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 Ahima, Andrew Wolfe, James Segars, Sheng Wu
Zhiqiang Wang, Mingxiao Feng, Olubusayo Awe, Yaping Ma, Mingjie Shen, Ping Xue, Rexford Ahima, Andrew Wolfe, James Segars, Sheng Wu
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Research Article Endocrinology Reproductive biology

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

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.

Authors

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

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Figure 3

Fertility assessment.

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Fertility assessment. (A) Female mice were mated with proven fertile mal...
(A) Female mice were mated with proven fertile male mice for 90 days, and the number of litters and pups were recorded. Plots of mating outcomes for Con-DHT (top) and PitARKO-DHT mice (bottom). Each line represents an individual female mouse, black dots represent the day that each litter was born after introduction to the male, and the number above each line represents the number of pups per litter. (B) Number of litters per female. (C) Number of pups per female. n = 6–9 females/group. Data were compared by 2-way ANOVA followed by Sidak’s multiple comparisons test. Different letters represent significant difference. Data from B and C were compared by 2-way ANOVA. (D–G) Ovary histology. Ovary was sectioned and H&E stained. Representative sections of ovaries from Con–no DHT, PitARKO–no DHT, Con-DHT, PitARKO-DHT. CL, corpora lutea. (H) Quantitative analysis of CL number. CLs were recorded in each group of ovaries. n = 6–19 mice. Open bars, vehicle treated; black bars, DHT treated. Data were compared by 2-tailed Student’s t test. *P < 0.05; ***P < 0.0001.