Androgen Receptor in the Ovary Theca Cells Plays a Critical Role in Androgen-Induced Reproductive Dysfunction

Abstract

Androgen and its receptor (AR) play a critical role in reproductive function under both physiological and pathophysiological conditions. Female AR global knockout mice are subfertile due to both neuroendocrine and ovarian defects. Female offspring from prenatally androgenized heterozygous AR pregnant mice showed rescued estrous cyclicity and fertility. Ar is expressed in granulosa cells, theca interstitial cells, and oocytes in the ovary. We created mice with theca-specific deletion of Ar (ThARKO) by crossing Cyp17-iCre mice that express Cre recombinase under cytochrome P450 17A1 (Cyp17) promoter with Arfl/fl mice. ThARKO mice exhibited no significant differences in pubertal onset or fertility compared with control littermates, and neither estrogen or testosterone levels were different between these groups. Therefore, Ar expression in theca cells likely does not influence fertility nor androgen levels in female mice. We then tested the role of AR in theca cells under hyperandrogenemic condition. After treatment with a pathophysiological level of dihydrotestosterone (DHT), control mice (control-DHT) showed acyclicity and infertility. However, estrous cycles and fertility were altered to a significantly less degree in ThARKO-DHT mice than in control-DHT mice. Messenger RNA (mRNA) levels of Lhcgr (luteinizing hormone receptor) and Timp1 (tissue inhibitor of metalloproteinase 1, and inhibitor of matrix metalloproteinase) were significantly lower in control-DHT ovary compared with control-no DHT ovaries, whereas mRNA levels of Fshr (follicle-stimulating hormone receptor) were significantly higher. Timp1 gene expression was comparable in the ThARKO-DHT and the control-no DHT ovary. We speculate that the preserved level of Timp1 in ThARKO-DHT mice contributes to retained reproductive function.

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

“…Due to the interconnected nature of the hypothalamic-pituitary-gonadal axis, effects of excess androgens could be exerted at multiple levels of the axis (22,32). While some androgen effects occur in the brain, as reported by others (32, 33), whether ARs in gonadotropes contribute to the dysregulation of female estrous cycles and gonadotropin secretion is unknown.…”

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women with PCOS (4,[24][25][26][27][28][29][30]. Notably, the 2xDHT mice do not exhibit alterations of basal serum estradiol, testosterone, or luteinizing hormone (LH); do not develop obesity; and show similar ovarian weight, serum levels of cholesterol, free fatty acids, leptin, TNFα, and IL-6 relative to controls even up to 3.5 months after DHT insertion (21,22,31).Due to the interconnected nature of the hypothalamic-pituitary-gonadal axis, effects of excess androgens could be exerted at multiple levels of the axis (22,32). While some androgen effects occur in the brain, as reported by others (32, 33), whether ARs in gonadotropes contribute to the dysregulation of female estrous cycles and gonadotropin secretion is unknown.

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“…women with PCOS (4,[24][25][26][27][28][29][30]. Notably, the 2xDHT mice do not exhibit alterations of basal serum estradiol, testosterone, or luteinizing hormone (LH); do not develop obesity; and show similar ovarian weight, serum levels of cholesterol, free fatty acids, leptin, TNFα, and IL-6 relative to controls even up to 3.5 months after DHT insertion (21,22,31).…”

Dysregulation of hypothalamic‐pituitary estrogen receptor α–mediated signaling causes episodic LH secretion and cystic ovary

“…It has been previously reported that 5a-dihydrotestosterone treatment to the rodent generated PCOS-like phenotypes, such as disturbing the estrous cycle and obesity (34,35). Recently, Ma et al (36) reported that the theca cell-specific androgen receptor (AR) KO mice show a reduced response to excess 5a-dihydrotestosterone and lack PCOSlike phenotypes. This suggests that the overproduced testosterone in theca cells could affect the estrous cycle through AR in theca cells.…”

The Role of Central Androgen Receptor Actions in Regulating the Hypothalamic-Pituitary-Ovarian Axis

“…Moreover, while the nonaromatizable androgen DHT can be used, this is also not ideal as DHT is irreversibly metabolized to 3β-diol which interacts with ERβ permitting ER-mediated estrogen-like effects to occur [10, 11]. In the early 2000s, several global AR knockout (ARKO) female mouse models were generated [12-14], followed by a range of cell-specific ARKO female mouse models (granulosa cells and oocyte [15]; granulosa cells [16]; pituitary [17]; theca cells [18]) which have collectively proved a key role for androgen actions mediated via the AR in optimizing female fertility and reproductive function.…”