Whether health outcomes of menopausal estrogen therapy differ between women with and without bilateral salpingo-oophorectomy (BSO) is unknown.
To examine estrogen therapy outcomes by BSO status, with additional stratification by 10-year age groups.
Subgroup analyses of the randomized Women's Health Initiative Estrogen-Alone Trial. (ClinicalTrials.gov: NCT00000611)
40 U.S. clinical centers.
9939 women aged 50 to 79 years with prior hysterectomy and known oophorectomy status.
Conjugated equine estrogens (CEE) (0.625 mg/d) or placebo for a median of 7.2 years.
Incidence of coronary heart disease and invasive breast cancer (the trial's 2 primary end points), all-cause mortality, and a “global index” (these end points plus stroke, pulmonary embolism, colorectal cancer, and hip fracture) during the intervention phase and 18-year cumulative follow-up.
The effects of CEE alone did not differ significantly according to BSO status. However, age modified the effect of CEE in women with prior BSO. During the intervention phase, CEE was significantly associated with a net adverse effect (hazard ratio for global index, 1.42 [95% CI, 1.09 to 1.86]) in older women (aged ≥70 years), but the global index was not elevated in younger women (P trend by age = 0.016). During cumulative follow-up, women aged 50 to 59 years with BSO had a treatment-associated reduction in all-cause mortality (hazard ratio, 0.68 [CI, 0.48 to 0.96]), whereas older women with BSO had no reduction (P trend by age = 0.034). There was no significant association between CEE and outcomes among women with conserved ovaries, regardless of age.
The timing of CEE in relation to BSO varied; several comparisons were made without adjustment for multiple testing.
The effects of CEE did not differ by BSO status in the overall cohort, but some findings varied by age. Among women with prior BSO, in those aged 70 years or older, CEE led to adverse effects during the treatment period, whereas women randomly assigned to CEE before age 60 seemed to derive mortality benefit over the long term.
Primary Funding Source:
The WHI program is funded by the National Heart, Lung, and Blood Institute; National Institutes of Health; and U.S. Department of Health and Human Services. Wyeth Ayerst donated the study drugs.
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Author, Article, and Disclosure Information
JoAnn E. Manson,
Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts (J.E.M., S.S.B.)
Fred Hutchinson Cancer Research Center, Seattle, Washington (A.K.A., G.L.A., R.L.P.)
City of Hope National Medical Center, Duarte, and Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California (R.T.C.)
National Heart, Lung, and Blood Institute, Bethesda, Maryland (J.E.R.)
MedStar Health Research Institute, Bonita Springs, Florida, and Georgetown-Howard Universities, Washington, DC (B.V.H.)
Mel & Enid Zuckerman College of Public Health, University of Arizona, Tucson, Arizona (C.A.T.)
Stanford Prevention Research Center, Stanford, California (M.L.S.)
University of Florida College of Medicine-Jacksonville, Jacksonville, Florida (A.M.K.)
David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California (C.J.C.)
Alpert Medical School of Brown University, Providence, Rhode Island (C.B.E., S.L.)
Stanford University, Stanford, California (V.W.H.)
Brown University, Providence, Rhode Island; Indiana University, Bloomington, Indiana (J.L.)
Albert Einstein College of Medicine, Bronx, New York (T.R.)
University of California, San Diego School of Medicine, La Jolla, California (A.H.S.)
University of Kentucky, Lexington, Kentucky (G.W.)
University at Buffalo, the State University of New York, Buffalo, New York (J.W.)
Note: Dr. Manson and Mr. Aragaki had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Disclaimer: The opinions expressed are those of the authors and do not necessarily reflect the views of the NHLBI, National Institutes of Health, or the U.S. Department of Health and Human Services.
Acknowledgment: The authors thank the WHI investigators, staff, and the trial participants for their outstanding dedication and commitment.
Financial Support: The WHI program is funded by the National Heart, Lung, and Blood Institute; National Institutes of Health; and the U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C. Wyeth Ayerst donated the study drugs.
Disclosures: Dr. Manson reports grants from the National Institutes of Health during the conduct of the study. Dr. Chlebowski reports personal fees from AstraZeneca, Novartis, Genentech, PUMA, Immunomedics, and Amgen during the conduct of the study. Dr. Anderson reports grants from National Heart, Lung, and Blood Institute during the conduct of the study. Dr. Kaunitz reports grants from Bayer, Allergan, Mithra, and Therapeutics MD and personal fees from Bayer, Mithra, and Pfizer outside the submitted work. Dr. Eaton reports grants from National Institutes of Health-WHI during the conduct of the study. Dr. Wactawski-Wende reports grants from the National Institutes of Health during the conduct of the study. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M19-0274.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Catharine B. Stack, PhD, MS, Deputy Editor, Statistics, reports that she has stock holdings in Pfizer, Johnson & Johnson, and Colgate-Palmolive. Christina C. Wee, MD, MPH, Deputy Editor, reports employment with Beth Israel Deaconess Medical Center. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Yu-Xiao Yang, MD, MSCE, Deputy Editor, reports that he has no financial relationships or interest to disclose.
Data Sharing Statement: The following data will be made available beginning 1 July 2021: deidentified participant data and data dictionary (information about data sharing for the Women's Health Initiative can be found at www.whi.org/researchers/data/Documents/WHI%20Data%20Sharing%20Statement.pdf. For these analyses, data will be publicly available 2 years after publication of this article). The following supporting documents are available: statistical/analytic code (Supplement) and informed consent form (www.whi.org/researchers/studydoc/SitePages/Protocol%20and%20Consents.aspx).
