Neuroendocrine consequences of prenatal androgen exposure in the female rat: absence of luteinizing hormone surges, suppression of progesterone receptor gene expression, and acceleration of the gonadotropin-releasing hormone pulse generator

Biol Reprod. 2005 Jun;72(6):1475-83. doi: 10.1095/biolreprod.105.039800. Epub 2005 Mar 2.

Abstract

Preovulatory GnRH and LH surges depend on activation of estrogen (E2)-inducible progesterone receptors (PGRs) in the preoptic area (POA). Surges do not occur in males, or in perinatally androgenized females. We sought to determine whether prenatal androgen exposure suppresses basal or E2-induced Pgr mRNA expression or E2-induced LH surges (or both) in adulthood, and whether any such effects may be mediated by androgen receptor activation. We also assessed whether prenatal androgens alter subsequent GnRH pulsatility. Pregnant rats received testosterone or vehicle daily on Embryonic Days 16-19. POA-hypothalamic tissues were obtained in adulthood for PgrA and PgrB (PgrA+B) mRNA analysis. Females that had prenatal exposure to testosterone (pT) displayed reduced PgrA+B mRNA levels (P < 0.01) compared with those that had prenatal exposure to vehicle (pV). Additional pregnant animals were treated with vehicle or testosterone, or with 5alpha-dihydrotestosterone (DHT). In adult ovariectomized offspring, estradiol benzoate produced a 2-fold increase (P < 0.05) in PgrA+B expression in the POA of pV females, but not in pT females or those that had prenatal exposure to DHT (pDHT). Prenatal testosterone and DHT exposure also prevented estradiol benzoate-induced LH surges observed in pV rats. Blood sampling of ovariectomized rats revealed increased LH pulse frequency in pDHT versus pV females (P < 0.05). Our findings support the hypothesis that prenatal androgen receptor activation can contribute to the permanent defeminization of the GnRH neurosecretory system, rendering it incapable of initiating GnRH surges, while accelerating basal GnRH pulse generator activity in adulthood. We propose that the effects of prenatal androgen receptor activation on GnRH neurosecretion are mediated in part via permanent impairment of E2-induced PgrA+B gene expression in the POA.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Androgens / adverse effects*
  • Animals
  • Dihydrotestosterone / adverse effects
  • Estradiol / pharmacology
  • Female
  • Gene Expression / drug effects
  • Gonadotropin-Releasing Hormone / blood*
  • Gonadotropin-Releasing Hormone / pharmacology
  • Hormones / blood
  • Luteinizing Hormone / blood*
  • Neurosecretory Systems / drug effects*
  • Neurosecretory Systems / physiology
  • Ovulation / physiology
  • Pituitary Gland / drug effects
  • Pituitary Gland / physiology
  • Pregnancy
  • Prenatal Exposure Delayed Effects*
  • Preoptic Area / drug effects
  • Preoptic Area / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Progesterone / drug effects*
  • Receptors, Progesterone / genetics

Substances

  • Androgens
  • Hormones
  • Receptors, Progesterone
  • progesterone receptor A
  • progesterone receptor B
  • Dihydrotestosterone
  • Gonadotropin-Releasing Hormone
  • Estradiol
  • Luteinizing Hormone