Polycystic Ovary Syndrome: A “Perfect Example” of “Imperfection” in the Metabolic Health

Polycystic ovary syndrome (PCOS) is one of the most common multisystemic endocrinological diseases that can affect a woman of childbearing age. The crux of the disease lies in its heterogeneity in presentations.[1] It is reckoned that every 1 in 10 reproductive-age women suffers from PCOS. Interestingly, it starts from adolescence and can continue beyond menopause.[2] Oligomenorrhea and hyperandrogenism are the prototype symptoms of PCOS and insulin resistance and metabolic syndrome are the usual metabolic features.[3] The exact etiology and pathogenetic mechanisms of PCOS have long eluded clinicians and endocrinologists. Environmental, genetic, and epigenetic factors can contribute to the pathogenesis and influence the in utero phase of a future PCOS woman. ETIOLOGICAL FACTORS Epigenetic mechanisms It suggests inheritable alterations in genome and gene expression without any changes in DNA sequence. This includes adding or omitting chemical components on DNA or histone.[4] Leutinizing hormone (LH) is the main mediator of steroidogenesis in theca cells, and its receptor hypomethylation leads to higher gene expressions and increased sensitivity to LH.[5] Overproduction of epoxide hydrolase-1 inhibits the expression of aromatase and estradiol formation from testosterone. Hypermethylation of Peroxisome proliferative activated receptor (PPAR-γ), hypomethylation of nuclear co-repressor 1, and alteration in acetylation of histone deacetylase 3 contribute to the mechanism of PCOS.[6] Environmental toxins Endocrine disrupters interfere with the synthesis, secretion, transport, binding, action, or elimination of the hormones inside the body, and they are proposed to cause many endocrinological diseases such as PCOS.[7] They can act as hormonal receptor agonists or antagonists. Bisphenol A (BPA) affects oogenesis by interacting with the estrogen receptor (ER) and nonclassical membrane ER and G-protein coupled receptor 30, and it also increases testosterone secretion from theca cells.[8] BPA is a synthetic compound frequently used in polycarbonate plastics, epoxy resins, dental fillings, baby bottles, and polyvinyl chloride.[9] Due to its exposures, 17-hydroxylase (P450c17), cholesterol side-chain cleavage enzyme (P450scc), and steroidogenic acute regulatory protein are dysregulated. BPA also affects the intrafollicular environment and oocyte maturation. BPA additionally upregulates adipocyte-related genes and adipocyte differentiation, converts cortisone to cortisol, and releases interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). All these lead to increasing insulin resistance and adipogenesis and, thus, metabolic disturbances in PCOS.[8] Parabens, a group of alkyl esters of p-hydroxybenzoic acid, are used as antimicrobial agents and preservatives in personal care products, foods, and pharmaceuticals. It has been shown to mimic the effects of 17β-estradiol by binding to ERs, and a linear relationship between parabens and cell proliferative potency has been described in the literature.[10] Triclosan (2, 4, 4 1-trichloro-2 1-hydroxydiphenyl ether) is used in personal care, pharmaceutical, veterinary, and industrial purposes due to its antibacterial and antifungal properties. It can bind to ER and has a higher binding affinity to ERα over Erβ. Its estrogenic effect and anti-oxidant properties can lead to PCOS-like pathogenesis. In addition, it results in decreased levels of gonadotrophins, progesterone, and resultant reduction in antral follicles and corpora lutea.[11] Physical and emotional stress Chronic stress increases adipogenesis and results in insulin resistance in PCOS. It is postulated to be associated with adipokine secretion, attraction, and activation of stromal fat immune cells. Higher inflammatory markers such as TNF-α and IL-6 are secreted in chronic stress and disrupt the body’s anti-oxidant mechanisms. Increasing the glucocorticoid response leads to visceral fat accumulation, gluconeogenesis, and lipolysis in PCOS.[12] Dietary factors Excessive intake of saturated fatty acids can trigger inflammation by increasing the TNF-α level in circulation. Calcitriol upregulates insulin receptors and increases insulin sensitivity by activating PPAR-γ receptors and regulating intracellular calcium metabolism. Vitamin D deficiency, which is endemic in South Asian countries, can lead to insulin resistance.[13] PATHOGENIC MECHANISMS Hyperandrogenism Higher testosterone levels in PCOS convert estradiol to estrone in adipose tissue. The relative increase in estrone compared to estradiol affects follicular growth and increases the LH to Follicular stimulating hormone (FSH) ratio. Hyperandrogenism is additionally associated with Anti-mullerian hormone (AMH) upregulation, reduced Insulin like growth factor (IGF)-II concentrations in intra-follicular fluid, and modulation of the γ-Aminobutyric acid sub-type A receptors, which in turn triggers GnRH neurons and weakens the response to negative progesterone feedback. Hyperandrogenism reduces the insulin sensitivity and expression of GLUT-4, resultantly decreasing insulin degradation in the liver. Inflammatory chemicals such as lipopolysaccharides induce IL-6 formation in 3T3-L1 adipocytes by activating adipokine signaling pathways.