Pathophysiological effects of contemporary lifestyle on evolutionary-conserved survival mechanisms in polycystic ovary syndrome

Jim Parker

School of Medicine, University of Wollongong, Australia; jimparker@ozemail.com.au

Correspondence: jimparker@ozemail.com.au

Simple Summary: Polycystic ovary syndrome is a common multisystem disorder involving dysregulation of the microbiome, immune system, reproduction, central nervous system, skin, and metabolism. Understanding this problem involves unravelling the complex web of bidirectional interactions between all the biological, cellular, and whole-body regulatory systems. An Evolutionary Model provides a structured framework that links the observed biological components to our contemporary lifestyle and environment. This new model proposes that polycystic ovary syndrome arises as a result of a mismatch between ancient adaptive survival mechanisms and our rapid cultural development. This review summarizes the factors that activate the core changes, chronic systemic inflammation and insulin resistance, and how they relate to dysregulation of other body systems. This model provides a basis for answering the main question asked by women diagnosed with this disorder; What is polycystic ovary syndrome? “Polycystic ovary syndrome is an inherited problem resulting in symptoms such as irregular periods, acne, and excess hair growth, that can be controlled by attention to diet and other lifestyle factors. Women with polycystic ovary syndrome can have healthy active lives, with normal fertility.”

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 predispose the offspring to develop PCOS. Postnatal exposure to lifestyle and environmental risk factors results in epigenetic activation of developmentally programmed genes. 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 may play 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, autonomic nervous system). PCOS can be a progressive metabolic condition that leads to obesity, gestational diabetes, type 2 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: polycystic ovary syndrome, evolution, inflammation, insulin resistance, hyperinsulinaemia, immune, infertility, endocrine disrupting chemicals, environment, lifestyle, diet

Graphical Abstract: Pathogenesis of polycystic ovary syndrome.

1. Introduction

There is general agreement that PCOS is a polygenic multisystem disorder arising from an interaction between genetic and environmental factors (1). Comprehensive International Guidelines recommend a range of lifestyle-based interventions as first-line management for all women diagnosed with PCOS (2). These recommendations are based on evidence that lifestyle therapies, such as diet and exercise, can control and reverse many of the biochemical and endocrine features of PCOS (2,3). It has been hypothesized that contemporary lifestyle and environmental exposures are instrumental in the pathogenesis of PCOS due to a mismatch between our ancient and modern lifestyle and environment (1,4–6).

PCOS affects 8-13% of reproductive aged women, is thought to be increasing in prevalence globally, and is estimated to affect up to 200 million women world-wide (6,7). Women affected with PCOS present with a wide variety of symptoms (menstrual disturbance, acne, hirsutism, alopecia, subfertility, anxiety and depression) that reflect the underlying multisystem pathophysiology (8–10). Women with PCOS have an increased risk of pregnancy complications (deep venous thrombosis, pre-eclampsia, macrosomia, growth restriction, miscarriage stillbirth and preterm labour) (11), psychological problems (anxiety, depression) (12), and can progress to a range of other metabolic-related conditions (obesity, gestational diabetes, type 2 diabetes (T2DM), metabolic-associated fatty liver disease (MAFLD), metabolic syndrome, cardiovascular disease, and cancer) (13–15). The population attributable risk of PCOS to T2DM alone has been estimated at 19-28% of women of reproductive age (16). PCOS can be a progressive metabolic disease and therefore makes a significant contribution to the chronic disease epidemic (17).

The prime directive of all life is to optimise reproduction and species survival (18). Reproduction and metabolism are intimately linked so that optimal reproductive fitness requires optimal metabolism (19,20). There is always an evolutionary trade-off to optimise metabolism and/or reproduction, depending on the species and prevailing environmental conditions (21). This is achieved by a complex network of hormonal and signaling molecules that link metabolism to reproductive cycles, via hormonal regulatory processes, post-translational modification of enzymes, substrate level inhibition of metabolic pathways, and epigenetic regulation of gene expression (22–24).

