Gonadotrope androgen receptor mediates pituitary responsiveness to hormones and androgen-induced subfertility.
Gonadotrope androgen receptor mediates pituitary responsiveness to hormones and androgen-induced subfertility.
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促性腺激素雄激素受体介导垂体对激素和雄激素引起的生育力低下的反应。
DOI：
10.1172/jci.insight.127817
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发表时间：
2019
期刊：
影响因子：
8
通讯作者：
Wu,Sheng
中科院分区：
文献类型：
--
作者：
Wang,Zhiqiang;Feng,Mingxiao;Awe,Olubusayo;Ma,Yaping;Shen,Mingjie;Xue,Ping;Ahima,Rexford;Wolfe,Andrew;Segars,James;Wu,Sheng
许多患有高雄激素血症的女性会出现月经不规律和不孕症。然而，雄激素是否直接影响生殖尚不清楚。由于高雄激素诱导的不孕症动物模型与肥胖有关，肥胖可能影响生殖功能，因此我们通过植入低剂量的5α-二氢睾酮（DHT）颗粒，建立了雄激素水平升高的瘦小鼠模型，以分离雄激素水平升高与肥胖的影响。下丘脑-垂体-性腺轴控制生殖。虽然我们已经证明雄激素会损害卵巢功能，但雄激素也会破坏大脑和/或垂体水平的神经内分泌功能，从而导致不孕。为了了解雄激素水平升高如何作用于垂体促性腺激素从而影响生殖功能，我们制造了垂体促性腺激素（PitARKO）中雄激素受体（Ar）基因被破坏的雌性小鼠。dht处理的垂体Ar （Con-DHT）完好的对照小鼠，在钙信号和黄体生成素（LH）分泌水平上，垂体对促性腺激素释放激素（GnRH）的反应性降低，表现出发情周期和生育能力被破坏。这些作用在dht处理的PitARKO小鼠中得到改善。钙信号控制GnRH对LH囊泡外溢的调节。我们的数据表明垂体中GEM（一种电压依赖性钙通道抑制剂）的上调是雄激素病理作用的潜在机制。这些结果表明促性腺激素AR作为卵巢外调节因子在生殖病理生理中起着重要作用。
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.