Complement activation in polycystic ovary syndrome occurs in the postprandial and fasted state and is influenced by obesity and insulin sensitivity

Abstract

Objective: Polycystic ovary syndrome (PCOS) is associated with metabolic risk. Complement proteins regulate inflammation and lipid clearance but their role in PCOS-associated metabolic risk is unclear. We sought to establish whether the complement system is activated in PCOS in the fasting and postprandial state.

Design: Case-control study.

Patients: Fasting complement levels were measured in 84 women with PCOS and 95 healthy controls. Complement activation post-oral fat tolerance test (OFTT) was compared in 40 additional subjects (20 PCOS, 20 controls).

Measurements: Activation pathway (C3, C4, C3a(desArg), factor B, factor H, properdin, Factor D) and terminal pathway (C5, C5a, terminal complement complex [TCC]) proteins were measured by commercial or in-house assays.

Results: Fasting C3, C3a(desArg) and TCC concentrations were increased in insulin-resistant (adjusted differences: C3 0.13 g/L [95%CI 0-0.25]; C3a(desArg) 319.2 ng/mL [19.5-619]; TCC 0.66 μg/mL [0.04-1.28]) but not in insulin-sensitive women with PCOS. C3 and factor H levels increased with obesity. Post-OFTT, C3 and C4 levels increased to a similar extent in PCOS subjects and controls, whist factor H levels increased more in women with PCOS compared to controls (adjusted differences (area under the curve): 12 167 μg min/mL [4942-19 392]), particularly in the presence of concomitant obesity.

Conclusions: Activation and terminal complement pathway components are elevated in patients with PCOS, especially in the presence of insulin resistance and obesity.

Keywords: complement system proteins; insulin resistance; obesity; polycystic ovary syndrome.

Figure 1

Influence of BMI on fasting C3, C3adesArg and TCC concentrations in PCOS and control subjects (cohort 1). Boxplots of C3 (A), C3adesArg (B) and TCC levels in PCOS subjects and metabolically healthy controls. Data grouped according to BMI (lean: BMI 18.5‐24.99; overweight: BMI 25‐29.99 and obese: BMI ≥ 30 kg/m²). Middle lines show the medians of the data and the boxes highlight the 25th and 75th percentiles (Quarter 1 and Quarter 3). C3 levels were significantly higher in obese subjects with PCOS compared to obese controls (mean difference ± SEM; 0.222 ± 0.099 g/L, P < .05). TCC: terminal complement complex. n = 84 PCOS, n = 95 Controls

Figure 2

Effects of postprandial lipaemia on triglyceride and complement concentrations in PCOS and control subjects. Postprandial triglyceride (A), factor H (B), TCC (C), C3 (D), C4 (E), properdin (F) and C3adesArg (G) levels in response to OFTT in PCOS cohort and control groups (cohort 2). Data are mean ± SEM. n = 20 PCOS, n = 20 Controls

Figure 3

Influence of obesity on factor H, C3 and TCC responses to postprandial lipaemia. Postprandial factor H (A), TCC (B) and C3 (C) responses to OFTT in obese (BMI ≥ 30 kg/m²) and non‐obese (BMI < 30 kg/m²) PCOS and control subjects (cohort 2). Obese and non‐obese controls. n = 20 PCOS, n = 20 Controls

Figure 4

Relationship between factor H area under the curve (AUC), body fat and metabolic parameters. Data represent PCOS subjects and controls in cohort 2 (n = 40)

Figure 5

Correlation between fasting factor H concentrations and BMI. Data represent correlations between factor H levels and BMI in different age groups in PCOS subjects (triangles, dashed line) and controls (circles, solid line; cohort 1). Factor H levels correlated positively with BMI in both PCOS (n = 84) and controls (n = 95) in all age groups