Attention has been directed at identifying the mechanisms by which lifestyle and environmental exposures alter this regulatory framework (25–27). A root-cause analysis of the proximate causes of PCOS has identified a wide variety of lifestyle and environmental exposures that are likely to contribute to the pathogenesis of PCOS (1,2,5,28). These include, diet and nutritional factors, exercise and sedentary behaviour, sleep and circadian disruption, endocrine disrupting chemicals, stress, direct and indirect effects of climate change, and community support systems (1). Contemporary lifestyle exposures are significantly different to the environmental conditions that existed throughout most of human evolution. Namely, starvation, predation, fear, increased maternal mortality and exposure to different climatic conditions (4,29,30). The reduction of chronic diseases following lifestyle interventions such as diet, exercise and smoking cessation, has provided strong evidence for contemporary culture as the primary “cause” of many diseases (31).

It is now appreciated that more than one pathophysiological mechanism is involved in the development of PCOS (32,33). When viewed from an evolutionary perspective, PCOS represents dysregulation of the hallmarks of health (table 2) (34). This narrative review outlines the relationship between lifestyle and environmental risk factors and the underlying pathophysiological mechanisms identified in women with PCOS. These include immune dysregulation (chronic systemic inflammation, oxidative stress), metabolic dysfunction (insulin resistance (IR), hyperglycaemia, hyperinsulinemia), hormonal dysregulation (hyperandrogenism, estrogen, follicle stimulating hormone, luteinizing hormone) and gastrointestinal dysbiosis (decreased alpha diversity, increased gastrointestinal mucosal permeability) (figure 1). The pathological processes are discussed in the context of the Evolutionary Model of PCOS (1).

Figure 1. 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, and at multiple different sites, and are responsible for the pathogenesis of PCOS. The influence of the exposome on developmentally programmed susceptibility genes causes the phenotypic manifestations of PCOS during childhood, adolescence, and adulthood.

2. Materials and Methods

The literature search focused on research publications related to the pathophysiology and pathogenesis of PCOS using the keywords listed above and related mesh terms for data on the evolutionary aspects of PCOS, chronic systemic inflammation, in-utero developmental epigenetic programming, insulin resistance, hyperinsulinemia, hyperandrogenism, reproductive changes, infertility, microbiome, dysbiosis, endocrine disrupting chemicals, lifestyle, diet, and physical activity. The databases searched included PubMed, Scopus, Cochrane, and Google Scholar. The literature has been searched repeatedly over the past 10 years. A glossary of abbreviations is included. The present manuscript provides a summary of the pathogenesis and pathophysiology of PCOS in the context of the Evolutionary Model (1) and the Hallmarks of Health (34).

3. Chronic Systemic Inflammation

3.1 Evolution and the advantages of a proinflammatory design

Inflammation is a normal physiological process that is an evolutionary conserved homeostatic mechanism in cells and tissues throughout the body (35). Optimal health is achieved when a balance between pro- and anti-inflammatory processes removes aging, damaged or infected cells, and restores normal cellular function (36). Inflammation is a protective mechanism in response to specific environmental conditions and occurs at a cost to normal tissue function (37,38). Acute inflammation is a physiological process that is spatially and temporally limited by multiple mechanisms (34). Local anti-inflammatory mediators attempt to limit the systemic spread of inflammation and contain the inflammatory response. Temporal limitation, or resolution of inflammation, is facilitated by removal of the primary cause, local negative feedback loops, systemic regulation by the autonomic nervous system (ANS) (39), and glucocorticoids (34). Chronic low-grade systemic inflammation can occur as a result of failure of any of these homeostatic mechanisms and is a cornerstone of PCOS pathophysiology (40). Large systematic reviews confirm an important role for chronic systemic inflammation in the pathogenesis of PCOS (8,41).

Rapid changes in the contemporary human environment have outpaced genetic adaptation, leading to a mismatch between our modern exposures and selected metabolic and reproductive traits. This mismatch has resulted in a dysregulated inflammatory response that has increased susceptibility to many common chronic diseases including obesity, type 2 diabetes, metabolic syndrome, cardiovascular disease, neuroinflammatory diseases, and PCOS (36).

