Effects of estrogen and estrogen-progestin on mammographic parenchymal density. Postmenopausal Estrogen/Progestin Interventions (PEPI) Investigators.

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.