Inflammation and cardio-metabolic risks in polycystic ovary syndrome

Abstract

Polycystic Ovary Syndrome (PCOS) is the most common reproductive and endocrine disorder in females during their reproductive life. The syndrome is characterized by a constellation of symptoms and signs including menstrual disturbance, hyperandrogenism and polycystic ovaries. Other features of PCOS include obesity, metabolic syndrome, insulin resistance and an increased risk of developing diabetes mellitus and cardiovascular disease. Recently, PCOS has been recognized as a low grade inflammatory condition. Several inflammatory markers have been found to be raised in PCOS, such as interleukin-6, tumour necrosis factor-alpha and Interleukin-18. Low grade inflammation may potentially produce an insulin resistant state and promote the development of atherosclerosis. Insulin sensitzers such as metformin and pioglitazone have been shown to have a favourable effect not only on the symptoms of PCOS, but also on the hormonal and metabolic parameters in those subjects. In my thesis I primarily focussed on IL-18, B cells activating factor (BAFF), and the hepatokine, Fetuin-A, all linked to insulin resistance. IL-18 has a strong affinity towards its natural inhibitor, IL-18 binding protein (BP) and binding of IL-18 to IL-18 BP results in neutralization of IL-18, and consequently reduced free IL-18; the active form of the molecule. I have shown that PCOS women have a higher free IL-18, with hyperinsulinaemia the main factor that determines IL-18 in vitro. Furthermore, I have shown that Pioglitazone treatment for 12 weeks decreased both the total and free IL-18 in PCOS women. The reduction of IL-18 was accompanied by an improvement in IR. On the other hand, metformin treatment for six months failed to improve insulin sensitivity and did not influence IL-18 levels. BAFF, a novel adipokine, was studied in PCOS subjects, and I found lower BAFF levels in this cohort of patients. In vivo, BAFF correlated negatively with androgens, and in vitro work revealed that androstenedione as a negative regulatory factor for BAFF production Fetuin-A also known human protein α2-Heremans-Schmid glycoprotein, is a known natural inhibitor for insulin and abundantly expressed and secreted by the liver; fetuin-A has been suggested to act as a link between obesity, insulin resistance and MS. The circulating levels of Fetuin A are increased in women with PCOS, which is more pronounced when associated with MS. Metformin decreases Fetuin A in vivo, and also decreases both the expression and secretion of Fetuin A from HepG2 cells