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Parker, J. Mechanisms of Chronic Systemic Inflammation in Polycystic Ovary Syndrome. Encyclopedia. Available online: (accessed on 20 June 2024).
Parker J. Mechanisms of Chronic Systemic Inflammation in Polycystic Ovary Syndrome. Encyclopedia. Available at: Accessed June 20, 2024.
Parker, Jim. "Mechanisms of Chronic Systemic Inflammation in Polycystic Ovary Syndrome" Encyclopedia, (accessed June 20, 2024).
Parker, J. (2023, April 27). Mechanisms of Chronic Systemic Inflammation in Polycystic Ovary Syndrome. In Encyclopedia.
Parker, Jim. "Mechanisms of Chronic Systemic Inflammation in Polycystic Ovary Syndrome." Encyclopedia. Web. 27 April, 2023.
Mechanisms of Chronic Systemic Inflammation in Polycystic Ovary Syndrome

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.

polycystic ovary syndrome evolution inflammation insulin resistance hyperinsulinemia immune

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 [1]. Optimal health is achieved when a balance between pro- and anti-inflammatory processes removes aging, damaged or infected cells, and restores normal cellular function [2]. Inflammation is a protective mechanism in response to specific environmental conditions and occurs at a cost to normal tissue function [3][4]. Local anti-inflammatory mediators attempt to limit the systemic spread of inflammation and contain the inflammatory response. The resolution of inflammation is facilitated by the removal of the primary cause, local negative feedback loops, systemic regulation by the autonomic nervous system (ANS) [5], and glucocorticoids [6]. Chronic low-grade systemic inflammation can occur as a result of the failure of any of these homeostatic mechanisms and is a cornerstone of PCOS pathophysiology [7]. Large systematic reviews confirm the important role of chronic systemic inflammation in the pathogenesis of PCOS [8][9].
Rapid changes in the contemporary human environment have outpaced genetic adaptation, leading to a mismatch between 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 two diabetes, metabolic syndrome, cardiovascular disease, neuroinflammatory diseases, and PCOS [2]. Chronic low-grade inflammation or metaflammation, caused by poor-quality diet, nutritional excess, and other environmental factors, is maintained at a subacute level over long periods of time, enhancing inflammatory and metabolic signal transduction pathways that lead to the symptoms and diseases associated with PCOS [10]. The concept of metaflammation refers to the pathophysiological association between metabolic disorders and the immune system and is proposed to originate from the evolutionary crosstalk between immune and metabolic pathways [4].

2. Overview of the Inflammatory Response

The human body has two parallel systems of cellular defence (innate and adaptive immunity) that work co-operatively to protect cells, individuals, and ultimately the species [11]. Billions of years of evolution have equipped unicellular organisms with a range of stress responses to abiotic environmental threats, such as temperature, salinity, sunlight exposure, heavy metals, and oxygen [12]. In addition, multicellular organisms possess elaborate innate and adaptive immune responses to defend against exposure to non-infectious (reactive oxygen species, uric acid, cholesterol, microparticles, and exosomes) and infectious agents (bacteria, viruses, protozoa, parasites, fungi) [13]. 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) [14].

