Gonadotrope androgen receptor mediates pituitary responsiveness to hormones and androgen-induced subfertility

Zhiqiang Wang, Mingxiao Feng, Olubusayo Awe, Yaping Ma, Mingjie Shen, Ping Xue, Rexford S Ahima, Andrew Wolfe, James Segars, Sheng Wu

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Article numbere127817
JournalJCI Insight
Volume4
Issue number17
DOIs
StatePublished - Aug 8 2019

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Androgen Receptors
Infertility
Androgens
Hormones
Dihydrotestosterone
Calcium Signaling
Luteinizing Hormone
Gonadotropin-Releasing Hormone
Reproduction
Obesity
Menstruation
Periodicity
Calcium Channels
Fertility
Up-Regulation
Animal Models
Brain
Genes

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Gonadotrope androgen receptor mediates pituitary responsiveness to hormones and androgen-induced subfertility. / Wang, Zhiqiang; Feng, Mingxiao; Awe, Olubusayo; Ma, Yaping; Shen, Mingjie; Xue, Ping; Ahima, Rexford S; Wolfe, Andrew; Segars, James; Wu, Sheng.

In: JCI Insight, Vol. 4, No. 17, e127817, 08.08.2019.

Research output: Contribution to journalArticle

Wang, Zhiqiang ; Feng, Mingxiao ; Awe, Olubusayo ; Ma, Yaping ; Shen, Mingjie ; Xue, Ping ; Ahima, Rexford S ; Wolfe, Andrew ; Segars, James ; Wu, Sheng. / Gonadotrope androgen receptor mediates pituitary responsiveness to hormones and androgen-induced subfertility. In: JCI Insight. 2019 ; Vol. 4, No. 17.
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