Effect of Estrogen plus Progestin on Risk for Biliary Tract Surgery in Postmenopausal Women with Coronary Artery Disease: The Heart and Estrogen/progestin Replacement Study

2 October 2001 | Volume 135 Issue 7 | Pages 493-501

Background: Animal and observational epidemiologic studies have reported that estrogens may increase the risk for gallstones. No major clinical trials have examined the effect of estrogen plus progestin therapy in postmenopausal women on the risk for biliary tract surgery.

Objective: To determine the effect of estrogen plus progestin on the risk for biliary tract surgery in postmenopausal women with known coronary artery disease.

Design: Randomized, double-blind placebo-controlled trial of postmenopausal hormone therapy for coronary heart disease.

Setting: 20 U.S. clinical centers.

Participants: 2253 postmenopausal women with a gallbladder, 44 to 79 years of age at baseline, in the Heart and Estrogen/progestin Replacement Study (HERS).

Intervention: Conjugated equine estrogens, 0.625 mg, plus medroxyprogesterone acetate, 2.5 mg, daily in one tablet or identical placebo.

Measurements: Documented biliary tract surgery.

Results: A total of 147 women (7%) were hospitalized for biliary tract surgery in HERS. Treatment with estrogen plus progestin resulted in a marginally significant 38% increase in the relative risk for biliary tract surgery (P = 0.05). A small absolute difference in risk suggested that for every 185 women treated with estrogen plus progestin, one additional woman had biliary tract surgery per year. After adjustment for baseline and in-study statin use, the association was attenuated further (P = 0.09). After adjustment for treatment assignment and other variables, increased body mass index, fibric acid use, and a history of nonsurgical gallbladder disease were associated with an increased risk for biliary tract surgery, whereas statin use was associated with a decreased risk (for each comparison, P < 0.05).

Conclusion: Estrogen plus progestin therapy among postmenopausal women with known coronary disease resulted in a marginally significant increase in the risk for biliary tract surgery.

Author and Article Information

From Veterans Affairs Medical Center, San Francisco, and University of California, San Francisco, School of Medicine, San Francisco, California; Burns and Allen Research Institute, Cedars-Sinai Medical Center, Los Angeles, California; University of Minnesota School of Medicine, Minneapolis, Minnesota; Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania; and Wyeth-Ayerst Research, Radnor, Pennsylvania.

Disclosures: Dr. Picker is a full-time salaried employee of Wyeth-Ayerst Research; all other authors received research support (for most authors, specifically for work on the HERS trial) from Wyeth-Ayerst Research. Dr. Agarwal is a speaker for Wyeth-Ayerst Research and for Pfizer, Inc. Dr. Simon has received donations (for research on vitamin C) from Roche Vitamins, Inc., and is a member of the scientific advisory committee to the California Walnut Marketing Board. Dr. Cauley has received research support from Roche Pharmaceuticals, honoraria from Proctor & Gamble, and both research support and honoraria from Eli Lilly and Co. and Merck & Co., Inc.

Acknowledgments: The authors thank Josephine Fong, MS, for help with the initial data analyses and Eric Vittinghoff, PhD, for assistance in developing the statistical approaches used in the final analyses.

Grant Support: By Wyeth-Ayerst Laboratories.

Requests for Single Reprints: Joel A. Simon, MD, MPH, General Internal Medicine Section (111A1), San Francisco Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, California 94121; e-mail, jasimon{at}itsa.ucsf.edu.

Current Author Addresses: Dr. Simon: General Internal Medicine Section (111A1), Medical Service, Veterans Affairs Medical Center, San Francisco, CA 94121.

Dr. Hunninghake: Heart Disease Prevention Clinic, Box 192, 151 Variety Club Heart and Research Center, 401 East River Parkway, Minneapolis, MN 55455.

Dr. Agarwal: Department of Obstetrics and Gynecology, Burns and Allen Research Institute, Cedars-Sinai Medical Center, 8635 West 3rd Street, Suite 160, Los Angeles, CA 90048.

Ms. Lin and Ms. Ireland: Prevention Sciences Group, Department of Epidemiology and Biostatistics, School of Medicine, University of California, San Francisco, 74 New Montgomery Street, Suite 600, San Francisco, CA 94105.

Dr. Cauley: Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, 130 DeSoto Street, Pittsburgh, PA 15261.

Dr. Pickar: Wyeth-Ayerst Research, Box 42528, Philadelphia, PA 19101.

Author Contributions: Conception and design: J.A. Simon.

Analysis and interpretation of the data: J.A. Simon, D.B. Hunninghake, S.K. Agarwal, J.H. Pickar.

Drafting of the article: J.A. Simon, D.B. Hunninghake, S.K. Agarwal, J.H. Pickar.

Critical revision of the article for important intellectual content: J.A. Simon, S.K. Agarwal, J.A. Cauley, C.C. Ireland.

Final approval of the article: J.A. Simon, D.B. Hunninghake, F. Lin, J.A. Cauley.

Provision of study materials or patients: D.B. Hunninghake, S.K. Agarwal.

Statistical expertise: F. Lin.

Administrative, technical, or logistic support: C.C. Ireland.

Collection and assembly of data: S.K. Agarwal, J.A. Cauley.