Dimethyl itaconate mitigates histological distortions, inflammation, and oxidative stress in the rat model of polycystic ovary syndrome

Polycystic ovary syndrome (PCOS) is the most common cause of anovulation and infertility in women. Inflammation and oxidative stress are considered to be the causes of ovarian dysfunction in PCOS. Dimethyl itaconate, as a macrophage-derived immunometabolite, has anti-inflammatory and antioxidative properties, but limited data are available about its effect on female reproductive dysfunctions. The present study aimed to determine the effects of dimethyl itaconate, a cell-permeable derivative of itaconate, on the histological changes, oxidative stress, and inflammation in the ovaries of PCOS rats. In this experimental study, 48 mature female Wistar rats (180-200 g) were randomly divided into the six groups including control, PCOS, PCOS+DMI, PCOS+ metformin, control DMI and control metformin. Following PCOS induction by using testosterone enanthate (1 mg/100 g/day for 35 days), the animals were treated with DMI (50 mg/kg) or metformin (300 mg/kg) for 30 days. At the end of the experimental period, the insulin resistance markers (serum insulin and glucose concentrations, and the homeostasis model assessment of basal insulin resistance (HOMA-IR), oxidative stress index (OSI), and inflammatory cytokines were measured. The process of Folliculogenesis was evaluated by histological examination of the ovary. The results showed that DMI improved insulin resistance and decreased TNF- and IL-1β levels and OSI in the ovarian tissue of rats following androgen-induced PCOS. It also improved steroidogenesis and Folliculogenesis by reducing cystic follicles and ovarian tissue structure. Results indicated that DMI may be a potential candidate to ameliorate PCOS adverse effects by reducing insulin resistance, inflammation, and oxidative stress and restoring ovarian Folliculogenesis.