TY - JOUR
T1 - Gonadotrope androgen receptor mediates pituitary responsiveness to hormones and androgen-induced subfertility
AU - Wang, Zhiqiang
AU - Feng, Mingxiao
AU - Awe, Olubusayo
AU - Ma, Yaping
AU - Shen, Mingjie
AU - Xue, Ping
AU - Ahima, Rexford
AU - Wolfe, Andrew
AU - Segars, James
AU - Wu, Sheng
N1 - Funding Information:
We thank Ursula Kaiser (Harvard Medical School) for sharing the pituitary primary cell culture protocols. This work was supported by the NIH (grant R00-HD068130 to SW) and the Baltimore Diabetes Research Center: Pilots and Feasibility Grant (to SW).
Publisher Copyright:
© 2019 American Society for Clinical Investigation.
PY - 2019/8/8
Y1 - 2019/8/8
N2 - 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.
AB - 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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U2 - 10.1172/jci.insight.127817
DO - 10.1172/jci.insight.127817
M3 - Article
C2 - 31393859
AN - SCOPUS:85072252221
SN - 2379-3708
VL - 4
JO - JCI insight
JF - JCI insight
IS - 17
M1 - e127817
ER -