Effects of Estrogen and Estrogen–Progestin on Mammographic Parenchymal Density

Effects of Estrogen and Estrogen–Progestin on Mammographic Parenchymal Density

Gail A. Greendale, MD;
Beth A. Reboussin, PhD;
Angela Sie, MD;
H. Rosy Singh, MD;
Linda K. Olson, MD;
Olga Gatewood, MD;
Lawrence W. Bassett, MD;
Carol Wasilauskas, RN, MS;
Trudy Bush, PhD;
Elizabeth Barrett-Connor, MD; and
for the Postmenopausal Estrogen/Progestin Interventions (PEPI) Investigators*

From University of California, Los Angeles, School of Medicine, Los Angeles, California; Wake Forest School of Medicine, Winston-Salem, North Carolina; Johns Hopkins University and University of Maryland Medical School, Baltimore, Maryland; and University of California at San Diego, San Diego, California.

Abstract

Background: In longitudinal studies, greater mammographic density is associated with an increased risk for breast cancer.

Objective: To assess differences between placebo, estrogen, and three estrogen–progestin regimens on change in mammographic density.

Design: Subset analysis of a 3-year, multicenter, double-blind, randomized, placebo-controlled trial.

Setting: Seven ambulatory study centers.

Participants: 307 of the 875 women in the Postmenopausal Estrogen/Progestin Interventions Trial. Participants had a baseline mammogram and at least one follow-up mammogram available, adhered to treatment, had not taken estrogen for at least 5 years before baseline, and did not have breast implants.

Intervention: Treatments were placebo, conjugated equine estrogens (CEE), CEE plus cyclic medroxyprogesterone acetate (MPA), CEE plus daily MPA, and CEE plus cyclic micronized progesterone (MP).

Measurements: Change in radiographic density (according to American College of Radiology Breast Imaging Reporting and Data System grades) on mammography.

Results: Almost all increases in mammographic density occurred within the first year. At 12 months, the percentage of women with density grade increases was 0% (95% CI, 0.0% to 4.6%) in the placebo group, 3.5% (CI, 1.0% to 12.0%) in the CEE group, 23.5% (CI, 11.9% to 35.1%) in the CEE plus cyclic MPA group, 19.4% (CI, 9.9% to 28.9%) in the CEE plus daily MPA group, and 16.4% (CI, 6.6% to 26.2%) in the CEE plus cyclic MP group. At 12 months, the odds of an increase in mammographic density were 13.1 (95% CI, 2.4 to 73.3) with CEE plus cyclic MPA, 9.0 (CI, 1.6 to 50.1) with CEE plus daily MPA, and 7.2 (CI, 1.3 to 40.0) with CEE plus cyclic micronized progesterone compared with CEE alone.

Conclusions: Further study of the magnitude and meaning of increased mammographic density due to use of estrogen and estrogen–progestins is warranted because mammographic density may be a marker for risk for breast cancer.

*For a partial list of the PEPI Investigators, see Appendix.

Article and Author Information

Grant Support: The PEPI Trial is supported by cooperative agreement research grants U01-HL40154, U01-HL40185, UL-HL40195, U01-HL40205, U01-HL40207, U01-HL40231, U01-HL40232, and U01-HL40273 from the National Heart, Lung, and Blood Institute; the National Institute of Child Health and Human Development; the National Institute of Arthritis and Musculoskeletal and Skin Diseases; the National Institute of Diabetes and Digestive and Kidney Diseases; and the National Institute on Aging. Packaged medication and placebos were provided by Wyeth-Ayerst Laboratories, the Schering-Plough Research Institute, and the Upjohn Company. For this work, Dr. Greendale was supported by the Iris Cantor-UCLA Women's Center and the UCLA Center of Excellence in Women's Health (PHS 282-97-0025).
Requests for Reprints: Gail A. Greendale, MD, Division of Geriatrics, University of California, Los Angeles, School of Medicine, 10945 Le Conte Avenue, Suite 2339, Los Angeles, CA 90095-1687.
Current Author Addresses: Dr. Greendale: Division of Geriatrics, University of California, Los Angeles, School of Medicine, 10945 Le Conte Avenue, Suite 2339, Los Angeles, CA 90095-1687.
Dr. Reboussin and Ms. Wasilauskas: Department of Public Health Sciences, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1063.
Dr. Sie: Radia Medical Imaging, 1632 116th Avenue, NE, Suite D, Bellevue, WA 98004-3035.
Dr. Singh: Advanced Radiology, 7253 Ambassador Road, Baltimore, MD 21244-2714.
Dr. Olson: Radiology Department, University of California, San Diego, Medical Center-Hillcrest, 200 West Arbor Drive, San Diego, CA 92103-8756.
Dr. Gatewood: Radiology and Radiological Science, Johns Hopkins University School of Medicine, 600 North Wolfe Street, Baltimore, MD 21287-5999.
Dr. Bassett: Radiological Sciences, University of California, Los Angeles, BL-428 CHS, Box 951721, Los Angeles, CA 90095-1721.
Dr. Bush: Department of Epidemiology and Preventive Medicine, University of Maryland Medical School, Howard Hall, Room 133, 660 West Redwood Street, Baltimore, MD 21201-1596.
Dr. Barrett-Connor: Department of Family and Preventive Medicine, University of California, San Diego, Clinical Science Building, Room 347, 0628, 9500 Gilman Drive, La Jolla, CA 92093-0628.