Androgen excess is one of the most common endocrine disorders of reproductiveaged women, affecting up to 20% of this population. Women with elevated androgens often exhibit hyperinsulinemia and insulin resistance. The mechanisms of how elevated androgens affect metabolic function are not clear.Hyperandrogenemia in a dihydrotestosterone (DHT)-treated female mouse model induces whole body insulin resistance possibly through activation of the hepatic androgen receptor (AR). We investigated the role of hepatocyte AR in hyperandrogenemia-induced metabolic dysfunction by using several approaches to delete hepatic AR via animal-, cell-, and clinical-based methodologies.

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. To define how androgen/AR in the pituitary contributes to reproductive dysfunction, and the molecular mechanisms that are underlying the pathophysiology, we used the 2xDHT mouse model with intact (Control; AR fl/fl , Cre -) or disrupted AR in gonadotropes (PitARKO; AR fl/fl , Cre +/-) (34) to probe the role of AR in gonadotrope cells (Figure 1). Since pituitary responsiveness to gonadotropin-releasing hormone (GnRH) stimulation is disrupted by high androgen levels (35) in vitro, and because GnRH-mediated increases in cytosolic Ca 2+ are crucial for exocytosis of LH granules (36, 37), we studied GEM, a GTP-binding protein that binds calmodulin to reduce Ca 2+ influx (36-38). Our findings demonstrate important roles for gonadotropic AR in reproduction as an extraovarian regulatory factor. Gonadotropic AR-mediated reproductive dysfunction may act through GEM, reducing LH secretion from the pituitary in the presence of DHT. insight.jci.org

The kisspeptin receptor, crucial for hypothalamic control of puberty and reproduction, is also present in the pituitary gland. Its role in the pituitary gland is not defined. Kisspeptin signaling via the Kiss1r could potentially regulate reproductive function at the level of pituitary gonadotrope. Using Cre/Lox technology, we deleted the Kiss1r gene in pituitary gonadotropes (PKiRKO). PKiRKO males have normal genital development (anogenital distance WT: 19.1 ± 0.4 vs. PKiRKO: 18.5 ± 0.4 mm), puberty onset, testes cell structure on gross histology, normal testes size, and fertility. PKiRKO males showed significantly decreased serum FSH levels compared to WT males (5.6 ± 1.9 vs. 10.2 ± 1.8 ng/ml) with comparable LH (1.1 ± 0.2 vs. 1.8 ± 0.4 ng/ml) and testosterone levels (351.8 ± 213.0 vs. 342.2 ± 183.0 ng/dl). PKiRKO females have normal puberty onset, cyclicity, LH and FSH levels and fertility. Overall, these findings indicate that absence of pituitary Kiss1r reduces FSH levels in male mice without affecting testis function. PKiRKO mice have normal reproductive function in both males and females.