Plasma Homocysteine Is Weakly Correlated with Plasma Endothelin and von Willebrand Factor but not with Endothelium-dependent Vasodilatation in Healthy Postmenopausal Women Gerdien W. de Valk-de Roo, 1 Coen D.A. Stehouwer, 2 Jan Lambert, 2 Casper G. Schalkwijk, 4 Marius J. van der Mooren, 3 Cornelis Kluft, 5 and Coen Netelenbos 1* Background: Hyperhomocysteinemia is an independent cardiovascular risk factor, possibly through the induc- tion of endothelial dysfunction. The postmenopausal state is associated with increased plasma homocysteine. We examined whether increased homocysteine is asso- ciated with impaired endothelial function. Methods: Sixty-three hysterectomized but otherwise healthy postmenopausal women (54.8  3.5 years) par- ticipated in this study. Fasting total plasma homocys- teine (tHcy) was measured as free plus protein-bound homocysteine. Endothelial function was assessed by measuring plasma concentrations of the endothelium- derived proteins endothelin (ET), von Willebrand factor (vWF), and plasminogen activator inhibitor type 1 (PAI-1) as well as brachial artery flow-mediated, endo- thelium-dependent vasodilatation (FMD). Results: Plasma tHcy was 9.6  2.5 mol/L. After adjustment for possible confounders, a 1 mol/L in- crease in tHcy was associated with an increase in ET of 0.08 ng/L (P  0.045) and an increase in vWF of 4.2% (P  0.05). No statistically significant association was present between tHcy and PAI-1 or FMD. Conclusions: Increased fasting homocysteine in post- menopausal women may impair some aspects of endo- thelial function. It is of clinical interest to study whether homocysteine lowering can improve endothelial func- tion and thus cardiovascular morbidity and mortality in postmenopausal women. © 1999 American Association for Clinical Chemistry Hyperhomocysteinemia is an independent risk factor for atherosclerosis and thromboembolic disease. These associa- tions are not limited to severe hyperhomocysteinemia, such as that related to homozygous cystathionine--synthase de- ficiency; they are also observed when fasting or postmethi- onine concentrations are moderately increased (1–3 ). In- creased total homocysteine (tHcy) 6 is thought to confer a graded risk of atherothrombotic disease and may be attrib- uted to commonly occurring genetic and acquired factors such as the C677T mutation in the methylenetetrahydrofo- late reductase gene, impaired renal function, inadequate folic acid and/or vitamin B 6 and B 12 intake, and the use of certain medications. Sex steroids also affect the tHcy concen- tration (4 ). The tHcy concentration is higher in men than in women (5, 6). Low tHcy concentrations are present during pregnancy, a state characterized by high concentrations of endogenous estrogens (7 ), as well as in premenopausal compared with postmenopausal women (8 ). In addition, in postmenopausal women, administration of hormone re- placement therapy has been reported to lower homocysteine (9 –11 ). It may, therefore, be hypothesized that a meno- pause-associated increase in homocysteine contributes to the postmenopausal increase in cardiovascular risk. From the project “Ageing Women”: 1 Department of Endocrinology, Research Institute for Endocrinology, Reproduction and Metabolism; Departments of 2 Internal Medicine and 3 Ob- stetrics and Gynaecology, Institute for Cardiovascular Research-Vrije Univer- siteit; and 4 Department of Clinical Chemistry, University Hospital Vrije Universiteit Amsterdam, De Boelelaan 1117, Postbus 7057, 1007 MB Amster- dam, The Netherlands. 5 The Gaubius Laboratory, TNO-PG, Postbus 2215, 2301 CE Leiden, The Netherlands. *Author for correspondence. Fax 31-20-4440502; e-mail C.Netelen@azvu.nl. Received March 18, 1999; accepted May 18, 1999. 6 Nonstandard abbreviations: tHcy, total plasma homocysteine; ET, endo- thelin; vWF, von Willebrand factor; PAI-1, plasminogen activator inhibitor type 1; FMD, flow-mediated, endothelium-dependent vasodilatation; FSH, follicle-stimulating hormone; BMI, body mass index; WHR, waist-to-hip ratio; and NTG, nitroglycerin. Clinical Chemistry 45:8 1200 –1205 (1999) Enzymes and Protein Markers 1200