304 Endothelial function is associated with cardiac risk fac- tor status. 1 Estrogen administration induces positive ef- fects on endothelial function and on blood flow in normal and atherosclerotic arteries in nonhuman pri- mates and in postmenopausal women. 2-4 Estrogen recep- tors, which are present in the vascular endothelium, play an integral role, especially in the generation of nitric oxide. 5 Selective estrogen receptor modulators (SERMs) have estrogen-agonistic actions in some tissues and estro- gen-antagonist actions in others. Estrogen-like actions in arteries have been reported for several different SERMs, including raloxifene, in human cell culture and animal studies 6-8 and for tamoxifen and droloxifene in post- menopausal women. 9 Two recent reports of the effects of raloxifene on endothelial function in healthy post- menopausal women are discrepant; one report shows a significant increase in blood flow–mediated vasodilation after raloxifene, and the other report shows no signifi- cant improvement. 10,11 Brachial artery imaging 12 and laser Doppler veloci- metry (LDV) 13 have been used to assess endothelial function. There is a close relation between endothelium- dependent vasomotor responses in the human coronary and peripheral circulations. 14 We therefore used these techniques simultaneously to assess the effects of ralox- ifene on brachial artery and microcirculatory endothelial responses in healthy postmenopausal women in a ran- domized, double-blind, placebo-controlled crossover trial. Material and methods Subjects. Twenty healthy postmenopausal women were enrolled, of whom 1 was subsequently deemed ineligible because of undisclosed Raynaud’s phenomenon; the re- maining cohort of 19 women was studied. Postmenopausal From the Departments of Obstetrics and Gynecology a and Epidemiology and Public Health, b Yale University School of Medicine, and the Yale Prevention Research Center. c Supported by Eli Lilly and Company, Indianapolis, Ind. Received for publication May 17, 2002; revised July 12, 2002; accepted September 23, 2002. Reprint requests: Philip M. Sarrel, MD, Yale-Griffin Prevention Re- search Center, 130 Division St, Derby, CT 06418. E-mail: philip.sar- rel@Yale.edu © 2003, Mosby, Inc. All rights reserved. 0002-9378/2003 $30.00 + 0 doi:10.1067/mob.2003.28 Raloxifene and endothelial function in healthy postmenopausal women Philip M. Sarrel, MD, a Haq Nawaz, MD, MPH, b,c Wendy Chan, MPH, c Melissa Fuchs, MD, b and David L. Katz, MD, MPH b,c New Haven and Derby, Conn OBJECTIVE: The purpose of this study was to determine the effects of raloxifene on endothelial function in healthy, postmenopausal women. STUDY DESIGN: This was a randomized, double-blind, placebo-controlled crossover trial. Subjects (n = 19; mean age, 61 years) underwent endothelial function testing at baseline and after treatment with placebo or raloxifene (60 mg per day for 6 weeks). RESULTS: Brachial artery diameter change (flow-mediated dilation) increased 5.0% with placebo and 8.56% with raloxifene (SE = 1.83, P = .03) in response to a hyperemic stimulus; an adjustment of this response for a variation in stimulus intensity resulted in greater discrimination (P = .009). The ratio of area under the curve response to area under the curve reference with the use of laser Doppler measures was 1.18 for placebo and 1.28 for raloxifene (P = .05). Flow-mediated dilation and area under the curve ratio correlated signifi- cantly (r = 0.33, P = .04). CONCLUSION: Treatment with raloxifene enhanced endothelial-mediated dilation in brachial arteries and digital vessels in healthy, postmenopausal women.A potential mechanism for a cardioprotective effect of raloxifene is suggested and warrants further study. (Am J Obstet Gynecol 2003;188:304-9.) Key words: Endothelial response, raloxifene, healthy postmenopausal women EDITOR’S CHOICE