Many women with hyperandrogenemia suffer from irregular menses and infertility. However, it is unknown whether androgens directly affect reproduction. Since animal models of hyperandrogenemia-induced infertility are associated with obesity, which may impact reproductive function, we have created a lean mouse model of elevated androgen levels using implantation of low-dose 5α-dihydrotestosterone (DHT) pellets to separate the effects of elevated androgen levels from obesity. The hypothalamic-pituitary-gonadal axis controls reproduction. While we have demonstrated that androgens impair ovarian function, androgens could also disrupt neuroendocrine function at the level of brain and/or pituitary to cause infertility. To understand how elevated androgen levels might act on pituitary gonadotropes to influence reproductive function, female mice with disruption of the androgen receptor (Ar) gene specifically in pituitary gonadotropes (PitARKO) were produced. DHT-treated control mice with intact pituitary Ar (Con- DHT) exhibited disrupted estrous cyclicity and fertility with reduced pituitary responsiveness to gonadotropin-releasing hormone (GnRH) at the level of both calcium signaling and luteinizing hormone (LH) secretion. These effects were ameliorated in DHT-treated PitARKO mice. Calcium signaling controls GnRH regulation of LH vesicle exotocysis. Our data implicate upregulation of GEM (a voltage-dependent calcium channel inhibitor) in the pituitary as a potential mechanism for the pathological effects of androgens. These results demonstrate that gonadotrope AR, as an extraovarian regulator, plays an important role in reproductive pathophysiology.
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