Effects of metformin with or without supplementation with folate on homocysteine levels and vascular endothelium of women with polycystic ovary syndrome

Diabetes Care. 2010 Feb;33(2):246-51. doi: 10.2337/dc09-1516. Epub 2009 Nov 23.


Objective: To evaluate whether the administration of metformin exerts any effects on serum homocysteine (Hcy) levels in patients with polycystic ovary syndrome (PCOS) and whether supplementation with folate enhances the positive effects of metformin on the structure and function of the vascular endothelium.

Research design and methods: A total of 50 patients affected by PCOS, without additional metabolic or cardiovascular diseases, were enrolled in a prospective nonrandomized placebo-controlled double-blind clinical study. They were grouped into two treatment arms that were matched for age and BMI. Patients were treated with a 6-month course of metformin (1,700 mg daily) plus folic acid (400 microg daily; experimental group, n = 25) or placebo (control group, n = 25). Complete hormonal and metabolic patterns, serum Hcy, folate, vitamin B12, endothelin-1 levels, brachial artery diameter at the baseline (BAD-B) and after reactive hyperemia (BAD-RH), flow-mediated dilation, and intima-media thickness in both common carotid arteries were evaluated.

Results: After treatment, a significant increase in serum Hcy levels was observed in the control group compared with the baseline values and the experimental group. A beneficial effect was observed in the concentrations of BAD-B, BAD-RH, flow-mediated dilation, intima-media thickness, and serum endothelin-1 in both groups. However, the results were improved more significantly in the experimental group than in the control subjects.

Conclusions: Metformin exerts a slight but significant deleterious effect on serum Hcy levels in patients with PCOS, and supplementation with folate is useful to increase the beneficial effect of metformin on the vascular endothelium.

Trial registration: ClinicalTrials.gov NCT00953355.

MeSH terms

  • Adult
  • Body Mass Index
  • Brachial Artery / drug effects
  • Brachial Artery / physiopathology
  • Double-Blind Method
  • Endothelin-1 / blood
  • Endothelium, Vascular / drug effects
  • Endothelium, Vascular / physiopathology*
  • Exercise / physiology
  • Female
  • Folic Acid / therapeutic use*
  • Homocysteine / blood*
  • Humans
  • Hypoglycemic Agents / therapeutic use*
  • Leisure Activities
  • Metformin / therapeutic use*
  • Placebos
  • Polycystic Ovary Syndrome / blood
  • Polycystic Ovary Syndrome / drug therapy*
  • Polycystic Ovary Syndrome / physiopathology
  • Tunica Intima / drug effects
  • Tunica Intima / pathology
  • Tunica Media / drug effects
  • Tunica Media / pathology
  • Vasodilation / drug effects
  • Vitamin B 12 / blood
  • Waist-Hip Ratio


  • Endothelin-1
  • Hypoglycemic Agents
  • Placebos
  • Homocysteine
  • Metformin
  • Folic Acid
  • Vitamin B 12

Associated data

  • ClinicalTrials.gov/NCT00953355