Prenatal androgens alter GABAergic drive to gonadotropin-releasing hormone neurons: Implications for a common fertility disorder

Abstract

Polycystic ovary syndrome, a fertility disorder affecting Ϸ7% of women, is characterized by elevated androgens, disrupted reproductive cycles, and high luteinizing hormone, the latter reflecting increased gonadotropin-releasing hormone (GnRH) release. In animal models, a similar reproductive endocrine phenotype occurs after prenatal androgen exposure. To study the effects of in utero androgen exposure directly on GnRH neurons, the central regulators of fertility, we prenatally androgenized (PNA) transgenic mice that express GFP in these cells. Pregnant females were injected with dihydrotestosterone, and their female offspring were studied as adults. PNA mice had irregular estrous cycles and elevated testosterone and luteinizing hormone levels, suggesting altered hypothalamo-pituitary-gonadal axis function. GnRH neurons receive a major input from ␥-aminobutyric acid (GABA)ergic neurons, and GABA type A receptor activation may play a role in their regulation by steroids. We tested whether PNA alters GABAergic drive to GnRH neurons by comparing frequency and size of GABAergic postsynaptic currents in GnRH neurons from PNA and control females. Both postsynaptic current frequency and size were increased in PNA mice; these effects were reversed by in vivo treatment with the androgen receptor antagonist flutamide, suggesting that androgens mediated these effects. Changes in postsynaptic current frequency and size were action potentialindependent, suggesting the possibility that PNA increased connectivity between GABAergic and GnRH neurons. The ability of prenatal steroid exposure to initiate changes that alter functional inputs to GnRH neurons in adults has important implications for understanding the regulation of normal reproduction as well as the hypothalamic abnormalities of fertility disorders.

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

“…Interestingly, the increase in spine density did correlate with increased GABAergic appositions with GnRH neurons, including an increase in the percentage of GnRH neuron spines contacted by vGaT-ir puncta. These data are compatible with previous findings showing increased GABAergic postsynaptic currents in PNA mice (15). Although principally recognized as an inhibitory neurotransmitter in the adult brain, there is now a consensus that GABA acts through GABA A receptors to activate adult GnRH neurons (36).…”

“…The PNA mouse model elicits a phenotype that possesses the majority of the reproductive deficits seen in the clinic, including hyperandrogenism, disrupted estrous cyclicity, and modified ovarian morphology (14,15,26), but reflects only minor metabolic disturbances (27), suggesting that this model is most representative of the "lean PCOS phenotype" (28). Women with PCOS present with a reduced ability for estrogen and P4 to slow the GnRH/LH pulse generator (6).…”

“…Many P4-sensitive populations have been identified throughout the hypothalamus, including neurons expressing gamma-aminobutyric acid (GABA) (16), glutamate (17), and various neuropeptides (18,19). Both endogenous GnRH neuron firing activity and GABAergic postsynaptic currents are increased in PNA mice (15,20). However, the specific P4-sensitive neuronal phenotype that relays feedback signals to GnRH neurons is so far unknown.…”

“…Women exposed to elevated prenatal androgens (PNAs) develop the cardinal reproductive and endocrine features of PCOS in adulthood (12,13), and PNA treatment produces a PCOS-like phenotype in all mammalian species studied to date (11). In the mouse, PNA elicits many of the key neuroendocrine features of the syndrome, suggestive of impaired steroid hormone feedback to the GnRH pulse generator (14,15), however, it remains to be determined directly whether P4 negative feedback and LH pulse frequency are modified.…”

Supraphysiological leptin levels shift the profile of steroidogenesis in porcine ovarian follicles toward progesterone and testosterone secretion through increased expressions of CYP11A1 and 17β-HSD: a tissue culture approach

“…Several studies show that prenatal, perinatal, or postnatal androgen exposure in monkeys (Abbott et al 2002), sheep (West et al 2001), rats , Mannerås et al 2007, and mice (Sullivan & Moenter 2004) can induce cyst formation. Exposure of female monkey and sheep fetuses to excess androgen concentrations resulted in an excess of LH and enlarged ovaries that were polyfollicular, anovulatory and hyperandrogenic (Birch et al 2003, Abbott et al 2005.…”