Polycystic ovary syndrome (PCOS) is the most common endocrine condition in reproductive-age women. By comprising reproductive, endocrine, metabolic and psychological features—the cause of PCOS is still unknown. Consequently, there is no cure, and management is persistently suboptimal as it depends on the ad hoc management of symptoms only. Recently it has been revealed that androgens have an important role in regulating female fertility. Androgen actions are facilitated via the androgen receptor (AR) and transgenic Ar knockout mouse models have established that AR-mediated androgen actions have a part in regulating female fertility and ovarian function. Considerable evidence from human and animal studies currently reinforces the hypothesis that androgens in excess, working via the AR, play a key role in the origins of polycystic ovary syndrome (PCOS). Identifying and confirming the locations of AR-mediated actions and the molecular mechanisms involved in the development of PCOS is critical to provide the knowledge required for the future development of innovative, mechanism-based interventions for the treatment of PCOS. This review summarises fundamental scientific discoveries that have improved our knowledge of androgen actions in PCOS etiology and how this may form the future development of effective methods to reduce symptoms in patients with PCOS.

The gut microbiome has been implicated in polycystic ovary syndrome (PCOS) pathophysiology. PCOS is a disorder with reproductive, endocrine and metabolic irregularities, and several studies report that PCOS is associated with a decrease in microbial diversity and composition. Diet is an important regulator of the gut microbiome, as alterations in macronutrient composition impact the balance of gut microbial communities. This study investigated the interplay between macronutrient balance and PCOS on the gut microbiome of control and dihydrotestosterone (DHT)-induced PCOS-like mice exposed to diets that varied in protein (P), carbohydrate (C) and fat (F) content. The amount of dietary P, C and F consumed significantly altered alpha (α) and beta (β) diversity of the gut microbiota of control and PCOS-like mice. However, α-diversity between control and PCOS-like mice on the same diet did not differ significantly. In contrast, β-diversity was significantly altered by PCOS pathology. Further analysis identified an operational taxonomic unit (OTU) within Bacteroides (OTU3) with 99.2% similarity to Bacteroides acidifaciens, which is inversely associated with obesity, to be significantly decreased in PCOS-like mice. Additionally, this study investigated the role of the gut microbiome in the development of PCOS traits, whereby PCOS-like mice were transplanted with healthy fecal microbiota from control mice. Although the PCOS gut microbiome shifted toward that of control mice, PCOS traits were not ameliorated. Overall, these findings demonstrate that while diet exerts a stronger influence over gut microbiota diversity than PCOS pathology, overall gut microbiota composition is affected by PCOS pathology.

Lifestyle, mainly dietary, interventions are first-line treatment for women with polycystic ovary syndrome (PCOS), but the optimal diet remains undefined. We combined a hyperandrogenized PCOS mouse model with a systematic macronutrient approach, to elucidate the impact of dietary macronutrients on the development of PCOS. We identify that an optimum dietary macronutrient balance of a low protein, medium carbohydrate and fat diet can ameliorate key PCOS reproductive traits. However, PCOS mice display a hindered ability for their metabolic system to respond to diet variations, and varying macronutrient balance did not have a beneficial effect on the development of metabolic PCOS traits. We reveal that PCOS traits in a hyperandrogenic PCOS mouse model are ameliorated selectively by diet, with reproductive traits displaying greater sensitivity than metabolic traits to dietary macronutrient balance. Hence, providing evidence to support the development of evidence-based dietary interventions as a promising strategy for the treatment of PCOS, especially reproductive traits.

Polycystic ovary syndrome (PCOS) is a common and heterogeneous disorder; however, the etiology and pathogenesis of PCOS are poorly understood and current management is symptom-based. Defining the pathogenesis of PCOS traits is important for developing early PCOS detection markers and new treatment strategies. Hyperandrogenism is a defining characteristic of PCOS, and studies support a role for androgen-driven actions in the development of PCOS. Therefore, we aimed to determine the temporal pattern of development of PCOS features in a well-characterized dihydrotestosterone (DHT)-induced PCOS mouse model after 2, 4, and 8 weeks of DHT exposure. Following 2 weeks of treatment, DHT induced the key PCOS reproductive features of acyclicity, anovulation, and multifollicular ovaries as well as a decrease in large antral follicle health. DHT-treated mice displayed the metabolic PCOS characteristics of increased body weight and exhibited increased visceral adiposity after 8 weeks of DHT treatment. DHT treatment also led to an increase in circulating cholesterol after 2 weeks of exposure and had an overall effect on fasting glucose levels, but not triglycerides, aspartate transaminase (AST) and alanine transaminase (ALT) levels, or hepatic steatosis. These data reveal that in this experimental PCOS mouse model, acyclicity, anovulation, and increased body weight are early features of a developing PCOS phenotype whereas adiposity, impaired glucose tolerance, dyslipidemia, and hepatic steatosis are later developing features of PCOS. These findings provide insights into the likely sequence of PCOS trait development and support the addition of body weight criteria to the early diagnosis of PCOS.

