• Selectively inhibits (inhibin) or stimulates
  (activin) FSH
• Also found in antral fluid of females
• Leptin
• Produced by adipose (fat) cells
• Stimulates GnRH release
• Galanin (Gal)
• Colocalized in GnRH neurons, and stimulates GnRH
  release (with NPY)
• Released with GnRH, also stimulates LH (but not
  FSH)

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Feedback - testis
10
Feedback - ovary
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Gonadal axis regulation

• Mechanism of pulsatile GnRH release
• GnRH neurons have intrinsic oscillatory capacity
• May be enhanced or paced by extra-ARC
  transmitters
• NE, NPY, GABA pulse synchronously with GnRH
• NPY GABA are transmitters used for timing by
  SCN
• GnRH 2nd messengers are Gs AC cAMP or IP3
  Ca calmodulin
• Autocrine feedback control
• Pacemaker Voltage-gated Ca exocytosis
  GnRH
• GnRH GnRH-R (autoreceptors) IP3/Ca
• Ca NOS NO (more) GnRH
• Ultrashort negative feedback inhibits spontaneous
  pulsatility during 2nd phase (habituation of
  autoreceptor action?)

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Endocrine Positive Feedback

• In females E2 is monitored by anterior
  hypothalamus
• At E2 and daytime threshold GnRH surge stimulated
• Circadian rhythm timed by SCN
• Regulated by AVP and VIP
• E2 threshold adds Glu to NE stimulation
• Glu stimulates VIP in SCN, too

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Androgen target cells

• Secondary sex characteristics (facial hair,
  rooster comb, phallus development)
• 5a-reductase
• T ------------- 5a-DHT
• intracellular conversion
• DHT binds to cytoplasmic/nuclear receptors (A-R)
• Muscle has no 5a-reductase
• Although A-R has a higher affinity for 5a-DHT, T
  may bind when concentrations are high enough
• Brain (and other adipose tissue)
• aromatase
• T -------------- E2
• bind to E-R

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Feedback alterations

• Importance of negative feedback of HPG axis by
  non-gonadal steroids
• Athletes taking anabolic steroids (androgens)
• Both LH and FSH inhibited
• No spermatogenesis because no FSH
• Little endogenous testosterone synthesis
• Women on birth control pills (a combination of
  low doses of estrogen and progesterone)
• Both LH and FSH inhibited
• No follicular growth because of no FSH
• No ovulation because of no LH

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Exogenous steroidal compounds
Testosterone agonist
5a-reductase inhibitor
Testosterone antagonists
Plant-derived Estrogen agonists