2.1. Oxidative Stress in PCOS

The evolution of life chemistry and metabolism dates back 3.5 billion years [15]. The first cellular life forms arose in an anaerobic environment and most of the pathways of intermediate metabolism (glycolysis, fatty acid synthesis and oxidation, pentose phosphate pathway, Krebs cycle, electron transport, and many more), developed in an environment where oxygen was toxic [16]. Approximately 2.4 billion years ago, cyanobacteria started producing oxygen from photosynthesis, raising the atmospheric oxygen to 2–4%. A billion years later, during the Pre-Cambrian period, oxygen levels rose, and multicellular organisms flourished. This resulted in the ability of cells to use oxygen to make adenosine triphosphate (ATP) and produce ROS (superoxide, hydroxyl radical) as a metabolic by-product, and for the purposes of cell signalling and defence, and detoxifying oxygen with a variety of antioxidant systems [17]. ROS contain an unpaired electron that makes them extremely unstable and reactive. ROS attempt to stabilize themselves by scavenging electrons from healthy cells and cause oxidative damage.
Living cells can be differentiated from dead cells because of the cessation of the coordinated flow of energy that occurs due to electron transfer from one molecule to another during metabolism, following failure of adaptive responses to restore cellular homeostasis [18]. When the flow of electrons to the mitochondrial electron transport chain is disrupted by environmental factors, such as microbial infection, chemical toxins, accumulation of metabolic intermediates, due to nutritional excess, and other cellular stressors, metabolic mismatch occurs [17]. Electrons are diverted away from mitochondria, mitochondrial oxygen consumption falls, and cytoplasmic oxygen rises. This redox imbalance creates ROS and reactive nitrogen species (RNS) that initiate innate immune responses designed to defend and protect the cell [19]. Mitochondrial structure, dynamics, biogenesis, and membrane potential are altered in women with PCOS [20].
The body has an in-built system of antioxidants to stabilize and neutralize ROS and protect the cell. Antioxidants are highly stable molecules that have the unique ability to serve as electron donors to help stabilize free radicals without becoming reactive themselves. Oxidative stress refers to the imbalance between the production of oxidant species and antioxidant defences, and the generation of excessive amounts of ROS that underlie the various forms of cell death [21]. Oxidative stress can arise from endogenous (leakage of ROS from mitochondrial oxidative phosphorylation, cytochrome P-450 detoxification enzyme systems, peroxisomal oxidases, and nicotinamide dinucleotide adenine phosphate oxidases) or exogenous sources (environmental chemicals, cigarette smoke, alcohol, ionizing radiation, microbial infection, stress, and sleep deprivation) [21][22] and is a potent stimulator of inflammation [23][24]. Oxidative stress has been found to play a central role in the pathogenesis of PCOS [21]. Oxidative stress can impair insulin signalling and cause IR [25] and dysregulate follicular calcium which results in reproductive and menstrual dysfunction [26], oxidize plasma proteins that may act as pro-inflammatory mediators [27], cause lipid peroxidation [28], and induce DNA damage [29] in women with PCOS.
Cumulative studies show an association between oxidative stress and PCOS [19][21]. In addition, oxidant and antioxidant status has been found to vary between individuals because of differences in diet, lifestyle, and enzymatic and dietary antioxidants [19][23]. A recent case-control study showed that plant-based dietary pattern is associated with a lower odds ratio of PCOS and suggested that antioxidant-rich foods may protect the body against oxidative damage [30]. Dietary total antioxidant capacity was subsequently assessed using the Nutrient Data Laboratory of the United States Department of Agriculture reference values. The investigators reported a significant reduction in the odds of PCOS in women that consumed a high total antioxidant containing plant-based diet [31]. These findings support the existing body of dietary pattern research that recommend healthy diets for the management of PCOS [32][33].