Polycystic ovary syndrome (PCOS) is a common, multifactorial disorder characterized by endocrine, reproductive, and metabolic dysfunction. As the etiology of PCOS is unknown, there is no cure and symptom-oriented treatments are suboptimal. Hyperandrogenism is a key diagnostic trait, and evidence suggests that androgen receptor (AR)-mediated actions are critical to PCOS pathogenesis. However, the key AR target sites involved remain to be fully defined. Adipocyte and muscle dysfunction are proposed as important sites involved in the manifestation of PCOS traits. We investigated the role of AR signaling in white adipose tissue (WAT), brown adipose tissue (BAT), and skeletal muscle in the development of PCOS in a hyperandrogenic PCOS mouse model. As expected, dihydrotestosterone (DHT) exposure induced key reproductive and metabolic PCOS traits in wild-type (WT) females. Transplantation of AR-insensitive (AR^−/−) WAT or BAT from AR knockout females (ARKO) into DHT-treated WT mice ameliorated some metabolic PCOS features, including increased body weight, adiposity, and adipocyte hypertrophy, but not reproductive PCOS traits. In contrast, DHT-treated ARKO female mice transplanted with AR-responsive (AR^+/+) WAT or BAT continued to resist developing PCOS traits. DHT-treated skeletal muscle-specific AR knockout females (SkMARKO) displayed a comparable phenotype with that of DHT-treated WT females, with full development of PCOS traits. Taken together, these findings infer that both WAT and BAT, but less likely skeletal muscle, are key sites of AR-mediated actions involved in the experimental pathogenesis of metabolic PCOS traits. These data further support targeting adipocyte AR-driven pathways in future research aimed at developing novel therapeutic interventions for PCOS. NEW & NOTEWORTHY Hyperandrogenism is a key feature in the pathogenesis of polycystic ovary syndrome (PCOS); however, the tissue sites of androgen receptor (AR) signaling are unclear. In this study, AR signaling in white and brown adipose tissue, but less likely in skeletal muscle, was found to be involved in the development of metabolic PCOS traits, highlighting the importance of androgen actions in adipose tissue and obesity in the manifestation of metabolic disturbances.

Polycystic ovary syndrome (PCOS) is a common endocrine disorder, defined by reproductive and endocrine abnormalities, with metabolic dysregulation including obesity, insulin resistance and hepatic steatosis. Recently, it was found that skeletal muscle insulin sensitivity could be improved in obese, post-menopausal, pre-diabetic women through treatment with nicotinamide mononucleotide (NMN), a precursor to the prominent redox cofactor nicotinamide adenine dinucleotide (NAD⁺). Given that PCOS patients have a similar endocrine profile to these patients, we hypothesised that declining NAD levels in muscle might play a role in the pathogenesis of the metabolic syndrome associated with PCOS, and that this could be normalized through NMN treatment. Here, we tested the impact of NMN treatment on the metabolic syndrome of the dihydrotestosterone (DHT) induced mouse model of PCOS. We observed lower NAD levels in the muscle of PCOS mice, which was normalized by NMN treatment. PCOS mice were hyperinsulinaemic, resulting in increased adiposity and hepatic lipid deposition. Strikingly, NMN treatment completely normalized these aspects of metabolic dysfunction. We propose that addressing the decline in skeletal muscle NAD levels associated with PCOS can normalize insulin sensitivity, preventing compensatory hyperinsulinaemia, which drives obesity and hepatic lipid deposition, though we cannot discount an impact of NMN on other tissues to mediate these effects. These findings support further investigation into NMN treatment as a new therapy for normalizing the aberrant metabolic features of PCOS.