Neuroendocrinology

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

Abstract
Preovulatory gonadotropin-releasing hormone (GNRH, also known as GnRH) and LH surges depend upon 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 if prenatal androgen exposure suppresses basal or E₂-induced Pgr mRNA expression and/or E₂-induced LH surges in adulthood, and whether any such effects may be mediated by androgen receptor (AR) activation. We also assessed whether prenatal androgens alter subsequent GnRH pulsatility. Pregnant rats received testosterone (T) or vehicle (V) daily on embryonic days 16-19. POA-hypothalamic tissues were obtained in adulthood for PgrA and PgrB (PgrA+B) mRNA analysis. Prenatally T-exposed (pT) females displayed reduced PgrA+B mRNA levels (p<0.01) compared to prenatally V-exposed (pV) rats. Additional pregnant animals were treated with V or T, or with 5-dihydrotestosterone (DHT). In adult ovariectomized (OVX) offspring, estradiol benzoate (EB) produced a 2-fold increase (p<0.05) in PgrA+B expression in the POA of pV females, but not in pT or prenatally DHT-exposed (pDHT) rats. Prenatal T and DHT exposure also prevented EB-induced LH surges observed in pV rats. Blood sampling of OVX rats revealed increased LH pulse frequency in pDHT versus pV females (p<0.05). Our findings support the hypothesis that prenatal AR 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 AR activation on GnRH neurosecretion are mediated in part via permanent impairment of E₂-induced PgrA+B gene expression in the POA.

Key words: Androgen receptor • Gene regulation • Gonadotropin-releasing hormone • Luteinizing hormone • Progesterone receptor

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