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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, for the Postmenopausal Estrogen/Progestin Interventions (PEPI) Investigators*
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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.

Ann Intern Med. 1999;130(4_Part_1):262-268. doi:10.7326/0003-4819-130-4_Part_1-199902160-00003
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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.


Grahic Jump Location
Diagram of the Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial mammographic density study showing numbers of and reasons for exclusions.

HRT = hormone replacement therapy.

Grahic Jump Location




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