Corresponding Author: JoAnn E. Manson, MD, DrPH, Brigham and Women's Hospital, Harvard Medical School, 900 Commonwealth Avenue, 3rd Floor, Boston, MA 02215; e-mail, jmanson@rics.
Current Author Addresses: Drs. Manson and Bassuk: Brigham and Women's Hospital, Harvard Medical School, 900 Commonwealth Avenue, 3rd Floor, Boston, MA 02215.
Mr. Aragaki, Dr. Anderson, and Dr. Prentice: Women's Health Initiative, Clinical Coordinating Center, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North M3-A410, PO Box 19024, Seattle, WA 98109-1024.
Dr. Chlebowski: Los Angeles Biomedical Research Institute, 1124 West Carson Street, N16, Torrance, CA 90502.
Dr. Rossouw: National Heart, Lung, and Blood Institute, National Institutes of Health. 6701 Rockledge Avenue, 10th Floor, Bethesda, MD 20892.
Dr. Howard: MedStar Health Research Institute, 26331 Rookery Lake Drive, Bonita Springs, FL 34134.
Dr. Thomson: 3950 South Country Club Road, Suite 330, Tucson, AZ 85714.
Dr. Stefanick: Stanford Prevention Research Center, Stanford University, Medical School Office Building, 1265 Welch Road, Room X308, Palo Alto, CA 94305-5411.
Dr. Kaunitz: University of Florida College of Medicine-Jacksonville, 653-1 West 8th Street, Jacksonville, FL 32209.
Dr. Crandall: David Geffen School of Medicine at University of California, Los Angeles, 1100 Glendon Avenue, Suite 850 - Room 858, Los Angeles, CA 90024.
Dr. Eaton: Brown University Center for Primary Care and Prevention, Care England Medical Group and Specialty Services, Second Floor, 111 Brewster Street, Pawtucket, RI 02860.
Dr. Henderson: Stanford University, 259 Campus Drive, MC 5405, Stanford, CA 94305.
Dr. Liu: Brown University, 121 South Main Street, 2nd Floor, Providence, RI 02912.
Dr. Luo: Indiana University, 1025 East 7th Street, Bloomington, IN 47405.
Dr. Rohan: Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461.
Dr. Shadyab: University of California, San Diego School of Medicine, 9500 Gilman Drive #0725, La Jolla, California 92093.
Dr. Wells: University of Kentucky, 900 South Limestone, Wethington Building, Suite 326, Lexington, KY 40536-0200.
Dr. Wactawski-Wende: Women's Health Initiative Northeast Regional Center, University at Buffalo, 401 Kimball Tower, Buffalo, NY 14214.
Author Contributions: Conception and design: J.E. Manson, A.K. Aragaki, J.E. Rossouw, R.L. Prentice.
Analysis and interpretation of the data: J.E. Manson, A.K. Aragaki, S.S. Bassuk, R.T. Chlebowski, G.L. Anderson, C.A. Thomson, M.L. Stefanick, C.J. Crandall, C.B. Eaton, S. Liu, A.H. Shadyab, G. Wells, R.L. Prentice.
Drafting of the article: J.E. Manson, A.K. Aragaki, S.S. Bassuk, R.L. Prentice.
Critical revision of the article for important intellectual content: J.E. Manson, A.K. Aragaki, S.S. Bassuk, R.T. Chlebowski, G.L. Anderson, B.V. Howard, M.L. Stefanick, A.M. Kaunitz, C.J. Crandall, C.B. Eaton, V.W. Henderson, S. Liu, J. Luo, T. Rohan, A.H. Shadyab, G. Wells, J. Wactawski-Wende, R.L. Prentice.
Final approval of the article: J.E. Manson, A.K. Aragaki, S.S. Bassuk, R.T. Chlebowski, G.L. Anderson, J.E. Rossouw, B.V. Howard, C.A. Thomson, M.L. Stefanick, A.M. Kaunitz, C.J. Crandall, C.B. Eaton, V.W. Henderson, S. Liu, J. Luo, T. Rohan, A.H. Shadyab, G. Wells, J. Wactawski-Wende, R.L. Prentice.
Provision of study materials or patients: J.E. Manson, R.T. Chlebowski, B.V. Howard, C.A. Thomson, M.L. Stefanick, A.M. Kaunitz, C.B. Eaton, S. Liu, J. Wactawski-Wende.
Statistical expertise: A.K. Aragaki, G.L. Anderson, S. Liu, R.L. Prentice.
Obtaining of funding: J.E. Manson, R.T. Chlebowski, J.E. Rossouw, B.V. Howard, M.L. Stefanick, C.B. Eaton, J. Wactawski-Wende, R.L. Prentice.
Administrative, technical, or logistic support: J.E. Manson, A.K. Aragaki, R.T. Chlebowski, C.A. Thomson, J. Wactawski-Wende.
Collection and assembly of data: J.E. Manson, A.K. Aragaki, R.T. Chlebowski, B.V. Howard, M.L. Stefanick, C.B. Eaton, S. Liu, J. Wactawski-Wende, R.L. Prentice.
This article was published at Annals.org on 10 September 2019.
* For members of the WHI investigator team, see the Appendix.