2.2. Advanced Glycation End Products and PCOS

Advanced glycation end-products are reactive molecules that are formed by non-enzymatic reactions of carbohydrates with proteins, lipids, or nucleic acids [34]. Advanced glycation end products result in the irreversible cross-linking of proteins and loss of protein structure and function and can initiate apoptosis [35]. Advanced glycation end products can be generated endogenously under normal conditions, and can be ingested in food, particularly a cooked fast-food diet, and with cigarette smoking [36]. Advanced glycation end products can cause oxidative stress and inflammation, resulting in cellular and tissue damage when produced or ingested in excessive amounts [37]. Protective circulating anti-inflammatory receptors called soluble receptors for advanced glycation end products and membrane-bound receptors of advanced glycation end-products (RAGE) are associated with protection against AGE [38].
The interaction of AGE with their membrane receptors activates intracellular signalling pathways that lead to increased oxidative stress, inflammation, IR, diabetes, hyperandrogenism, obesity, and ovulatory dysfunction, all of which have been associated with PCOS [39][40]. Recent data have shown elevated circulating levels of AGE and increased expression of RAGE receptors in ovarian tissue [41][42]. Proinflammatory AGE–RAGE signalling has been found to cause altered steroidogenesis and follicle development in ovarian granulosa cells in PCOS [43][44]. In addition, hyperandrogenism induces endoplasmic reticulum stress in granulosa cells, resulting in increased accumulation of AGE in the ovary [42].
Modern Western diets are rich in AGE which is absorbed through the intestine [40]. A high-glycaemic diet and excessive glucose ingestion result in elevated blood glucose levels and the generation of AGE that bind with cell membrane-bound RAGE and activate inflammation [45][46]. Ligand binding by glycated proteins and lipids to RAGE stimulates intracellular signalling events that activate nuclear factor kappa-light-chain-enhancer of activated B (NF-κB). Nuclear factor kappa B controls several genes involved in inflammation, and RAGE itself is upregulated by NF-κB, establishing a positive feedback cycle that leads to chronic inflammation [46].
Studies have demonstrated that the intake of the low-AGE containing diet is associated with favourable metabolic and hormonal profiles as well as fewer oxidative stress biomarkers in patients with PCOS [47]. One study employed a low-AGE diet, consisting of Mediterranean-style foods cooked at temperatures below 180 degrees by boiling, poaching, stewing, or steaming [47]. High-temperature cooking above 220 degrees Celsius by roasting, grilling, and baking was avoided. Dietary recommendations for minimising ingestion of AGE includes increasing consumption of a whole foods that include vegetables, fruits, seafood, and whole grains while reducing the consumption of high AGE containing foods. These include highly processed foods (packaged meats, cheese, and snack foods), excessive sugar in sweets and beverages, and fried foods [33][40]. Adoption of other healthy lifestyle behaviours, such as exercise, maintaining normal body weight, and cessation of tobacco consumption, are also important for reducing AGE [40][48].

2.3. Pattern Recognition Receptors and the Innate Immune System

The existence of receptors expressed by innate immune cells that were responsible for detecting microbial products was first proposed by Charles Janeway in 1989 [49]. Polly Matzinger subsequently proposed the “Danger Theory”, suggesting that the immune system produced molecules that initiate and propagate inflammation in response to tissue stress, damage, or infection [50]. In 2013, Robert Naviaux further expanded this concept to the “Cell Danger Response” (CDR) [51]. Naviaux proposed that evolutionary selection has preserved a similar response to a variety of threats as cells have a limited number of ways they can mobilize existing cellular machinery and energy. The CDR is, therefore, an evolutionary-conserved cellular protective response that is activated when a cell encounters a chemical, physical, or microbial threat that could injure or kill the cell [51]. More recent research has characterized the molecular details of an elaborate danger detection system, involving PRR, damage-associated molecular patterns (DAMPS), pathogen-associated molecular patterns (PAMPS), inflammasomes, and an intricate system of signalling molecules that activate a system-wide network of innate and adaptive immune responses [14]. This has been called the “Integrated Stress Response” and is reviewed in detail in previous reports [52][53].
There are five types of PRR that can be classified into two main groups based on their cellular localization [54]. Toll-like receptors (TLR) and C-type lectin receptors (CLR) are transmembrane receptors that allow sensing of host-derived DAMPS and PAMPS at the cell surface or within membrane-bound intracellular compartments. Specific cytoplasmic-based receptors also provide an intracellular recognition system for sensing DAMPS and PAMPS. Pattern recognition receptors are also excreted extracellularly and can be found in interstitial fluid and the bloodstream, where they play an important role in pathogen recognition [14]. Pattern recognition receptors also activate multiple types of cell death pathways, such as apoptosis and pyroptosis (a rapid pro-inflammatory form of cell death), if cellular defence against PAMPS and DAMPS is unsuccessful [4][14].
There are three main types of molecules involved in signal transduction following infectious or danger-related ligand binding to PRR: protein kinases, adaptor proteins, and transcription factors [54]. Signal transduction occurs via several common pathways, including NF-κB, mitogen-activated protein kinase (MAPK), and inflammasomes [4][54]. The signals they generate can crosstalk with each other and can converge into several common pathways. Each of the PRR initiate signalling cascades that cause epigenetic modulation of gene expression and posttranslational modification of cytokine precursors. This results in activation of the innate immune response and leads to degradation of microbes, production of inflammatory cytokines, and recruitment of the adaptive immune response [14][55]. Once PAMPS and DAMPS bind with TLR and nod-like receptors, they activate the formation of inflammasome complexes that form an essential element of the innate immune response [4][56].
Unlike adaptive immunity, innate immunity does not recognize every possible antigen. Innate immunity recognizes PAMPS shared by related groups of microbes that are not found in mammalian cells, such as lipopolysaccharide (LPS) from gram-negative bacterial cell walls. This early induced innate immunity (4–96 h) involves the formation of inflammasomes that lead to the release of chemokines and recruitment of defence cells. The recruited defence cells include phagocytic leukocytes, such as neutrophils, eosinophils, and monocytes and tissue phagocytic cells, such as macrophages, macrophages, and mast cells, that release inflammatory mediators and basophils, eosinophils, and natural killer cells [14].
Pattern recognition receptors represent evolutionarily conserved pathogen and damage recognition mechanisms that constitute the starting point for the inflammatory response. These cell-autonomous stress responses have evolved to form the basis of the non-antigen-dependent defence mechanisms that characterize innate immunity [50][57]. Lipopolysaccharide released by gram-negative bacteria in the dysbiotic gastrointestinal microbiome binds with TLR on sub-mucosal macrophages, resulting in the activation of NF-κB and inflammatory cytokine production and secretion [58]. This mechanism is thought to be a major contributor to chronic inflammation in women with PCOS and plays a significant role in the pathogenesis (discussed in Section 6) [7][59].

