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.