3.2 Overview of the inflammatory response

The human body has two parallel systems of cellular defense (innate and adaptive immunity) that work co-operatively to protect cells, individuals, and ultimately the species (42). Billions of years of evolution has equipped unicellular organisms with a range of stress responses to abiotic environmental threats such as temperature, salinity, sunlight exposure, heavy metals and oxygen (43). In addition, multicellular organisms possess elaborate innate and adaptive immune responses to defend against exposure to noninfectious (reactive oxygen species, uric acid, cholesterol, microparticles, and exosomes), and infectious agents (bacteria, viruses, protozoa, parasites, fungi) (44). These responses are activated by a range of biological mechanisms including oxidative stress and reactive oxygen species (ROS), advanced glycation end-products (AGE), and via pattern recognition receptors (PRR) (45).

3.3 Neuroimmunomodulation and the link between the nervous system and PCOS

Both the immune and nervous systems share many similarities and have unique qualities that allow them to sense changes in the internal and external environments and counteract deviations in homeostasis (46). Communication between the nervous, endocrine and immune systems involves evolutionary-conserved mechanisms that are essential for host defense and survival (47). The immune system and ANS can respond to numerous common regulatory molecules including cytokines, neurotransmitters, and glucocorticoids (48). The brain is the ultimate regulator of whole-body homeostasis of all physiological parameters. This includes blood glucose, thermoregulation, hydration, electrolyte levels, blood pressure, stress responses, feeding, behavior, reproduction, body weight, and whole-body inflammatory balance (22,33).

Regulation of the inflammatory response has previously been thought to be autonomous (49). Substantial evidence now suggests that the nervous system exerts an active role in maintaining inflammatory homeostasis (33,50,51). The brain participates in a bidirectional network of mediators including hormones, cytokines, and neurotransmitters, that monitor, co-ordinate and regulate the systemic inflammatory response (figure 2)(47,51). The magnitude of the inflammatory response is crucial to adaptation and survival. An inefficient response can result in immunodeficiency, infection and cancer, and an excessive response can lead to morbidity and mortality (52). Abnormalities in the neuroendocrine-immune response are implicated in the pathogenesis of many chronic diseases including obesity, atherosclerosis, autoimmune disease, depression, and PCOS (33,48,53,54).

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.

3.4 Hyperandrogenism and chronic inflammation

Chronic systemic inflammation can cause hyperandrogenism (41), and elevated androgens can affect immune cells, resulting in predominately anti-inflammatory effects on the immune system (55). There is debate in the literature regarding the direction of causation, physiological importance, and evolutionary significance of these processes. The preponderance of evidence, and the most widely accepted current view, is that hyperandrogenism is secondary to the synergistic actions of chronic systemic inflammation and IR, through upregulation of ovarian theca cell androgen synthesis (discussed in section 4.5) (56). The evidence presented in the current review also supports this paradigm.

The influence of androgens in the pathogenesis and pathophysiology of PCOS is undisputable, despite the debate regarding the primary mechanism of causation. Data derived mostly from animal models of PCOS clearly indicate that intrauterine exposure to elevated androgen levels induces the development of PCOS traits in adult females. PCOS can also develop in women with other hyperandrogenic syndromes such as congenital adrenal hyperplasia, lipodystrophy, and ovarian or adrenal tumors. In addition, there has also been debate regarding the evolutionary “advantage” of hyperandrogenism in PCOS. Inflammation-induced hyperandrogenism has been proposed as a possible compensatory mechanism to restore homeostasis within the immune system, given the anti-inflammatory effects of androgens in women (41).

In summary, accumulating evidence suggests that the ovaries are not the primary cause of hyperandrogenism in most women with PCOS. It is also possible that hyperandrogenism (due to inflammation and/or hyperinsulinemia) may represent an adaptive physiological mechanism to down-regulate reproduction during periods of environmental (infection, starvation, climatic) and personal stress. In addition, there may be other individual advantages such as increased strength and fitness.

3.5 Summary of the role of inflammation in PCOS from an evolutionary perspective

A significant body of literature supports the role of chronic inflammation in the pathogenesis of PCOS. Billions of years of evolution have constructed a co-operative system of sensors, receptors, hormones, cytokines, chemokines, and other signalling molecules that invoke intracrine, autocrine, paracrine, and neuroendocrine mechanisms designed to regulate cellular, tissue and whole-body inflammatory responses. This process forms part of the repertoire of adaptive survival responses that are intimately connected with total body metabolic homeostasis to ensure individual survival. Inflammation invokes a series of adaptive metabolic survival mechanisms, such as IR, to ensure adequate energy supply to immune cells. Neuroendocrine mechanisms act as a counter-regulatory anti-inflammatory mechanism to control inflammation and restore homeostasis. In addition, immune and metabolic physiology are intimately linked to reproduction, to optimize fertility and ensure species survival. As a result, both chronic inflammation and IR can contribute to hyperandrogenemia, which also has adaptive survival advantages that restore immune homeostasis and temporarily down-regulate reproduction.