2.4. Inflammasomes in PCOS

Inflammasomes are multiprotein self-assembling complexes in the cytoplasm that form an integral part of the innate immune response [60]. They are produced in response to a variety of danger signals and are also involved in cellular apoptosis and pyroptosis [4]. Inflammasomes act as finely tuned alarm systems that trigger and amplify innate defence mechanisms in response to cellular stresses and infection [56]. The inflammasome complex contains a sensor molecule, an adaptor protein, and a pro-inflammatory caspase-1 enzyme [60]. Once activated by DAMPS (such as LPS) and PAMPS, the inflammasome complex converts procaspase-1 to the active caspase-1 enzyme which subsequently activates pro-inflammatory cytokines (IL-1B, IL-18) that are released into tissues and circulation [61].
Inflammasomes form an integral part of the common CDR pathway for cellular protection from multiple types of threatening stimuli [3][50]. Interruption to the flow of electrons in metabolism, generation of ROS, and other mechanisms discussed above, activate innate intracellular defence mechanisms in an attempt to contain and eliminate cellular threats [17]. The CDR also includes the release of purinergic signalling to neighbouring cells and immune cells that activate inflammation [62]. If the threat is contained, the CDR resolves and normal cellular function is restored [3]. If the CDR is unsuccessful, pyroptosis pathways are activated and the cell is sacrificed in a further attempt to contain the threat and protect the organism [4]. If the inciting stimulus persists, activation of chronic inflammation can result in tissue damage and disease, such as PCOS.
Inflammasomes and their pro-inflammatory cytokines and chemokines have been investigated for their role in inflammation, oxidative stress, ovulation, fertilization, steroidogenesis, glucose metabolism, IR, and adipogenesis and may be involved in the pathogenesis of PCOS [56][63][64]. These and other inflammatory mediators, such as adipokines (leptin, adiponectin, vaspin, resistin, visfatin, and omentin-1), cyclophilin A, vascular dysfunction mediators (endothelin-1, vascular cell adhesive molecule-1), NF-κB, and epigenetic regulators (microRNAs) are thought to have a role in the pathogenesis of PCOS and have recently been reviewed [61].

