The Polycystic Ovary Syndrome and the Metabolic Syndrome: A Possible Chronobiotic-Cytoprotective Adjuvant Therapy

Abstract

Polycystic ovary syndrome is a highly frequent reproductive-endocrine disorder affecting up to 8-10% of women worldwide at reproductive age. Although its etiology is not fully understood, evidence suggests that insulin resistance, with or without compensatory hyperinsulinemia, and hyperandrogenism are very common features of the polycystic ovary syndrome phenotype. Dysfunctional white adipose tissue has been identified as a major contributing factor for insulin resistance in polycystic ovary syndrome. Environmental (e.g., chronodisruption) and genetic/epigenetic factors may also play relevant roles in syndrome development. Overweight and/or obesity are very common in women with polycystic ovary syndrome, thus suggesting that some polycystic ovary syndrome and metabolic syndrome female phenotypes share common characteristics. Sleep disturbances have been reported to double in women with PCOS and obstructive sleep apnea is a common feature in polycystic ovary syndrome patients. Maturation of the luteinizing hormone-releasing hormone secretion pattern in girls in puberty is closely related to changes in the sleep-wake cycle and could have relevance in the pathogenesis of polycystic ovary syndrome. This review article focuses on two main issues in the polycystic ovary syndrome-metabolic syndrome phenotype development: (a) the impact of androgen excess on white adipose tissue function and (b) the possible efficacy of adjuvant melatonin therapy to improve the chronobiologic profile in polycystic ovary syndrome-metabolic syndrome individuals. Genetic variants in melatonin receptor have been linked to increased risk of developing polycystic ovary syndrome, to impairments in insulin secretion, and to increased fasting glucose levels. Melatonin therapy may protect against several metabolic syndrome comorbidities in polycystic ovary syndrome and could be applied from the initial phases of patients' treatment.

Figure 1

White adiposity characteristics in normal and PCOS adult rats. Representative images of parametrial adipose tissue pads stained with hematoxylin and eosin (a). Lower 3-diagram panel showing data from parametrial pad adipocyte (in left-right order) size, mass, and in vitro leptin secretion. Finally, parametrial pad adiponectin protein content (Western blot) (b). Magnification ×400; scale bars: 50 μm. ^∗P < 0.05 versus respective normal-group values (adapted from Alzamendi et al. [34]).

Figure 2

White adipose tissue (WAT) and inflammation: endocrine-metabolic consequences. A combination of genetic background and endogenous androgen excess could induce WAT mass hypertrophic expansion associated with macrophage infiltration, leading to an abnormal pattern of adipokine secretion. Enhanced WAT-derived leptin release, in turn, impairs tissue sensitivity to insulin (insulin resistance (IR)). Prolonged hyperleptinemia could induce long-form leptin receptor (ObRb) downregulation, namely, at the pancreatic (β- and α-cell) level, thus impairing its negative feedback mechanism on insulin (and glucagon) secretion; moreover, increased release of proinflammatory signals (TNF, IL-1, IL-6, and C-reactive protein (CRP), among others) worsens several functions. In fact, overall WAT dysfunction promotes multiple endocrine-metabolic dysfunctions, such as generalized IR, enhanced reticulum endoplasmic oxidative stress (REOS), enhanced lipolytic activity, cell hypoxia, and apoptosis. These alterations, in turn, affect multiple peripheral organs, namely, liver, muscle, endocrine pancreas, and endothelium functions. FFA: free fatty acid; JUNK: Janus kinase; NF-κB: nuclear factor-κB; HGP: hepatic glucose production; NAFLD: nonalcoholic fatty liver disease; NASH: nonalcoholic steatohepatitis; DMT2: diabetes mellitus type 2 (adapted from Pagano et al. [108]).

Figure 3

Follicular developmental stage of the ovaries obtained from normal and PCOS adult rats (a). Values are expressed in percentages. ^∗P < 0.05 versus normal-group values. Representative images (b) of the ovaries from normal (A, C, and E) and PCOS (B, D, and F) adult rats showing ovarian structures at different magnifications: (A) and (B): 10x (bars: 100 μm); (C) and (D): 20x (scale bars: 50 μm); (E) and (F): 40x (scale bars: 25 μm). CL: corpus luteum; IG: interstitial glands; FC: follicular cyst; G: granulosa; TI: theca interna; Ov: ovocyte (adapted from Ongaro et al. [45]).

Figure 4

Effect of melatonin in PCOS associated with metabolic syndrome. Melatonin normalizes high blood pressure (BP) and circulating indexes of inflammation. It also improves insulin sensitivity and restores disrupted circadian rhythms. Melatonin directly affects ovarian function: it is concentrated in human ovarian follicles in relation to the level in plasma, and it improves granulosa cell steroidogenesis and follicular function in humans (adapted from Reiter et al. [61]).