4. Insulin Resistance and reduced insulin sensitivity

4.1 Physiological actions of insulin

Insulin is a peptide hormone (51 amino acids) produced by the beta cells in the islets of Langerhans in the pancreas. Insulin binds with its receptor which is a large (320 kDa) transmembrane protein with an intracellular domain that acts as a tyrosine kinase. The insulin receptor is highly conserved from an evolutionary perspective, and is present on all mammalian cells, although the distribution is unequal (40 per red blood cell, 300,000 per adipocyte) (57).

Insulin has pleiotropic metabolic and growth-promoting anabolic effects throughout the body (58). Importantly, the cellular effects of insulin are tissue specific, and not all cells require insulin to transport glucose into cells. Insulin signalling increases the availability of GLUT-4 glucose transport proteins to the surface of insulin-dependent cells (skeletal and cardiac muscle, adipose tissue, vascular endothelium). Liver and brain are insulin-independent and use other GLUT transporters, in addition to using insulin-responsive GLUT-4 transporters. Insulin modulates a wide range of tissue specific physiological processes, in addition to facilitating glucose removal from the blood (table 1) (22).

Insulin also has a direct anti-inflammatory role by preventing hyperglycaemia-related generation of ROS and AGE, inhibiting NF-kB (by reducing the production of inflammatory cytokines), inducing vasodilation (via nitric oxide release), reducing leukocyte adhesion to the endothelium (59), and by inhibiting formation of the NLR inflammasome complex (60). As a result, hyperglycaemia and IR are pro-inflammatory states. Insulin resistance can cause inflammation, and inflammation can cause IR, in women with PCOS (59,61).

In summary, insulin’s overall role is to control energy conservation and utilization during feeding and fasting states (62). Insulin acts as a metabolic switch between anabolic and catabolic processes to regulate blood glucose levels and has a significant anti-inflammatory effect. Insulin provides a direct link between metabolism and immune regulation, and is paramount in activating numerous adaptive survival mechanisms (63). Dysregulation of the protective physiological functions of insulin are instrumental in the pathogenesis and progression of many chronic diseases, including PCOS (62,64,65). The physiological actions of insulin are summarized in table 1.

Table 1. Physiological actions of insulin.

Functions of Insulin	Mechanism
Energy storage	Adipose: triglyceride storage, lipolysis Muscle: glycogen synthesis Liver: glycogen synthesis, gluconeogenesis
Anti-inflammatory	Keeps BSL normal (ROS and AGE) Inhibits NF-κB activated cytokine production Inflammasome formation reduced Leukocyte adhesion to endothelium reduced
Volume expansion	Kidney: sodium reabsorption
Vasodilation	Blood vessels: endothelial nitric oxide
Tissue perfusion	Volume expansion and vasodilation
Evolutionary role of insulin	Tissue-specific energy storage and anabolic growth effects. Anti-inflammatory protective effect against excessive immune activation
Evolutionary role of insulin resistance	Maintain blood glucose to supply brain, immune cells, and fetus, during starvation, infection, stress and trauma. Proinflammatory

BSL, blood sugar levels; ROS, reactive oxygen species; AGE, advanced glycation end-products; NF-κB, nuclear factor kappa-B

4.2 Reduced insulin sensitivity versus insulin resistance in PCOS

Diminished tissue sensitivity to insulin has become characterized as a pathological condition known as IR, as a result of the association between IR, metabolic conditions, and chronic disease (16,65). Being able to vary the sensitivity of the cellular and tissue response to insulin is an evolutionarily-conserved protective mechanism used by many species (insects, worms, vertebrates, humans), to enhance survival (66). Insulin resistance is a categorical variable that has an arbitrary definition in research studies, but has no agreed definition or normal range in clinical practice (67,68). Reduced insulin sensitivity is a continuous variable that is considered a quantitative trait (interaction of multiple genes with the environment that results in a continuous distribution of phenotypes), in evolutionary medicine (69).