2.5. Adaptive Immune Response in PCOS

The adaptive immune system involves antigen-specific defence mechanisms that are designed to react to and remove specific antigens [65]. The adaptive system involves humeral and cell-mediated immunity and may take several days to become effective. The body recognizes an antigen as foreign when epitopes (fragments of an antigen that react with antibodies or lymphocyte receptors) bind to specific receptors on the surface of B-lymphocytes and/or T-lymphocytes [66]. It is estimated that the human body can recognize 107 epitopes and make up to 109 different antibodies [67]. Nevertheless, activation of both the innate and adaptive immune systems was primarily designed to be acute and short-lived in order to contain and eliminate a multitude of environmental threats.
The majority of the research on the role of adaptive immunity in PCOS has been conducted on T-cells and their subpopulations [65]. T-cells play a crucial role in mediating inflammation and IR by secreting proinflammatory cytokines [68][69]. T-cells promote follicle development and selection by releasing specific chemokines and growth factors and producing cytotoxic signals to induce apoptosis of granulosa cells [70]. Available evidence suggests that there may be a general decline in adaptive immunity and regulatory T-cell function in PCOS [65]. Recent studies have suggested that immune system dysregulation, including T-cell dysfunction [71][72], may play a role in the pathogenesis of PCOS [73].

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 [74]. Communication between the nervous, endocrine, and immune systems involves evolutionary-conserved mechanisms that are essential for host defence and survival [75]. The immune system and ANS can respond to numerous common regulatory molecules, including cytokines, neurotransmitters, and glucocorticoids [76]. 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, behaviour, reproduction, body weight, and whole-body inflammatory balance [77][78].
Regulation of the inflammatory response has previously been thought to be autonomous [79]. Substantial evidence now suggests that the nervous system exerts an active role in maintaining inflammatory homeostasis [78][80][81]. The brain participates in a bidirectional network of mediators, including hormones, cytokines, and neurotransmitters, that monitor, coordinate, and regulate the systemic inflammatory response [75][81]. 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 [82]. Abnormalities in the neuroendocrine-immune response are implicated in the pathogenesis of many chronic diseases, including obesity, atherosclerosis, autoimmune disease, depression, and PCOS [65][76][78][83].

3.1. Anatomy of Neuroendocrine-Immune Connections

Animal and human research over the past six decades have investigated the extensive network of afferent and efferent communication mechanisms that coordinate the systemic inflammatory response [75][83][84]. There is now a consensus that “the inflammatory reflex” is composed of (1) a system of sensors (that identify PAMPS and DAMPS), (2) an afferent arm which conveys information about systemic inflammatory status to the central nervous system (CNS), (3) processing centres in the brain that integrate and interpret incoming signals (hypothalamic nuclei and brain stem autonomic neurons), (4) and an efferent arm which exerts immunomodulatory functions (Hypothalamic-Pituitary-Adrenal (HPA)-axis, ANS) [80]. The brain exerts strong immunomodulatory effects on a variety of components of the immune system by activation of the HPA-axis and ANS.
The hypothalamus plays a central role in sensing and coordinating neural and humoral factors and can modulate inflammatory pathways [78]. Circulating cytokines, such as IL-1ẞ and Tumour Necrosis Factor-alpha (TNF-α), can cross the blood–brain barrier by a carrier-mediated mechanism [85] or via the circumventricular organs [86]. The hypothalamus can also receive input from visceral vagus afferent fibres after they synapse with the dorsal motor nucleus of the vagus nerve in the brainstem. This has been termed the “cholinergic anti-inflammatory pathway” [75]. Ascending connections reach the hypothalamus via the nucleus tractus solitarius [87]. The effector arm or efferent system is modulated by the HPA-axis and the sympathetic (SNS) and parasympathetic (PNS) components of the ANS [75][88].
The HPA-axis is a neurohormonal pathway that has classically been studied for its role in regulating the immune system [89]. The SNS modulates both pro- and anti-inflammatory activities [75]. The SNS innovates primary (thymus and bone marrow) and secondary (spleen, lymph nodes, and tissues) lymphoid organs. Sympathetic neurons release noradrenalin and adrenalin that interact with adrenoreceptors on lymphocytes and macrophages and stimulate the production of cytokines that result in anti-inflammatory effects [90]. The PNS also plays a significant role in modulating immune cells and inflammatory activity [75]. Evidence that vagal afferent fibres relay messages to the CNS that inflammation is present in other body sites has been demonstrated in animal models, although evidence for the mechanisms of activation is still not clear [83]. The parasympathetic nervous system has an anti-inflammatory effect through release of acetylcholine that interacts directly with nicotinic receptors on macrophages [91], and also indirectly with the spleen [83]. Overall, the SNS and PNS appear to act synergistically to downregulate inflammation.

