Prenatal androgens alter GABAergic drive to gonadotropin-releasing hormone neurons: implications for a common fertility disorder.
Polycystic ovary syndrome, a fertility disorder affecting approximately 7% 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 gamma-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 potential-independent, 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.
Sullivan
Shannon D
SD
Department of Internal Medicine, University of Virginia, Charlottesville, VA 22908, USA.
Moenter
Suzanne M
SM
D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D030762:Estrous Cycle / Q000187:drug effects; D005260:Female; D012739:Gonadal Steroid Hormones / Q000494:pharmacology*; D007987:Gonadotropin-Releasing Hormone / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects*; D011085:Polycystic Ovary Syndrome / Q000378:metabolism; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D005680:gamma-Aminobutyric Acid / Q000187:drug effects / Q000378:metabolism*
D000728:Androgens; D012739:Gonadal Steroid Hormones; D007987:Gonadotropin-Releasing Hormone; D005680:gamma-Aminobutyric Acid