It is important to distinguish between reduced insulin sensitivity and IR, as most women with PCOS have reduced insulin sensitivity, but not all women with PCOS meet the experimental criteria for insulin resistance. The reported prevalence of IR in PCOS has varied widely due to the heterogeneity of diagnostic criteria for PCOS, variety of assessment methods, and the arbitrary definition of IR selected for different studies (70). Nevertheless, IR has been considered a central feature in the majority of women with PCOS (71). A systematic review of hyperinsulinemic-euglycemic clamp studies found that women with PCOS have a 27% reduction in insulin sensitivity compared to matched controls (64).

When considered from an evolutionary perspective, women with a PCOS phenotype would have improved survival chances during times of increased physiological demand or imposed environmental stress, but be more vulnerable to the pathological effects of IR when exposed to contemporary lifestyle factors (1,5). When viewed as a continuous variable, it is likely that all women with PCOS, whether obese or lean, have reduced insulin sensitivity (64,72,73).

Figure 3. Pathophysiology of insulin resistance. Any of the causes listed above can impact insulin signaling 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 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.

4.3 Mechanisms of insulin resistance in PCOS

Insulin resistance can be caused by numerous mechanisms including hyperinsulinemia, insulin receptor variants, receptor antagonists and agonists, autoantibodies, oxidative stress, advanced glycation end-products, hormones, nutrient sensors, inflammatory cytokines, and metabolic intermediates (58,74). It is likely that more than one mechanism is involved in any individual, given the interactive nature of many of the pathophysiological processes and signaling pathways.

Insulin resistance has been related to the western diet via a variety of mechanisms (75). These include high-glycemic diet-related dysbiosis (40,76), chronic inflammation, and intracellular accumulation of metabolic intermediates (58). These mechanisms may act individually, or together, to produce the observed features of IR. The pathophysiology of IR is discussed in figure 3.

4.4 Evolutionary adaptive role of insulin resistance in PCOS

Human survival has relied on the ability to alter our physiology according to the changing demands of the environment, or to different internal states during various life stages (77). In evolutionary terms, physiological IR is an adaptive survival mechanism that allows organisms to selectively modulate cellular and tissue responses to a variety of environmental challenges (infection, starvation, dehydration, psychological stress, physical stress from injury) (78–80), and internal states (pregnancy, puberty, adolescence) (81,82). Pathological IR is a detrimental condition associated with metabolic syndrome, other chronic diseases, and PCOS (74).

In contemporary society, stress is more likely to be psychological rather than physical or infectious, but the systemic stress response is similar (77). The HPA-axis and SNS are activated, IR is implemented, but the metabolic demand is much less, and the mobilized energy is re-stored in adipose tissue. The stress is often protracted resulting in anxiety, increased appetite from cortisol excess and leptin-resistance, stress-eating, and central obesity (83). In evolutionary terms, chronic IR represents an evolutionary mismatch between ancestral survival responses and modern cultural demands and lifestyle. Women with PCOS experience increased levels of anxiety, depression and stress, and the International Guidelines recommend screening for emotional well-being (2,84). Women with a PCOS phenotype may have had an evolutionary advantage from having a better response to infection, dehydration and starvation, but are now more susceptible to stress, hypertension, metabolic syndrome, and PCOS, as a result of contemporary lifestyle and environmental exposures (1,5).

Insulin sensitivity decreases throughout pregnancy and is an evolutionary-conserved mechanism to limit maternal glucose use and shunt energy to the foetus, particularly during the second half of gestation (81). Insulin sensitivity gradually decreases up to 20 weeks gestation, followed by a more rapid decrease to 50% of the non-pregnant values by 40 weeks, in normal pregnancy (85). The pancreatic beta-cells respond by increasing insulin secretion by up to 250% to maintain euglycaemia (86). An inability to secrete adequate amounts of insulin results in elevated blood sugar levels and Gestational Diabetes Mellitis (GDM).

