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 Generator1

Abstract

Preovulatory GnRH and LH surges depend on activation of estrogen (E 2 )-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 E 2 -induced Pgr mRNA expression or E 2 -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 Ͻ 0.01) compared with those that had prenatal exposure to vehicle (pV). Additional pregnant animals were treated with vehicle or testosterone, or with 5␣-dihydrotestosterone (DHT). In adult ovariectomized offspring, estradiol benzoate produced a 2-fold increase (P Ͻ 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 Ͻ 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 E 2 -induced PgrA؉B gene expression in the POA.

Enhancement of a robust arcuate GABAergic input to gonadotropin-releasing hormone neurons in a model of polycystic ovarian syndrome

“…Reduced P4 sensitivity was most dramatic within the ARN, with a nearly 60% decrease in PR-positive cells. This finding is in line with previous work showing decreased PR mRNA within the hypothalamus of PNA rats (32) and the ARN of PNA ewes (33). Although the mechanism of reduced PR expression remains to be determined, we can rule out reduced estrogen or P4 levels, as these remain unchanged in PNA mice.…”

Prenatal androgen excess enhances stimulation of the GNRH pulse in pubertal female rats

“…Animal models have shown that prenatal androgen treatment induce accelerations of LH pulsatile release in primates (Abbott et al 2009), sheep (Forsdike et al 2007, Steckler et al 2009), and rodents (Foecking et al 2005), in accordance with the present results. Our observations confirm the concept that an early disturbance due to intrauterine androgen excess reprograms nervous tissue development of the fetus and irreversibly alters neuroendocrine function in female offspring.…”

“…On days 16-19 of gestation, the rats received s.c. injections of either 5 mg/day 5a-dihydrotestosterone (DHT; Dr. Ehrenstorfer GmbH, Augsburg, Germany) dissolved in 500 ml sesame oil (Sigma)/benzyl benzoate (Sigma) (DHT, nZ30) or a vehicle as a control (C, nZ24). The dose of DHT was selected on the basis of previous experiments (Foecking et al 2005, Yan et al 2013. All litters were weaned and females were separated from males at 21 days of age.…”

Prenatal androgen excess programs metabolic derangements in pubertal female rats

“…The testosterone levels of androgen-treated models of PCOS appear to vary between different studies. Some previous studies have reported that plasma testosterone levels did not differ between rodent models of PCOS and controls (Foecking et al 2005, Manneras et al 2007, whereas other studies showed elevated levels of testosterone in PNA animals (Sullivan & Moenter 2004, Abbott et al 2009, 2012. Androgen excess is considered to be the key feature of PCOS; however, only 80-85% of women with PCOS have clinical hyperandrogenism (Azziz et al 2009).…”