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Comparison of clinical outcomes among users of oral and transdermal estrogen therapy in the Women's Health Initiative Observational Study

Crandall, Carolyn J. MD, MS1; Hovey, Kathleen M. MS2; Andrews, Christopher PhD3; Cauley, Jane A. DrPH4; Stefanick, Marcia PhD5; Shufelt, Chrisandra MD, MS6; Prentice, Ross L. PhD7; Kaunitz, Andrew M. MD8; Eaton, Charles MD, MS9; Wactawski-Wende, Jean PhD10; Manson, JoAnn E. MD, DrPH11

doi: 10.1097/GME.0000000000000899
Original Articles

Objective: To examine associations of estrogen preparations with an index of health risks versus benefits.

Methods: Using data from 45,112 participants of the Women's Health Initiative Observational Study (average follow-up 5.5 years), we examined associations of estrogen type and oral conjugated equine estrogen (CEE) dose with time to first global index event (GIE), defined as coronary heart disease, breast cancer, stroke, pulmonary embolism, hip fracture, colorectal cancer, endometrial cancer, or death.

Results: Oral CEE less than 0.625 mg/d + progestogen (P) users had a lower risk of a GIE (adjusted hazard ratio 0.74, 95% confidence interval 0.56-0.97) than oral CEE 0.625 mg/d + P users. GIE risk in oral CEE 0.625 mg/d + P users was greater with at least 5-year use (adjusted hazard ratio 1.22, 95% confidence interval 1.06-1.41) than with less than 5-year use. In women with prior hysterectomy, compared with women taking oral CEE 0.625 mg/d for less than 5 years, GIE risk was similar with oral CEE below 0.625 mg/d, oral estradiol (E2), and transdermal E2, whether used for less than 5 years or for at least 5 years. There was no difference in GIE risk between users of the following: oral CEE + P versus oral E2 + P; oral CEE + P versus transdermal E2 + P; oral E2 + P versus transdermal E2 + P. Findings were similar among women with hysterectomy taking estrogen alone.

Conclusions: The summary index of risks versus benefits was similar for oral CEE versus oral or transdermal E2-containing regimens. CEE + P containing less than 0.625 mg/d of CEE (vs 0.625 mg/d) for less than 5 years appeared safer.

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1Department of Medicine, University of California, Los Angeles, Los Angeles, CA

2Dept of Epidemiology and Environmental Health, University at Buffalo, The State University of New York, Buffalo, NY

3Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor, MI

4Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA

5Department of Medicine, Stanford University School of Medicine, Stanford, CA

6Barbra Streisand Women's Heart Center, Cedars-Sinai Heart Institute, Los Angeles, CA

7Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA

8Department of Obstetrics and Gynecology, University of Florida College of Medicine-Jacksonville, Jacksonville, FL

9Department of Family Medicine and Epidemiology, Brown University Warren Alpert Medical School and School of Public Health, Pawtucket, RI

10Department of Epidemiology and Environmental Health, University at Buffalo, State University of New York, Buffalo, NY

11Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.

Address correspondence to: Carolyn J. Crandall, MD, MS, Professor of Medicine, David Geffen School of Medicine at University of California, Los Angeles, UCLA Medicine/GIM, 911 Broxton Ave., 1st floor, Los Angeles, CA 90024. E-mail:

Received 10 January, 2017

Revised 7 March, 2017

Accepted 7 March, 2017

Short list of WHI Investigators: Program Office (National Heart, Lung, and Blood Institute, Bethesda, Maryland)-Jacques Rossouw, Shari Ludlam, Dale Burwen, JoanMcGowan, Leslie Ford, and Nancy Geller; Clinical Coordinating Center (Fred Hutchinson Cancer Research Center, Seattle, WA)-Garnet Anderson, Ross Prentice, Andrea LaCroix, and Charles Kooperberg; Investigators and Academic Centers (Brigham and Women's Hospital, Harvard Medical School, Boston, MA)-JoAnn E. Manson; (MedStar Health Research Institute/Howard University, Washington, DC)-Barbara V. Howard; (Stanford Prevention Research Center, Stanford, CA)-Marcia L. Stefanick; (The Ohio State University, Columbus, OH)-Rebecca Jackson; (University of Arizona, Tucson/Phoenix, AZ)-Cynthia A. Thomson; (University at Buffalo, Buffalo, NY)-Jean Wactawski-Wende; (University of Florida, Gainesville/Jacksonville, FL)-Marian Limacher; (University of Iowa, Iowa City/Davenport, IA)-Robert Wallace; (University of Pittsburgh, Pittsburgh, PA)-Lewis Kuller; (Wake Forest University School of Medicine, Winston-Salem, NC)-Sally Shumaker.

Funding/support: The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts HSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, and HHSN271201100004C.

Financial disclosure/conflicts of interest: The following authors have no conflicts of interest: C.J.C., J.A.C., C.B.E., R.L.P., J.W.W., K.H., C.A., C.S., M.S., and J.E.M. A.K. serves on contraceptive advisory boards for Allergan, Bayer, Medicines360, Pfizer; Department (U of FL) receives research support from Bayer, Radius, and TherapeuticsMD. C.S. received honoraria for lectures from the Cardiometabolic Risk Summit Fall, American College of Physicians Southern California Regional Meeting.

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© 2017 by The North American Menopause Society.