3.2. Neuroimmunomodulation in PCOS

Several studies have examined the bi-direction connections between the nervous and immune systems in PCOS. Women with PCOS have been found to have increased SNS activity by muscle and skin microneurography, heart rate variability, measurement of nerve growth factor, and catecholamine metabolites [81][92]. Insulin has been found to stimulate SNS output, and there is a complex bidirectional relationship between IR and sympathetic activity in both the hypothalamus and ovary [92]. Although most of the research has focused on SNS overactivity, reduced PNS activity has also been demonstrated [88]. Impaired ANS function has been proposed as a contributor to hyperandrogenemia via mechanisms in the hypothalamus, adipose tissue, and ovary [93][94].
SNS activity can be reduced in women with PCOS by electroacupuncture, treatment of obstructive sleep apnoea with positive airway pressure, renal denervation in refractory hypertension, pharmacotherapy, exercise training, and weight loss [92][95]. Taken together, these data suggest that an imbalance of the ANS is likely to play a reversible role in the pathophysiology of PCOS.

4. Hyperandrogenism and Chronic Inflammation

Chronic systemic inflammation can cause hyperandrogenism [9] and elevated androgens can affect immune cells, resulting in predominately anti-inflammatory effects on the immune system [96]. There is debate in the literature regarding the direction of causation, physiological importance, and evolutionary significance of these processes. The preponderance of the 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) [97]. The evidence presented here also supports this paradigm.
Serum androgens can be derived from multiple tissues including the adrenal gland, adipose tissue, and ovaries [98]. Most serum androgens in PCOS are thought to be produced by the ovaries. Nevertheless, it is likely that multiple mechanisms are involved in excessive androgen production in different tissues in women with PCOS [98][99]. Low-grade chronic systemic inflammation is commonly found in patients with PCOS exhibiting hyperandrogenism, and ovarian inflammation and fibrosis are part of the histopathology [100]. Ovarian inflammatory mechanisms have been linked to systemic markers of inflammation (CRP and white cell count) [99][100][101] independent of body mass index (BMI) [102]. An extensive range of inflammatory cytokines have been associated with impaired folliculogenesis and androgen synthesis in women with PCOS [99]. Cytokines can influence the inflammatory response by epigenic mechanisms that alter gene expression or by posttranscriptional regulatory processes [9]. Oxidative stress has been reported to enhance ovarian steroidogenic enzymes and increase androgen levels in women with PCOS [22]. Endoplasmic reticular stress pathways are activated in the ovaries in mouse models and in humans and may contribute to the pathophysiology of PCOS through multiple effects in granulosa cells [103][104].
As discussed previously, AGE and RAGE have been found to cause altered steroidogenesis in granulosa cells in PCOS [43]. Dehydroepiandrosterone is a circulating pre-androgen produced in the adrenal cortex that has been found to stimulate inflammation and impair ovarian function in PCOS [105]. Increased luteinizing hormone (LH) levels, commonly found in PCOS, can amplify the abnormalities described in theca cell steroidogenesis [61]. The combined effects of these processes result in excess follicular androgens which combine with increased levels of insulin to downregulate aromatase levels in granulosa cells. This creates a continuous feedback loop between inflammation, IR, and hyperandrogenism with no apparent beginning or end. Despite these uncertainties, diet-induced inflammation can invoke hyperandrogenism [97], and effective treatment of inflammation can normalize androgen levels and restore fertility in women with PCOS [106]. In summary, accumulating evidence suggests that the ovaries are not the primary cause of hyperandrogenism in most women with PCOS (see Section 4.5).
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 tumours. 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 [9]. 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, and climatic) and personal stress. In addition, there may be other individual advantages, such as increased strength and fitness [107].

5. Summary of the Role of Inflammation in PCOS from an Evolutionary Perspective

A significant body of the literature supports the role of chronic inflammation in the pathogenesis of PCOS. Billions of years of evolution have constructed a cooperative 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 downregulate reproduction.


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