[14] Insulin resistance Insulin resistance in PCOS results primarily in adipogenesis and hyperandrogenism, but it is also highlighted in the pathogenesis of lean PCOS. The main sites of insulin resistance are skeletal muscle, liver, and adipose tissues, whereas adrenal glands and ovaries remain the insulin-sensitive sites. Excess insulin triggers androgen production from theca cells and stimulates ovarian P450c17 and P450scc enzyme activity. Hyperinsulinemia increases LH-binding sites and androgen-producing response to LH and reduces hepatic Sex hormone binding globulin (SHBG) leading to increased free testosterone levels. IGF-1 upregulation, a direct effect of hyperinsulinemia, accelerates granulosa cell apoptosis and inhibits folliculogenesis, leading to oligomenorrhea and infertility in PCOS.[15] Inflammation and oxidative stress TNF-α and IL-1 are the main inflammatory mediators described in PCOS. They interfere with the insulin signaling pathway and GLUT-4 downregulation. IL-1 inhibits the FSH and LH receptors and hinders follicular development and ovulation. In addition, they inhibit hepatocyte nuclear factor and stimulate inflammasomes. This results in follicular pyroptosis, ovarian fibrosis, and disturbances in follicular formation. The imbalance between pro-oxidants and anti-oxidants, reactive oxygen species, and reactive nitrogen species affects ovarian functions and affects neurons responsible for feeding behavior to induce hunger. Increased oxidative stress alters some protein kinases that trigger serine/threonine phosphorylation instead of normal tyrosine phosphorylation of insulin receptor substrate.[16] HYPERANDROGENISM AND METABOLIC SYNDROME IN POLYCYSTIC OVARY SYNDROME; A SOUTH ASIAN PERSPECTIVE In this issue of Bangladesh Journal of Endocrinology and Metabolism, the author’s group has come up with impressive cross-sectional data on metabolic and hormonal parameters in PCOS from the Endocrine Department of Ibn Sina Medical College Hospital and the National Healthcare Network, Uttara. The study included 237 patients of PCOS with significantly younger mean age (25.1 ± 13.2 years). The authors systematically recorded demographic details, clinical characteristics, and laboratory investigations. The hormonal pattern revealed a high LH:FSH ratio (46.8% of patients), along with 4.5% with biochemical hyperandrogenemia and 10.5% exhibiting hyperprolactinemia. Kamrul-Hasan et al. studied 370 PCOS cases in similar younger age groups diagnosed by the Rotterdam consensus criteria from various tertiary care hospitals in Bangladesh. Prehypertension or hypertension, abnormal glucose tolerance, and metabolic syndrome were found in 34.6%, 34.1%, and 57% of the PCOS women, respectively. A staggering 93.0% of patients were found to have dyslipidemia. Expectedly, the hyperandrogenic variants of PCOS were more associated with metabolic syndrome.[17] However, this difference was not noted in studies of Sachdeva et al. in India, Wijeyaratne et al. in Sri Lanka, and Sultana et al. in Bangladesh.[18-20] In contrast, Kar and Mehrabian et al. observed increased metabolic syndrome prevalence in hyperandrogenic phenotypes compared to normoandrogenic ones.[21,22] These studies did not find any consistent relationships between waist circumference, systolic blood pressure (BP), diastolic BP, fasting and postprandial plasma glucose, lipid profile parameters, and body mass index in various PCOS phenotypes. In one Indian study conducted in Manipal Hospital, acanthus nigricans were found in more than 50% of patients.[23] The prevalence of metabolic syndrome in PCOS widely varied in the available literature and was found to be slightly higher in Indian subcontinent countries compared to Western ones.[17] The prevalence of abnormal glucose tolerance was found to be high (around 35%) in young Indian women with PCOS, and it was found that a family history of diabetes was not a predictor in such cases.[24] Ganie et al. highlighted the possible association of increased cardiovascular risks with PCOS due to hyperandrogenism.[25] Imbalance in the sympathovagal output is the proposed etiology behind autonomic cardiac neuropathy in PCOS and increased mortality. CONCLUSION PCOS is a multifactorial disease with diverse etiological factors and pathogenetic mechanisms. What is unifying among all this is the presence of hyperandrogenism and its effect on metabolic health. With rapid urbanization and a westernized lifestyle, early-onset metabolic syndrome is quite common in the Indian subcontinent. Various cross-sectional studies from the Indian subcontinent have provided basic clinical characteristics and relationships between hyperandrogenemia and metabolic syndrome. Even though the relationship is well known, researchers have failed to draw any conclusion on any cutoff level of testosterone above which metabolic syndrome would be common. Future studies are warranted in this regard where we can predict the onset of metabolic syndrome in PCOS patients and know its predictors apart from hyperandrogenism. We can also undertake more robust cross-sectional screening studies on adolescents to detect PCOS at the earlier stages and prevent future metabolic complications.