Women with PCOS have a 25-50% chance of developing GDM in pregnancy (87,88). Women with GDM have up to 50% risk of developing T2DM in the 5-10 years following pregnancy (89,90). The population attributable risk of PCOS to T2DM has been estimated at 19-28% (16). Therefore, up to 28% of adult women with T2DM have pre-existing PCOS that progresses to T2DM. Up to 50% of individuals diagnosed with T2DM have complications (retinopathy, nephropathy, neuropathy, vascular), at the time of diagnosis (91). The International Diabetes Federation estimates that there are approximately 537 million diabetics in the world, and women with PCOS therefore make a significant contribution to this global epidemic (92). These data support the characterization of PCOS as a progressive metabolic disease. Recent studies have demonstrated that the risk of progression of GDM to T2DM can be reduced by greater than 90% by dietary and lifestyle interventions (93). PCOS therefore appears to be a progressive metabolic disease that is preventable.

Insulin resistance is thought to have evolved as an adaptation to environmental stressors such as starvation, infection and fear (1). Varying the levels of insulin sensitivity permits the redistribution of total body energy to organs of greater need, such as the brain, immune system, and fetus (77). In addition, it has been proposed that the development of selective insulin resistance is a mechanism that activates specific behavioural and reproductive survival strategies (94). Specific cells and tissues are protected from developing IR, including the brain, immune cells, placenta and ovaries (95,96). Areas of the brain do not develop IR and benefit from the redistribution of glucose from muscle and fat tissue. In pregnancy, the placenta is an insulin independent organ, and the development of maternal IR is expected to divert more nutrients through the placenta. The ovary does not develop IR and remains sensitive to the high levels of insulin that occur in IR and hyperinsulinemia (97,98). This may be a mechanism to downregulate fertility at times of physiological or psychological stress. In summary, both the physiological actions of insulin and the development of insulin resistance are tissue specific and facilitate a variety of adaptive survival responses.

In our modern environment, insulin resistance and hyperinsulinemia are thought to be primary factors in the development of hyperandrogenism in PCOS, in addition to chronic inflammation (98). Insulin has a number of known mechanisms that can increase androgen levels in the serum, liver, and ovaries (98,99). Insulin is reported to stimulate ovarian androgen production directly (via the PI3K and MAPK pathways), or indirectly by augmenting LH-stimulated androgen synthesis (99). Insulin increases the availability of insulin-like growth factor and decreases its binding protein, resulting in increased androgen stimulation (100). Insulin can increase the amplitude of gonadotropin releasing hormone stimulated LH pulses (101) that are known to occur in PCOS. Both insulin and testosterone decrease hepatic production of sex hormone binding globulin, resulting in increased free testosterone (102). In addition, hyperinsulinemia stimulates the HPA-axis leading to increased adrenal androgen production (103). Accumulating evidence suggests that the ovaries are not the primary abnormality in PCOS (98,104,105).

5. Evolutionary significance of adipose tissue in PCOS

Hundreds of millions of years of evolution have shaped adipose tissue (AT) into its current form (106–109). Taking an evolutionary perspective provides insight into the complex range of AT-related adaptive survival functions that form part of the network of interdependent homeostatic systems previously discussed. Adipose tissue is involved in a variety of functions including immune responses (innate, adaptive, inflammatory), metabolism (glucose and lipid metabolism, appetite regulation, maintenance of body weight, insulin resistance), and reproduction (pregnancy, lactation, hyperandrogenism) (106,110). Adipose tissue has a bidirectional relationship with the neuroendocrine, immune, metabolic, and reproductive systems, that facilitate these functions. This communication is achieved via a variety of cellular receptors and secretion of a large number of signalling molecules. These include adipokines (adiponectin, leptin, resistin, visfatin, retinol-binding protein 4, pigment epithelium-derived factor, endocannabinoids, and many more), cytokines (50 cytokines have been identified), metabolites, lipids, non-coding RNA’s or extracellular vesicles, and chemokines (109,111).

The anatomical and functional redistribution of adipose tissue, in women with PCOS, may have adaptive survival benefits in an ancestral environment (improved energy storage capacity, greater protection from infection) that become maladaptive in response to contemporary lifestyle and environmental exposures (diet, inactivity, stress). In addition, adipose tissue is closely linked to the reproductive system and clearly plays a significant role in the pathophysiology of PCOS.

