Context: Insulin resistance plays a significant role in the pathogenesis of the polycystic ovary syndrome (PCOS) and represents a link to the unfavourable cardiovascular risk profile frequently found in affected patients. The endogenous nitric oxide-synthase inhibitor asymmetric dimethyl-L-arginine (ADMA) is associated with atherosclerosis and represents an independent marker for cardiovascular morbidity and mortality.

Objective: In this study we investigated ADMA levels among other cardiovascular, metabolic and hormonal parameters in women with PCOS. Furthermore the effects of metformin treatment on these parameters were studied.

Design: A cross sectional study and clinical trial were performed.

Setting: This study was conducted at a university hospital with patients from gynaecology clinics.

Patients and participants: Women with PCOS (n = 83) compared to a control group of healthy women (n = 39) were studied.

Interventions: In a subgroup of patients with PCOS (n = 21) the effect of metformin (1700 mg daily) was assessed after 6 months treatment.

Main outcome measures: ADMA, intima media thickness (IMT), metabolic and hormonal parameters and markers of inflammation were investigated. To assess insulin sensitivity a 75-g oral glucose tolerance test (OGTT) was performed after an overnight fast. Insulin and glucose levels were measured in response to glucose ingestion.

Results: ADMA levels were significantly higher in the PCOS group compared with controls (0.57 ± 0.15 vs. 0.50 ± 0.11, P = 0.024) and were found to be decreased significantly after metformin treatment (0.53 ± 0.06 vs. 0.46 ± 0.09, P = 0.013). Androgens, hs-CRP, fasting C-peptide, AUC-Insulin, AUC-Glucose, HOMA-IR, fasting-insulin, HbA1c, Cholesterol, LDL-cholesterol, triglycerides and IMT were significantly higher in women with PCOS compared to controls. In PCOS patients ADMA was found to be positively correlated with BMI, WHR, parameters of insulin sensitivity (fasting insulin, HOMA-IR, AUC-Insulin), hyperandrogenemia (free testosterone, free androgen index) and IMT. In control individuals an inverse correlation between ADMA and HDL-cholesterol and positive correlations with hs-CRP and homocysteine were found. Treatment with metformin ameliorated hyperandrogenemia and decreased ADMA levels to controls range. Decrease in ADMA levels subsequent to metformin treatment did not correlate with change in BMI or metabolic parameters.

Conclusions: Our data show that women with PCOS have elevated levels of ADMA. The degree of insulin resistance confers the greatest influence on ADMA level in women with PCOS. Metformin treatment led to improvement of hormonal and metabolic parameters and decreased ADMA levels possibly independent of BMI and metabolic changes.