Combined Continuous Ethinyl Estradiol/Norethindrone Acetate Does Not Improve Forearm Blood Flow in Postmenopausal Women at Risk for Cardiovascular Events: A Pilot Study

OBJECTIVE: This study sought to determine whether combined continuous ethinyl estradiol and norethindrone acetate, a postmenopausal hormone therapy (HT) combination designed to have fewer side effects than cyclical therapies and therapies using medroxyprogesterone acetate (MPA), could improve vascular endothelial function in postmenopausal women with risk factors for cardiovascular disease (CVD). METHODS: Eighteen postmenopausal women (mean age 62 +/- 11 years) participated in a randomized, placebo-controlled, crossover design trial of 10 microg estradiol/1 mg norethindrone acetate given once daily for 3 months, with a 1-month washout period between placebo and active treatment phases. Vascular reactivity was assessed at each phase of the study using high-frequency brachial artery ultrasound in response to flow-mediated hyperemia, cold pressor testing, and sublingual nitroglycerin. Markers of cardiovascular risk, including cholesterol levels, inflammatory markers, fibrinolytic markers, and solubilized adhesion molecules, were also measured at each phase. RESULTS: We found no significant difference in vascular reactivity measurements during active treatment with ethinyl estradiol/norethindrone acetate vs. placebo. C-reactive protein (CRP) levels increased significantly during active treatment, and high-density lipoprotein (HDL) levels decreased significantly. Vascular cell adhesion molecule-1 (VCAM-1) levels declined during active treatment. Plasminogen activator inhibitor-1 (PAI-1) levels were inversely correlated with flow-mediated hyperemic vascular reactivity, independent of active treatment or placebo phases. CONCLUSIONS: In this older postmenopausal population with at least one cardiovascular risk factor, treatment with combined continuous ethinyl estradiol and norethindrone acetate failed to improve vascular endothelial function. The agent's proinflammatory effect or subclinical atherosclerosis in this population may have contributed to this finding.