6. Central role of the microbiome in the pathogenesis of PCOS

The microbiota is the sum of microbial organisms (bacteria, virus, archaea, fungi) that inhabit the interface between the external environment or habitat and the internal environment of the human body (112). This interface mainly occurs at mucosal surfaces (nasal, oral, respiratory, gastrointestinal, genitourinary), eyes, and skin. The gastrointestinal (GI) microbiome (microbial organisms and their genetic material), makes up 80% of the microbiota and is now considered to have a central role in human health and disease, including PCOS (76,113,114). The functions of the microbiome include inhibition of pathogen colonization, regulation of the mucosal and systemic immune systems, alteration of metabolism, energy balance, hormonal action, maintenance of the integrity of the GI barrier, and bidirectional signalling with most organs and tissues throughout the body (gut-brain, gut-bone, gut-immune, gut-liver etc). The GI microbiome therefore forms part of the whole-body homeostatic regulatory framework that maintains health, and is now appreciated to be part of the human-microbe meta-organism (34).

The dysbiosis of gut microbiota theory of PCOS proposes that poor-quality Western-style diets (high-glycemic, high fat, high calorie, highly processed, low nutrient, low fibre), result in an imbalanced microbiome which induces increased GI permeability and results in endotoxin-mediated chronic inflammation (40). Dysbiosis results in breakdown of the GI barrier function (loss of protective mucous, activation of the zonulin pathway and breakdown of intercellular tight junctions), and release of lipopolysaccharide from the cell walls of gram-negative bacteria, which can traverse the “leaky gut.” Lipopolysaccharide binds with lipopolysaccharide binding protein which together bind with Toll-like receptor 4 on the surface of submucosal macrophages. This activates the NF-κB inflammatory pathway resulting in release of inflammatory cytokines. Continuing ingestion of a poor-quality diet results in chronic inflammation, insulin resistance, hyperandrogenism, ovulatory dysfunction, and the clinical features of PCOS (1,40). A recent review of 31 proof-of-concept studies that specifically investigated this mechanism, concluded that preliminary evidence supports this theory (76).

As with the rest of the biological components involved in PCOS, the microbiome appears to have a significant bidirectional role in the pathophysiology of chronic systemic inflammation, insulin resistance, hyperandrogenism, and ovulatory dysfunction. Dysbiosis is an important part of the evolutionary model and represents a maladaptive response of the microbiome to contemporary lifestyle and the environment. Dysbiosis is a modifiable change that can be reversed with lifestyle, diet, prebiotics and probiotics (76).

7. Environmental and endocrine disrupting chemicals in PCOS

Endocrine disrupting chemicals are a global problem for human health and the environment (115). There is no doubt that anthropomorphic chemicals interfere with human physiology and have adverse health effects (116–119). Human exposure mainly occurs through mucosal surfaces (oral, gastrointestinal, respiratory, genitourinary), or via dermal absorption. EDC exposure is ubiquitous and numerous international organizations have issued warnings to doctors and patients, regarding the possible dangers to human health and pregnant women. These include The Royal College of Obstetricians and Gynaecologists (117), the International Federation of Gynecology and Obstetrics (118), and the Endocrine Society (119). They have recommended that all pregnant women be advised of the possible risks of EDC, and that education programmes be developed to inform health professionals of the risks.

Endocrine disrupting chemicals have a significant role in chronic systemic inflammation (120), insulin resistance (121), hyperandrogenism (122), microbiome disruption (123) neuroendocrine imbalance (124), obesity (125), oxidative stress (126), AGE (127), and inflammasomes (128), all of which are involved in the pathophysiology of PCOS. Women with a genetic susceptibility to PCOS may be at increased risk of adverse effects of EDC due to having a heightened proinflammatory design (section 3.1) and increased metabolic sensitivity (section 4.2). In addition, the in-utero developmental effects of EDC can be inherited by transgenerational transmission (129,130). Every effort should be made to inform women with PCOS about the potential risks of environmental chemicals and discuss ways to avoid or minimize exposure.

