Introduction
Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with hyperandrogenism, insulin resistance and dyslipidaemia. These disturbances lead to an increased risk of cardiometabolic disease including type 2 diabetes1. The underlying drivers of this process are unclear although chronic inflammation may play an important role2.
The complement system is a key regulator of inflammation and consists of three activation pathways: classical, alternative and lectin, which converge at the level of C3 to form C3 convertases. Whilst the classical and lectin pathway convertases depend on C2 and C4 cleavage, the alternative pathway convertase requires factor B and factor D. Further activation of the complement system through to the terminal pathway involves C5 cleavage and leads to formation of the membrane attack complex and its fluid-phase by-product, the terminal complement complex (TCC). Both positive and negative regulators exist, including the alternative pathway regulators properdin and factor H.
Components of the complement system, notably C3, have been shown to be increased in patients with metabolic syndrome3, type 2 diabetes4 and cardiovascular disease5. Postprandially, C3 activation has been shown to increase lipid clearance and storage in human adipocytes6,7; C3a, a product of C3 activation, is rapidly cleaved in plasma to form C3a(desArg). C3a(desArg) binds to its receptor, C5L2, on adipocytes to increase triglyceride synthesis6,8,9. Chylomicrons, transporters of lipids in the postprandial period, have been shown to increase C3 activation10, an event that is regulated in vivo by factor H11. Furthermore, activation pathway components (C3, C4, factor D and factor B) alter after a meal, and postprandial C3 responses differ in patients with and without cardiometabolic disease12-15. These findings suggest that dysregulated postprandial complement activation may influence metabolic health and contribute to the development of cardiometabolic pathology.
Only a few studies have examined the complement system in women with PCOS, finding increased levels of factor D16 and C3a(desArg)17,18, and increased18,19or no difference20,21 in C3 levels compared to matched controls. However, many of these studies are limited by fasting measurements only and small sample sizes. We therefore sought to establish whether the complement system is activated in women with PCOS and whether any abnormalities are evident in the postprandial as well as the fasting state.