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Metabolic Syndrome and PCOS: Comparison
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Please note this is a comparison between Version 2 by Dean Liu and Version 1 by Weixuan Chen.

Polycystic ovary syndrome (PCOS) is one of the most common endocrine diseases among women of reproductive age and is associated with many metabolic manifestations, such as obesity, insulin resistance (IR) and hyperandrogenism.

  • PCOS
  • metabolic syndrome
  • metabolites
  • gut microbiota

1. Introduction

Polycystic ovary syndrome (PCOS) is one of the most complicated and heterogeneous endocrine disorders, with a prevalence ranging from approximately 6% (applying the older diagnostic criteria: National Institutes of Health Consensus 1990) to 20% (according to the current most commonly used criteria: the Rotterdam 2003) in women of reproductive age [1,2,3][1][2][3]. There are three criteria included in actual diagnostic criteria, including the Rotterdam 2003, the Androgen Excess and PCOS Society 2006 and National Institutes of Health Consensus 2012. Among these criteria, the Rotterdam criteria are the most extensive and widely used [4]. According to these criteria, three characteristics are proposed: (1) clinical or biochemical hyperandrogenism or both, (2) oligo-anovulation, and (3) polycystic ovary morphology (PCOM) (ultrasonography indicating the presence of ≥12 follicles with a maximum diameter of 2–9 mm or any ovarian volume >10 mL). A woman with PCOS must meet at least two of the three characteristics, and other causes of hyperandrogenism, such as nonclassical congenital adrenal hyperplasia and hyperprolactinemia, must be ruled out [5]. According to these diagnostic criteria, PCOS is divided into four phenotypes according to severity [6,7][6][7] (Table 1). Although there are many versions of PCOS diagnostic criteria, the etiology of PCOS remains obscure. This may be explained by multiple factors, including genetics, environment, and lifestyle [8]. PCOS also shows heterogeneity in regard to metabolic disorders [1]. This background indicates that the daily lifestyle and diet as well as metabolites generated may have a substantial influence on the pathogenesis of PCOS. Consequently, the number of clinical and basic studies on metabolic manifestations and metabolites of PCOS has increased rapidly.

2. Insulin Resistance in PCOS

Insulin resistance (IR) is common in PCOS patients. IR has been reported in approximately 50–80% of women with different phenotypes of PCOS in different races [10,11,12][9][10][11]. Compensatory hyperinsulinism could also exist in many PCOS patients on account of low insulin sensitivity in peripheral tissues of skeletal muscle and adipose tissue and the abnormality of insulin receptors [13][12]. The main mechanism of insulin receptor abnormality leading to IR is the post-binding defect due to excessive serine phosphorylation and decreased tyrosine phosphorylation, which decrease insulin activation of the phosphatidylinositol-3-kinase (PI3k) signaling pathway that activates glucose transport [14][13]. In recent years, there are some new information about IR in PCOS. For example, the presence of microRNA alterations in PCOS has been confirmed by many studies, but the mechanism is unknown. Dong et al. have shown that one of microRNA: miR-122 may lead to IR by inhibiting the expression of insulin-like growth factor 1, which provides a new idea on the mechanism of IR in PCOS [15][14]. In addition, Zhang et al. recently discovered that there is a relationship between IR and autophagy. They clarified that high mobility group box 1, a damage-associated molecular pattern molecule, can contribute to IR in granulosa cells by exacerbating autophagy [16][15]. And it is well known that intestinal flora is disturbed in PCOS (we will discuss later), dysbiosis in PCOS may also participate in IR by some potential mechanisms such as endotoxemia, some gut-brain peptides, hyperandrogenism and some abnormal metabolites [17][16]. Lastly, mitochondrial dysfunction, endoplasmic reticulum stress (ER stress) and oxidative stress were also found to play a role in IR through electroacupuncture therapy [18,19][17][18].

3. Obesity in PCOS

Obesity, especially abdominal obesity, is a common manifestation of PCOS, and the prevalence depends on geographic location and ethnicity [20][19]. Studies have shown that abdominal obesity may be associated with a variety of clinical features of PCOS. For example, due to adipose tissue dysfunction, adipocytes secrete non-physiological levels of adipokines, including IL6, IL8, TNF-α, leptin, adiponectin, resistin, lipocalin 2, monocyte chemoattractant protein-1 (MCP1), retinol binding protein-4 (RBP4), and CXC-chemokine ligand 5 (CXCL5), which may be involved in IR [21,22,23,24][20][21][22][23]. In addition, a recent study has indicated that obesity may function as a better predictor of skeletal muscle mass in PCOS women than hyperandrogenism and IR, which may aggravate PCOS complications [25][24]. Interestingly, adipose tissue dysfunction can affect follicular development. A recent study showed that IL-10 secreted by adipocytes tampers with VEGF-induced angiogenesis and further disrupts folliculogenesis [26][25]. Moreover, molecular mechanisms about androgens and adipose function in PCOS were mentioned recently. Lerner et al. revealed that excess androgen can inhibit brown adipogenesis, attenuating the activation of thermogenesis and reducing mitochondrial respiration in brown adipose tissue [27][26]. Zhou et al. used bioinformatics analysis to identify CHRDL1 gene which may be responsible for obesity of PCOS by inhibiting bone morphogenetic protein 4 signaling or regulating IGF-1 [28][27].