8. Evolutionary Model of PCOS and the Hallmarks of Health

There has been a gradual paradigm shift in conceptualizing the causes of health and disease over the past 20 years. Seminal publications on the “Hallmarks of Cancer” summarize the properties of malignant cells and their interaction with their non-malignant environment (131). The “Hallmarks of Aging” focus on the interactions of molecular, cellular, and systemic processes that explain the deterioration of organisms over time (132). This is a paradigm shift that signals a move away from conventional anatomical and physiological-based conceptions of disease (individual cells, tissues, organs, and systems) to a more “organizational” structure focused on factors that are causatively involved in maintaining homeostasis and equilibrium.

The “Hallmarks of Health” has endeavored to define health as a “compendium of organizational and dynamic features that maintain physiology (34).” This contrasts with the usual definition of health as the “absence of disease.” The current conception of PCOS as a polygenic disorder (collection of normal alleles), that is programmed in-utero and then manifests in adolescence following exposure to lifestyle, nutritional and environmental influences, seems to be an excellent example of this new paradigm (1). Many of the inter-related components of the hallmarks of health are dysregulated in women with PCOS. There are disturbances at the molecular (ROS, AGE, metabolites), organelle (mitochondria, endoplasmic reticulum), cellular (immune, endocrine, neural), supracellular (gastrointestinal mucosa, mucosal immunity), organ (ovary, pancreas), systemic (endocrine, reproductive, immune), and meta-organism levels (host-microbiota interaction) (table 2). The previous sections of this manuscript have attempted to describe some of the detailed interactions that disrupt the organizational dynamics of the hallmarks of health in women with PCOS.

The Evolutionary Model of PCOS is consistent with the hallmarks of health paradigm (1,5). Seen from this new perspective, PCOS is a progressive disturbance of the overall organism involving multiple levels that usually operate to maintain internal homeostasis and equilibrium with the environment. Multiple contemporary lifestyle factors can derail the overall organization of the system resulting in complex pathophysiological interactions and feedback mechanisms, that have no apparent beginning or end. All the components are inter-related and inter-dependent, in a system where multiple lifestyle and environmental “causative” factors operate simultaneously and synergistically. Defining PCOS in a positive way, with an evolutionary and hallmarks of health perspective, opens new opportunities for understanding this complex condition, improving patient communication and compliance, and informing future research, prevention, and intervention strategies.

Table 2. Dysregulation of the Hallmarks of Health in Polycystic Ovary Syndrome.

Hallmark	Polycystic Ovary Syndrome
Barrier integrity	Gastrointestinal permeability Respiratory mucosa
Containment of local perturbations	Mucosal and adaptive immunity ROS, AGE, DAMPS, PAMPS
Recycling and turnover	Autophagy, apoptosis, pyroptosis GI stem cell turnover
Integration of circuitries	Metabolic, reproductive neurological, circadian
Rhythmic oscillations	Menstrual cycle, circadian GI peristalsis
Homeostatic resilience	Endocrine, ANS metabolic, immune, microbiome
Hormetic regulation	oxidative stress, inactivity xenohormesis#
Repair and regeneration	Endoplasmic reticular stress mitochondrial stress

^#xenohormesis=dietary phytochemical-induced; ANS=autonomic nervous system;

DAMPS=danger-associated molecular patterns; ROS=reactive oxygen species;

PAMPS=pathogen-associated molecular patterns; GI=Gastrointestinal;

AGE=advanced glycation end-products

6. Conclusions

Polycystic ovary syndrome is a common condition that affects women at all stages of the life cycle. The pathogenesis is related to a combination of nutritional and environmental exposures, in a genetically susceptible individual. Polycystic ovary syndrome can be characterized as an evolutionary mismatch disorder resulting from a disturbance to the hallmarks of health. Chronic systemic inflammation and insulin resistance are core mechanisms that operate at an organismal level in the physiology of survival, and play a central role in the pathophysiology of PCOS. Polycystic ovary syndrome is usually diagnosed in adolescence by the combination of oligomenorrhoea and hyperandrogenism and is a progressive condition that is associated with significant metabolic, hormonal, reproductive, and psychological problems. The symptoms and chronic sequelae can be controlled and prevented by lifestyle interventions, and the diagnosis of PCOS provides the ideal opportunity for prevention of chronic disease. This narrative review has outlined some components of the complex web of biological and pathophysiological changes that contribute to the pathogenesis of PCOS.

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