Neuroendocrine androgen action is a key extraovarian mediator in the development of polycystic ovary syndrome

Abstract

Polycystic ovary syndrome (PCOS) is a complex hormonal disorder characterized by reproductive, endocrine, and metabolic abnormalities. As the origins of PCOS remain unknown, mechanismbased treatments are not feasible and current management relies on treatment of symptoms. Hyperandrogenism is the most consistent PCOS characteristic; however, it is unclear whether androgen excess, which is treatable, is a cause or a consequence of PCOS. As androgens mediate their actions via the androgen receptor (AR), we combined a mouse model of dihydrotestosterone (DHT)-induced PCOS with global and cell-specific AR-resistant (ARKO) mice to investigate the locus of androgen actions that mediate the development of the PCOS phenotype. Global loss of the AR reveals that AR signaling is required for all DHT-induced features of PCOS. Neuron-specific AR signaling was required for the development of dysfunctional ovulation, classic polycystic ovaries, reduced large antral follicle health, and several metabolic traits including obesity and dyslipidemia. In addition, ovariectomized ARKO hosts with wild-type ovary transplants displayed normal estrous cycles and corpora lutea, despite DHT treatment, implying extraovarian and not intraovarian AR actions are key loci of androgen action in generating the PCOS phenotype. These findings provide strong evidence that neuroendocrine genomic AR signaling is an important extraovarian mediator in the development of PCOS traits. Thus, targeting AR-driven mechanisms that initiate PCOS is a promising strategy for the development of novel treatments for PCOS.PCOS | androgen | animal model | neuroendocrine P olycystic ovary syndrome (PCOS) is the most frequent endocrine disorder of young women, with a prevalence of 6 to 15% (1), and accounts for more than 75% of anovulatory infertility (2). It is characterized by reproductive hormone dysregulation involving luteinizing hormone (LH) hypersecretion and hyperandrogenism (3), the consequences of which can be acne and hirsutism, as well as reduced fertility, due to aberrant follicular maturation, ovulatory disturbance, and miscarriage (3). Associated nonreproductive abnormalities, such as obesity, metabolic syndrome, hyperinsulinemia, insulin resistance, hepatic steatosis, and dyslipidemia predispose affected women to heightened risk of cardiovascular disease and type 2 diabetes (3, 4). However, despite the high prevalence and significant health impact, the pathogenesis of PCOS remains unclear so that mechanism-based treatments remain unattainable.Hyperandrogenism, the most consistent feature of PCOS (5), is implicated as a key mediator in the pathogenesis of PCOS. Supportive evidence includes that androgen excess from endogenous [congenital adrenal hyperplasia (6)] or exogenous [female-to-male transsexuals (7)] sources can produce polycystic ovaries. Furthermore, androgens induce reproductive, metabolic, and endocrine features of PCOS in rodent, sheep, and primate animal models of PCOS (8-10). As all androgen action is mediated via the androgen receptor (AR),...

Neuronal androgen receptor: Molecular gateway to polycystic ovary syndrome?

“…Commendably, Caldwell et al (10) are not misled by DHT-minimized changes in vaginal cytology across the estrus cycle providing a false indication of anovulatory cycles in NeuroARKO females. DHT is likely disrupting ovulation-inducing gonadotropin surges by diminishing kisspeptin secretion (12) in AR-expressing kisspeptin/neurokinin B neurons in the hypothalamus (15,16), key neuronal regulators of GnRH release.…”

“…Caldwell et al (10) bred ARflox mice (AR exon 3 flanked by loxP sites inserted into the genome) to Sox2-Cre mice to delete AR from every cell in the body to derive the global ARKO mice (Sox2-Cre enables excision of AR exon 3 at loxP sites, blocking AR expression). Substitution of the universal deletor, Sox2-Cre, for the well-validated CamKIIα-Cre mouse produced NeuroARKO (Cre-enabled deletion of AR exon 3 only occurs in neurons), and substituting an antimullerian hormone-Cre mouse resulted in ovarian GCARKO (AR exon 3 deletion in granulosa cells only).…”

“…Caldwell et al (10) recognize this and include separate groups of each different type of ARKO female implanted with empty capsules as specific controls for their contemporaries implanted with DHT. For example, global ARKO without DHT treatment exhibit elevated circulating levels of T, DHT, and estrogenic metabolites of T, diminished estradiol (E 2 ) levels, diminished E 2 -mediated negative feedback on luteinizing hormone (LH), deficient ovulatory LH surges, normal pituitary LH responses to exogenous gonadotropin-releasing hormone (GnRH), diminished number of ovulation sites per estrus cycle and litter sizes, and increased numbers of abnormal ovarian follicles (12).…”

“…In examining the role of neuronal AR in mediating reproductive dysfunction, Caldwell et al (10) pinpoint the brain as the site of AR-mediated PCOS-like conversion: ovaries in both ARKO and NeuroARKO DHT-treated females still exhibit fresh corpora lutea, and wild-type ovaries transplanted to ARKO females at the onset of DHT treatment retain normal estrus cyclicity. Commendably, Caldwell et al (10) are not misled by DHT-minimized changes in vaginal cytology across the estrus cycle providing a false indication of anovulatory cycles in NeuroARKO females.…”

“…In contrast to ARKO, NeuroARKO fails to prevent DHTinduced hyperglycemia, diminished adipocyte release of adiponectin, and only partially prevents fatty liver and adipocyte hypertrophy. In the absence of insulin resistance, Caldwell et al (10) propose a causal contribution from AR-mediated dysregulation of hepatic glycogen. In addition, a recent series of studies in women demonstrating AR-mediated constraint on adipocyte maturation, as well as T-associated increases in visceral fat and hyperlipidemia in PCOS women with minimal loss of insulin sensitivity (23), implicate the adipocyte alongside the hepatocyte as potential future sites for organ specific blockade of AR expression, identifying specific contributions to PCOS-like lipid dysregulation.…”