Polycystic ovary syndrome (PCOS) is increasingly recognized as a complex metabolic disorder that manifests in genetically susceptible women following a range of negative exposures to nutritional and environmental factors related to contemporary lifestyle. The hypothesis that PCOS phenotypes are derived from a mismatch between ancient genetic survival mechanisms and modern lifestyle practices is supported by a diversity of research findings. The proposed evolutionary model of the pathogenesis of PCOS incorporates evidence related to evolutionary theory, genetic studies, in utero developmental epigenetic programming, transgenerational inheritance, metabolic features including insulin resistance, obesity and the apparent paradox of lean phenotypes, reproductive effects and subfertility, the impact of the microbiome and dysbiosis, endocrine-disrupting chemical exposure, and the influence of lifestyle factors such as poor-quality diet and physical inactivity. Based on these premises, the diverse lines of research are synthesized into a composite evolutionary model of the pathogenesis of PCOS. It is hoped that this model will assist clinicians and patients to understand the importance of lifestyle interventions in the prevention and management of PCOS and provide a conceptual framework for future research. It is appreciated that this theory represents a synthesis of the current evidence and that it is expected to evolve and change over time.

Diet-induced gastrointestinal dysbiosis has been hypothesized to play a significant role in stimulating an increase in gastrointestinal permeability and activating systemic inflammation in women with polycystic ovary syndrome (PCOS). We reviewed the current proof-of-concept studies on the proposed mechanism of dysbiosis in the pathogenesis of PCOS. A literature search was performed to identify articles on changes in the intestinal microbiome (dysbiosis) and increased intestinal mucosal permeability involving lipopolysaccharide (LPS), LPS-binding protein (LPS-BP), and zonulin. We also searched for systematic reviews and meta-analyses that synthesized the results of studies on the therapeutic effects of prebiotics, probiotics, or synbiotics in women with PCOS. Our search was confined to human studies between 2012 and 2021 using the PubMed, Scopus, and Cochrane databases. Thirty-one studies met the inclusion criteria (14 microbiota, 1 LPS, 1 LPS-BP, 1 LPS and LPS-BP, 5 zonulin, 9 systematic reviews). Our analysis revealed that most studies reported reduced alpha diversity and dysbiosis in women with PCOS. Preliminary studies suggest that LPS, LPS-BP, and zonulin may be involved in the pathophysiology of increased intestinal permeability. Treatment of PCOS with prebiotics, probiotics, and synbiotics appears to have a range of beneficial effects on metabolic and biochemical profiles. This review highlights the need for continued research into the pathophysiological mechanisms of dysbiosis and the clinical efficacy of prebiotics, probiotics, and synbiotics in women with PCOS.

Polycystic ovary syndrome (PCOS) is increasingly being characterized as an evolutionary mismatch disorder that presents with a complex mixture of metabolic and endocrine symptoms. The Evolutionary Model proposes that PCOS arises from a collection of inherited polymorphisms that have been consistently demonstrated in a variety of ethnic groups and races. In utero developmental programming of susceptible genomic variants are thought to predispose the offspring to develop PCOS. Postnatal exposure to lifestyle and environmental risk factors results in epigenetic activation of developmentally programmed genes and disturbance of the hallmarks of health. The resulting pathophysiological changes represent the consequences of poor-quality diet, sedentary behaviour, endocrine disrupting chemicals, stress, circadian disruption, and other lifestyle factors. Emerging evidence suggests that lifestyle-induced gastrointestinal dysbiosis plays a central role in the pathogenesis of PCOS. Lifestyle and environmental exposures initiate changes that result in disturbance of the gastrointestinal microbiome (dysbiosis), immune dysregulation (chronic inflammation), altered metabolism (insulin resistance), endocrine and reproductive imbalance (hyperandrogenism), and central nervous system dysfunction (neuroendocrine and autonomic nervous system). PCOS can be a progressive metabolic condition that leads to obesity, gestational diabetes, type two diabetes, metabolic-associated fatty liver disease, metabolic syndrome, cardiovascular disease, and cancer. This review explores the mechanisms that underpin the evolutionary mismatch between ancient survival pathways and contemporary lifestyle factors involved in the pathogenesis and pathophysiology of PCOS.