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Effects of estrogen and venlafaxine on menopause-related quality of life in healthy postmenopausal women with hot flashes

a placebo-controlled randomized trial

Caan, Bette DrPH1; LaCroix, Andrea Z. PhD2; Joffe, Hadine MD, MSc3,4; Guthrie, Katherine A. PhD5; Larson, Joseph C. MS5; Carpenter, Janet S. PhD, RN, FAAN6; Cohen, Lee S. MD7,8; Freeman, Ellen W. PhD9; Manson, JoAnn E. MD, DrPH3,8; Newton, Katherine PhD10; Reed, Susan MD, MPH11; Rexrode, Kathy MD, MPH3,8; Shifren, Jan MD7; Sternfeld, Barbara PhD1; Ensrud, Kris MD12

doi: 10.1097/GME.0000000000000364
Original Articles

Objective This study aims to evaluate the effects of low-dose estradiol (E2) or venlafaxine on menopause-related quality of life and associated symptoms in healthy perimenopausal and postmenopausal women with hot flashes.

Methods A double-blind, placebo-controlled, randomized trial of low-dose oral 17β-E2 0.5 mg/day and venlafaxine XR 75 mg/day, versus identical placebo, was conducted among 339 women (aged 40-62 y) experiencing two or more vasomotor symptoms (VMS) per day (mean [SD], 8.07 [5.29]) who were recruited at three clinical sites from November 2011 to October 2012. The primary trial outcome, as reported previously, was frequency of VMS at 8 weeks. Here, we report on secondary endpoints of total and domain scores from the Menopause-Specific Quality of Life Questionnaire (MENQOL) and from measures of pain (Pain, Enjoyment in life, and General activity scale), depression (Patient Health Questionnaire-9), anxiety (Generalized Anxiety Disorder Questionnaire-7), and perceived stress (Perceived Stress Scale).

Results Treatment with both E2 and venlafaxine resulted in significantly greater improvement in quality of life, as measured by total MENQOL scores, compared with placebo (E2: mean difference at 8 wk, −0.4; 95% CI, −0.7 to −0.2; P < 0.001; venlafaxine: mean difference at 8 wk, −0.2; 95% CI, −0.5 to 0.0; P = 0.04). Quality-of-life domain analyses revealed that E2 had beneficial treatment effects on all domains of the MENQOL except for the psychosocial domain, whereas venlafaxine benefits were observed only in the psychosocial domain. Neither E2 nor venlafaxine improved pain, anxiety, or depressive symptoms, although baseline symptom levels were low. Modest benefits were observed for perceived stress with venlafaxine.

Conclusions Both low-dose E2 and venlafaxine are effective pharmacologic agents for improving menopause-related quality of life in healthy women with VMS.

From the 1Division of Research, Kaiser Permanente of Northern California, Oakland, CA; 2University of California, San Diego, CA; 3Brigham and Women’s Hospital, Boston, MA; 4Dana Farber Cancer Institute, Boston, MA; 5MsFLASH Coordinating Center, Fred Hutchinson Cancer Research Center, Seattle, WA; 6School of Nursing, Indiana University, Indianapolis, IN; 7Massachusetts General Hospital, Boston, MA; 8Harvard Medical School, Boston, MA; 9Departments of Obstetrics/Gynecology and Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, PA; 10Group Health Research Institute, Seattle, WA; 11University of Washington School of Medicine, Seattle, WA; and 12VA Medical Center/University of Minnesota, Minneapolis, MN.

Received June 30, 2014; revised and accepted September 5, 2014.

Funding/support: This study was supported by a cooperative agreement issued by the National Institute on Aging, in collaboration with the Eunice Kennedy Shriver National Institute of Child Health and Development, the National Center for Complementary and Alternative Medicine, and the Office of Research on Women’s Health (grants U01 AG032656, U01AG032659, U01AG032669, U01AG032682, U01AG032699, and U01AG032700).

Clinical trial registration: NCT01418209 at

Financial disclosure/conflicts of interest: L.S.C. reports consultancies with Noven Pharmaceuticals and PamLab LLC and grants from Astra-Zeneca Pharmaceuticals, Bayer Healthcare Pharmaceuticals, Bristol-Myers Squibb, Cephalon Inc, Forest Laboratories, GlaxoSmithKline, Ortho-McNeill Janssen, Pfizer Inc, and Sunovion Pharmaceuticals. A.Z.L. reports consultancy with Amgen. H.J. reports consultancy with Noven and grants from Teva/Cephalon. E.W.F. reports a research grant from Forest Laboratories. K.R. reports consultancy with Pfizer. K.E. reports consultancy with Merck Sharpe and Dohme. The other authors report no conflicts of interest.

Address correspondence to: Bette Caan, DrPH, Division of Research, Kaiser Permanente of Northern California, 2000 Broadway, Oakland, CA 94612. E-mail:

© 2015 by The North American Menopause Society.