Insulin Resistance Is Associated With Impaired HDL Function and Atherogenic Modification of LDL in Polycystic Ovarian Syndrome

Background and Aims: Polycystic ovarian syndrome (PCOS) is associated with increased risk of cardiovascular disease (CVD). The aim of this study was to assess the association between PCOS and markers of HDL functionality and atherogenic LDL modification. Methods: This is a cross-sectional study of 104 women with PCOS [median (IQR); age 29 (24–36) years, and BMI 32.9 (25.7–38.5) kg/m(2)] and 103 BMI-matched healthy participants (age 34 (27–37) years, and BMI 31.1 (27.6–35.5) kg/m(2)). PCOS was defined using the NIH criteria. Measurement of lipid profile and glycaemic blood parameters were undertaken. Patients with PCOS were divided into tertiles of insulin resistance assessed using the homeostatic model assessment (HOMA-IR). Cholesterol efflux capacity (CEC), and paraoxonase-1 (PON1) activity were measured as markers of HDL functionality. Oxidized LDL (OxLDL), lipoprotein-associated phospholipase A2 (LpPLA2), oxidized phoshopholipids on apolipoprotein B-100 (OxPL-apoB) and apolipoprotein(a) (OxPL-apo(a)), and glycated apoB were used as markers of atherogenic modification of LDL. Results: Patients with PCOS in the upper tertile of insulin resistance had impaired HDL functionality compared to the lower tertile and controls, with lower CEC [13.7 (12.4–14.6) vs 14.9 (13.6–17.0), P=0.003; and 14.5 (13.0–16.0) %, P=0.063 respectively] and PON1 activity [77.2 (48.2–129.2) vs 112.9 (54.0–175.4), P=0.043; and 131.6 (89.5–195.1) nmol/ml/min, P<0.001 respectively]. Markers of atherogenic modification of LDL were also increased in the upper tertile compared to the lower tertile and controls, with higher levels of OxLDL [91.6 (58.8–120.9) vs 67.2 (20.1–86.3), P=0.016; and 74.8 (47.6–89.5) ng/ml, P=0.013 respectively], LpPLA2 [1.66 (1.48–1.84) vs 1.48 (1.39–1.60), P=0.004; and 1.53 (1.37–1.70) µg/ml, P=0.015 respectively], small-dense LDL cholesterol (sdLDL) [24.8 (16.8–35.0) vs 15.3 (11.3–20.1), P<0.001; and 20.9 (14.6–29.0) mg/dl, P<0.001 respectively], and glycated apoB [4.02 (3.63–4.33) vs 3.51 (3.27–3.70), P<0.001; and 3.48 (3.20–3.96), P<0.001 respectively]. Both BMI and insulin resistance were associated with adverse lipoprotein modification, correlating positively with OxLDL, LpPLA2, sdLDL, and glycated apoB (Spearman’s ρ=0.244–0.325 and Spearman’s ρ=0.254–0.377 respectively, all P<0.050); and negatively with CEC (Spearman’s ρ=-0.244 and Spearman’s ρ=0.254 respectively, both P<0.050). OxPL-apoB, OxPL-apo(a), and lipoprotein(a) did not differ between PCOS and controls. Conclusions: Insulin resistance is a key determinant of decreased HDL functionality and increased oxidative modification and glycation of LDL in PCOS, which is likely to contribute to the increased CVD risk.