Differential Expression of Complement Pathway Components in Unexplained Infertility Versus Male Factor Infertility: Insights from an Exploratory Pilot Study

Complement (C) proteins have been linked to infertility and reproductive outcomes. This study was undertaken to determine the association of complement proteins in non-obese women before in vitro fertilization (IVF) with unexplained infertility (UI) compared to women with male factor infertility (MFI) as controls. We hypothesized that complement protein factors may provide evidence for the underlying mechanism in UI. In this exploratory pilot study, 25 women (UI = 14 and MFI = 11) undergoing IVF had blood drawn on day 21 of the luteal phase. Slow Off-rate Modified Aptamer (SOMA)-scan plasma protein measurement was undertaken for 25 complement pathway-related proteins. Student’s t-test was used to compare group means and Pearson’s correlations to examine relationships with complement proteins. Baseline demographics and hormonal parameters did not differ between groups, and parameters of the response following IVF did not differ. In the UI group compared to the MFI group, there were lower levels of properdin (p = 0.03) that may reduce endometrial receptivity and impact follicular development, lower C3a anaphylatoxin des arginine (C3adesArg) (p = 0.02) that may reduce endometrial vascularity, lower C4 (C4) (p = 0.04), indicating reduced alternate pathway activation, and lower C8 (C8) (p = 0.04) that also may affect the endometrium. In UI alone, properdin negatively correlated with high-density lipoprotein cholesterol (HDL-c), and C8 positively correlated with thyroid-stimulating hormone (TSH) and Free-triiodothyronine (Free-T3) (p < 0.05). These preliminary findings indicate reduced complement activity among UI women, warranting further mechanistic investigation.