Differential effects on haemostatic markers by metformin and the contraceptive pill: A randomized comparative trial in PCOS

Background Polycystic ovarian syndrome (PCOS) affects up to 18% of reproductiveaged women with increased risks of cardiovascular disease and venous thromboembolic disease, related to metabolic and hormonal features, obesity and an apparent hypofibrinolytic state, possibly exacerbated by current PCOS treatments. Objective To investigate and comparehaemostatic impacts of common pharmacological treatments and explore relationships with hormonal and metabolic variables in PCOS. Patients/Methods This mechanistic sub-study using biobanked samples from a 6-month randomized comparative trial of pharmacological treatments assessed pro-And anti-Thromboticmarkers and overall haemostatic activity. Overweight women ofmean age 33.9 ± 6.7 years andmean BMI (bodymass index) of 36.5 ± 7.0 kg/m 2 with PCOS (n = 60) were randomized to eithermetformin, higher-dose oral contraceptive pill (OCP) or low-dose OCP + spironolactone (OCP + S). Primary outcome measures included changes in plasminogen activator inhibitor 1 (PAI-1), asymmetric dimethylarginine (ADMA), prothrombin fragments 1 and 2 (PF1 and 2), plasminogen, tissue plasminogen activator (tPA), thrombin activatable fibrinolysis inhibitor (TAFI) and thrombin generation (TG). Results PAI-1 activity fell in all groups, ADMA fell in higher-dose OCP, PF1 and 2 increased with metformin and higher-dose OCP, TG rose and tPA fell in both OCP groups, plasminogen increased in all and TAFI increased after higher-dose OCP. Conclusion Endothelial function (primary haemostasis) improved with higher dose with some improvement in low-dose OCP + S and metformin. Aberrant coagulation was noted in both OCP groups, but not with metformin. Fibrinolysis was reduced with higher-dose OCP. Our work suggests an additional dimension of treatment (haemostatic system effects) that favours metformin treatment over the OCP in PCOS.