Modulation of the Inflammatory Response in Polycystic Ovary Syndrome (PCOS)—Searching for Epigenetic Factors

Abstract

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age. Despite its incidence, the syndrome is poorly understood and remains underdiagnosed, and female patients are diagnosed with a delay. The heterogenous nature of this complex disorder results from the combined occurrence of genetic, environmental, endocrine, and behavioral factors. Primary clinical manifestations of PCOS are derived from the excess of androgens (anovulation, polycystic ovary morphology, lack of or scanty, irregular menstrual periods, acne and hirsutism), whereas the secondary manifestations include multiple metabolic, cardiovascular, and psychological disorders. Dietary and lifestyle factors play important roles in the development and course of PCOS, which suggests strong epigenetic and environmental influences. Many studies have shown a strong association between PCOS and chronic, low-grade inflammation both in the ovarian tissue and throughout the body. In the vast majority of PCOS patients, elevated values of inflammatory markers or their gene markers have been reported. Development of the vicious cycle of the chronic inflammatory state in PCOS is additionally stimulated by hyperinsulinemia and obesity. Changes in DNA methylation, histone acetylation and noncoding RNA levels are presented in this review in the context of oxidative stress, reactive oxygen species, and inflammatory signaling in PCOS. Epigenetic modulation of androgenic activity in response to inflammatory signaling is also discussed.

Gut microbiota dysbiosis in polycystic ovary syndrome: Mechanisms of progression and clinical applications

“…Gut microbiota affects the reproductive endocrine system by interacting with estrogen, androgen, insulin, etc (Qi et al, 2021). The typical characteristics of PCOS include abnormal levels of sex hormones, insulin resistance, polycystic changes in the ovary, chronic subclinical inflammation, etc (Szukiewicz et al, 2022). The gut microbiota disorder is involved in endotoxemia, SCFA production, bile acid metabolism, abnormal secretion of brain gut peptides, etc.…”

Pathophysiological Effects of Contemporary Lifestyle on Evolutionary-Conserved Survival Mechanisms that Disturb the Hallmarks of Health in Polycystic Ovary Syndrome

“…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 (65). Large systematic reviews confirm an important role for chronic systemic inflammation in the pathogenesis of PCOS (8,56).…”

“…Chronic systemic inflammation can cause hyperandrogenism (56), and elevated androgens can affect immune cells, resulting in predominately anti-inflammatory effects on the immune system (155). There is debate in the literature regarding the direction of causation, physiological importance, and evolutionary significance of these processes.…”

“…An extensive range of inflammatory cytokines have been associated with impaired folliculogenesis and androgen synthesis in women with PCOS (158). Cytokines can influence the inflammatory response by epigenic mechanisms that alter gene expression or by posttranscriptional regulatory processes (56). Oxidative stress has been reported to enhance ovarian steroidogenic enzymes and increase androgen levels in women with PCOS (162).…”

“…Rapid social evolution has created a contemporary lifestyle and environment that is out of step with our evolutionary past (1,4). Chronic disturbance to adaptive cellular signaling systems disrupts the epigenetic machinery and other regulatory processes, resulting in maladaptive metabolic, immune and physiological responses, that manifest as complex chronic diseases such as obesity, T2DM and PCOS (figure 1) (55,56). Health is a result of the successful integration of multidimensional subcellular, cellular, and systemic, integrated circuits and networks.…”