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Estrogen alone and joint symptoms in the Women’s Health Initiative randomized trial

Chlebowski, Rowan T. MD, PhD1; Cirillo, Dominic J. MD, PhD2; Eaton, Charles B. MD3; Stefanick, Marcia L. PhD4; Pettinger, Mary MS5; Carbone, Laura D. MD, MS6; Johnson, Karen C. MD, MPH7; Simon, Michael S. MD, MPH8; Woods, Nancy F. PhD, RN, FAAN9; Wactawski-Wende, Jean PhD10

doi: 10.1097/GME.0b013e31828392c4
Original Articles

Objective Although joint symptoms are commonly reported after menopause, observational studies examining exogenous estrogen’s influence on joint symptoms provide mixed results. Against this background, estrogen-alone effects on joint symptoms were examined in post hoc analyses in the Women’s Health Initiative randomized, placebo-controlled, clinical trial.

Methods A total of 10,739 postmenopausal women who have had a hysterectomy were randomized to receive daily oral conjugated equine estrogens (0.625 mg/d) or a matching placebo. The frequency and severity of joint pain and joint swelling were assessed by questionnaire in all participants at entry and on year 1, and in a 9.9% random subsample (n = 1,062) after years 3 and 6. Logistic regression models were used to compare the frequency and severity of symptoms by randomization group. Sensitivity analyses evaluated adherence influence on symptoms.

Results At baseline, joint pain and joint swelling were closely comparable in the randomization groups (about 77% with joint pain and 40% with joint swelling). After 1 year, joint pain frequency was significantly lower in the estrogen-alone group compared with the placebo group (76.3% vs 79.2%, P = 0.001), as was joint pain severity, and the difference in pain between randomization groups persisted through year 3. However, joint swelling frequency was higher in the estrogen-alone group (42.1% vs 39.7%, P = 0.02). Adherence-adjusted analyses strengthen estrogen’s association with reduced joint pain but attenuate estrogen’s association with increased joint swelling.

Conclusions The current findings suggest that estrogen-alone use in postmenopausal women results in a modest but sustained reduction in the frequency of joint pain.

From the 1Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA; 2Division of General Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, IA; 3The Memorial Hospital of Rhode Island, Pawtucket, RI; 4Stanford PreventionResearch Center, Department of Medicine, Stanford University, Stanford, CA; 5Fred Hutchinson Cancer Research Center, Seattle, WA; Departments of 6Medicine and 7Preventive Medicine, University of Tennessee Health Science Center, Memphis, TN; 8Karmanos Cancer Institute, Department of Oncology, Wayne State University, Detroit, MI; 9University of Washington, Seattle, WA; and 10The State University of New York, Buffalo, NY.

Received August 15, 2012; revised and accepted October 30, 2012.

The Women’s Health Initiative (WHI) project office at the National Heart, Lung, and Blood Institute (NHLBI; the sponsor) reviewed and approved the final manuscript but had no other role in the preparation of this report. Decisions concerning study design, data collection and analysis, interpretation of results, manuscript preparation, or submission of the manuscript for publication resided with committees composed of WHI investigators, including NHLBI representatives.

Funding/support: The WHI program was funded by the NHLBI, National Institutes of Health, US Department of Health and Human Services, through contracts N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, and 44221.

Financial disclosure/conflicts of interest: R.T.C. has served as consultant to AstraZeneca, Novartis, and Amgen; has received funding support from Amgen; and has served on speakers’ bureaus for AstraZeneca, Novartis, Amgen, and Celgene. N.F.W. reports board membership in Procter&Gamble. All other authors declare no conflicts of interest.

Address correspondence to: Rowan T. Chlebowski, MD, PhD, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, 1124 West Carson Street, Torrance, CA 90502. E-mail:

© 2013 by The North American Menopause Society.