Pathophysiological Effects of Contemporary Lifestyle on Evolutionary-Conserved Survival Mechanisms in Polycystic Ovary Syndrome

Abstract

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.

Keywords: diet; endocrine disrupting chemicals; environment; evolution; hyperinsulinemia; immune; infertility; inflammation; insulin resistance; lifestyle; microbiome; polycystic ovary syndrome.

Figure 2

Hypothalamic-Pituitary-Adrenal-Immune Axis (HPA). The hypothalamus releases corticotropin releasing hormone that stimulates production of adrenocorticotropic hormone (ACTH) from the anterior pituitary. ACTH stimulates the synthesis of immunosuppressive glucocorticoids (cortisol) from the adrenal cortex [133]. Pro-inflammatory cytokines and neural inputs activate the HPA-axis to release ACTH, and the HPA-axis is subject to a classic negative feedback loop by cortisol that inhibits both corticotropin releasing hormone and ACTH [136]. Sympathetic neural activation of chromaffin cells in the adrenal medulla leads to an increased release of catecholamines into the circulation. Sympathetic innervation of cortical cells leads to the release of glucocorticoids. CNS-controlled SNS output is, therefore, converted to hormonal immunoregulation in peripheral tissues. ANS, Autonomic Nervous System; Parasympathetic Nervous System (PNS); Sympathetic Nervous System (SNS); CRH, Corticotropin Releasing Hormone; Adrenocorticotropic Hormone (ACTH); IL-1ẞ, interleukin-1ẞ; TNF-α, tumour necrosis factor-α. © Designua|Dreamstime.com.

Figure 1

Pathophysiology of Polycystic Ovary Syndrome. Depicts the multi-directional interactions between nutritional and environmental lifestyle-related risk factors and the identified pathophysiological processes and symptoms in PCOS. Health is a result of the successful integration of multidimensional subcellular, cellular, and systemic, integrated circuits and networks. Disturbances in these networks due to dysbiosis, chronic inflammation, insulin resistance, and neuroendocrine deregulation in isolation or in combination can lead to loss of homeostatic resilience in the system. Combinations of adverse nutritional and environmental factors can disturb this network in a myriad of ways, at multiple different sites, and are responsible for the pathogenesis of PCOS. The influence of the exposome on developmentally programmed susceptibility genes programs the embryo/foetus to express the phenotypic manifestations of PCOS during childhood, adolescence, and adulthood, following exposure to lifestyle, dietary, and environmental factors. QOL, quality of life.

Figure 3

Pathophysiology of insulin resistance. Any of the causes listed above can impact insulin signalling pathways and lead to tissue-selective impairment of insulin action. Once insulin resistance occurs in muscle, glycogen synthesis and glucose uptake from the circulation are reduced. Since muscle constitutes approximately 50% of body mass, insulin resistance in muscle makes a significant contribution to hyperglycaemia. Insulin resistance in adipose tissue leads to impaired lipogenesis and continued lipolysis, with release of glycerol and free fatty acids into the circulation. Hepatic insulin resistance impairs glycogen synthesis and prevents insulin from inhibiting gluconeogenesis. Adipose lipolysis supplies substrates for continued hepatic gluconeogenesis. Together, the effects of decreased muscle glucose uptake, adipose lipolysis, and hepatic gluconeogenesis\result in hyperglycaemia. This causes the compensatory release of insulin from the pancreas and hyperinsulinemia. DNL, de novo lipogenesis; DAG, diacylglycerol; FFA, free fatty acid; IR, insulin resistance; VLDL, very low-density lipoprotein.