4. Hyperandrogenism in PCOS

One of the PCOS diagnosis criteria is hyperandrogenism. IR, obesity and hyperandrogenism are inseparable in the pathogenesis of PCOS. Hyperinsulinaemia caused by IR exerts a cogonadotropin effect on the ovaries and decreases the expression of sex hormone-binding protein (SHBG), leading to the onset of hyperandrogenism [29,30][28][29]. Androgens can induce the accumulation of adipose tissue, especially abdominal fat tissue, and cause IR in subcutaneous adipose tissue [31,32][30][31]. In humans, androgen plays a dual role in folliculogenesis: a low dose of androgens promotes follicle growth, while a high level of androgens could augment the secretion of anti-Müllerian hormone (AMH) in granulosa cells, thus inhibiting follicular development [33][32]. Several studies have also reported other potential mechanisms of hyperandrogenism-induced PCOS, such as dihydrotestosterone (DHT), which could contribute to mitochondrial fission in granulosa cells of PCOS patients, and excess androgens induce ER stress, which may damage oocyte quality [34,35][33][34]. Besides, Wang et al. found that hyperandrogenism may contribute to chronic low-grade inflammation in ovary and granulosa cells of PCOS by generating NLRP3 inflammasome, which further promotes granulosa cells pyroptotic death and ovarian fibrosis [36][35]. Therefore, hyperandrogenism plays a complicated role in PCOS.

5. Dyslipidaemia in PCOS

Dyslipidaemia is regarded as an important metabolic phenotype, although it is not a diagnostic criterion. It has been reported that the prevalence of dyslipidaemia in PCOS patients is 70%, and the levels of low-density lipoprotein cholesterol (LDL-c), very-low-density lipoprotein cholesterol (VLDL-c), triglycerides (Tgs), and free fatty acid are increased, while the levels of high-density lipoprotein cholesterol (HDL-c) are decreased [37,38][36][37]. Moreover, it seems that nonobese patients have a higher prevalence of hypertriglyceridemia and low HDL [39][38]. And there is evidence suggesting that black women with PCOS have lower Tgs than white women, although the risk of cardiometabolic disease is higher [40][39]. Dyslipidaemia were also reported to affect long-term outcomes of PCOS patients. Wekker et al. revealed that PCOS women had a more adverse lipid profile and had a higher risk for non-fatal cerebrovascular disease events [41][40].

6. Other Metabolic Consequences in PCOS

6.1. Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH)

Many metabolic manifestations, such as IR, hyperandrogenism and dyslipidaemia, in women with PCOS are similar to the metabolic manifestations of NAFLD and NASH. Additionally, many studies have confirmed a high prevalence of NAFLD in women with PCOS [42][41]. Additionally, the fact that high androgen levels are involved in the development of hepatic steatosis in women with PCOS is widely accepted [43][42]. In 2020, Li et al. have demonstrated that elevated endogenous testosterone induced by letrozole can result in hepatic steatosis in PCOS rats and they further found that hyperandrogenism inhibit the AMP-activated protein kinase alpha (AMPKa) signaling, which regulates lipid metabolism, in letrozole-treated livers and dihydrotestosterone (DHT)-treated HepG2 cells [44][43]. Additionally, recent studies on mitochondrial dysfunction have also implied a mechanism between PCOS and NAFLD [45,46][44][45]. Due to mitochondrial gene mutations like, persistent oxidative stress (OS) from abnormal mitochondrial may worsen hyperandrogenism, IR and lipid accumulation which contribute to NAFLD and PCOS [47][46]. However, the specific mechanism of NAFLD in PCOS patients remains to be clarified.

6.2. Cardiovascular Disease in PCOS

The metabolic characteristics of PCOS can lead to a variety of cardiovascular diseases (CVDs), such as hypertension, atherosclerosis, and coronary heart disease. An increased risk of CVD is demonstrated by surrogate markers such as flow-mediated dilation, carotid intima-media thickness and coronary artery calcification [48,49,50][47][48][49]. Accordingly, mitochondrial dysfunction may also play a role in CVDs of PCOS women, as cardiocytes needs much energy produced from mitochondria [51][50]. Apart from the influence of IR, obesity and dyslipidemia, excess androgen has been reported to lead to CVDs. Hyperandrogenism may activate the sympathetic nervous system by melanocortin-4 receptor, 20-hydroxyeicosatetraenoic acid and oxidative stress [52][51].However, whether these patients ultimately have a high risk of CVD is still unclear, as more detailed, larger and prospective cohort studies are still needed [53][52].

7. Summary of Metabolic Symptoms in PCOS

The metabolic symptoms of PCOS seem to be connected. It has been proposed that androgen excess is the beginning of a vicious cycle of metabolic disorders in PCOS patients. It is believed that with the induction of IR and hyperinsulinaemia, hyperandrogenaemia facilitates the formulation of visceral adipose tissue, which exacerbates the secretion of androgen in the ovaries and adrenal glands. Accordingly, the vicious cycle is the potential mechanism of steroidogenesis defects, and the severity depends on different factors [1,54][1][53].

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