A review of nitric oxide and oxidative stress in typical ovulatory women and in the pathogenesis of ovulatory dysfunction in PCOS

Abstract

Polycystic ovary syndrome (PCOS) is a heterogeneous functional endocrine disorder associated with a low-grade, chronic inflammatory state. Patients with PCOS present an increased risk of metabolic comorbidities and often menstrual dysregulation and infertility due to anovulation and/or poor oocyte quality. Multiple mechanisms including oxidative stress and low-grade inflammation are believed to be responsible for oocyte deterioration; however, the influence of nitric oxide (NO) insufficiency in oocyte quality and ovulatory dysfunction in PCOS is still a matter for debate. Higher production of superoxide (O₂^•-) mediated DNA damage and impaired antioxidant defense have been implicated as contributory factors for the development of PCOS, with reported alteration in superoxide dismutase (SOD) function, an imbalanced zinc/copper ratio, and increased catalase activity. These events may result in decreased hydrogen peroxide (H₂O₂) accumulation with increased lipid peroxidation events. A decrease in NO, potentially due to increased activity of NO synthase (NOS) inhibitors such as asymmetric dimethylarginine (ADMA), and imbalance in the distribution of reactive oxygen species (ROS), such as decreased H₂O₂ and increased O₂^•-, may offset the physiological processes surrounding follicular development, oocyte maturation, and ovulation contributing to the reproductive dysfunction in patients with PCOS. Thus, this proposal aims to evaluate the specific roles of NO, oxidative stress, ROS, and enzymatic and nonenzymatic elements in the pathogenesis of PCOS ovarian dysfunction, including oligo- anovulation and oocyte quality, with the intent to inspire better application of therapeutic options. The authors believe more consideration into the specific roles of oxidative stress, ROS, and enzymatic and nonenzymatic elements may allow for a more thorough understanding of PCOS. Future efforts elaborating on the role of NO in the preoptic nucleus to determine its influence on GnRH firing and follicle-stimulating hormone/Luteinizing hormone (FSH/LH) production with ovulation would be of benefit in PCOS. Consequently, treatment with an ADMA inhibitor or NO donor may prove beneficial to PCOS patients experiencing reproductive dysfunction and infertility.

Keywords: Abnormal nitric oxide pulsatility; Ano and oligo-anovulation; Oxidative stress; Polycystic ovary syndrome.

Fig. 1

Physiological requirements for the induction of ovulation

Fig. 2

Simplified model outlining NOS dysfunction and modulation of ROS in PCOS- High concentrations of ADMA functions to competitively inhibit NOS at the L-Arg binding site, resulting in O₂^•− and free L-Arg accumulation. The accumulated L-Arg may be consumed under these conditions by arginase to give ornithine and urea. Other sources for O₂^•− are NADPH oxidase, xanthine reductase, mitochondrial damage, zinc deficiency, and high macrophage activity, which may be increased in PCOS. O₂^•− without sufficient NO will not produce ONOO⁻ resulting in low observed protein nitration. Accumulation of O₂^•− either slowly decays to H₂O₂ or in the presence of sufficient zinc is dismutased by SOD into H₂O₂. The low reported zinc concentrations and high copper in PCOS suggests low SOD activity. H₂O₂ then is converted to H₂O by catalase and/or reacts with free metals such as iron and copper through the Fenton reaction to generate the highly toxic ^•OH, resulting in lipid peroxidation events