Hormone Replacement Therapy With Estrogen or Estrogen Plus Medroxyprogesterone Acetate Is Associated With Increased Epithelial Proliferation in the Normal Postmenopausal Breast

摘要

Despite its many clinical benefits, including a diminished risk of coronary artery disease, hormone replacement therapy (HRT) may increase the risk of breast cancer. Whether estrogen, progestin, or both serve to promote proliferative changes in the breast epithelium remains unclear. This cross-sectional observational study examined the proliferative effects of HRT using estrogen alone or combined with the progestin medroxyprogesterone acetate (MPA) in 86 postmenopausal women having surgical breast biopsy. All had been amenorrheic for 12 consecutive months, undergone bilateral ovariectomy at least 1 year earlier or who were 55 years of age or older. Hormones, taken daily, included conjugated equine estrogens (CEEs), micronized estradiol, and ethinyl estradiol. MPA was taken in a dose of 2.5 to 5 mg in conjunction with CEE or micronized estradiol. Biopsy specimens were examined immunohistochemically in a double-blinded manner using antindash;proliferative cell nuclear antigen (anti-PCNA) and Ki67 antibodies, which detect different proteins present in cycling cells.The PCNA index was significantly higher in women taking estrogen (E) alone or combined estrogen/progestin (E plus; P) HRT than in the no-HRT group (Fig. 1). In the E plus; P group, changes were most marked in the terminal duct-lobular unit (TDLU). Comparable results were obtained using Ki67 antibody, except that the E-alone and no-HRT groups did not differ significantly. PCNA indices correlated with the duration of either form of HRT, although not to a statistically significant degree. Epithelial-cell density was significantly greater in women given HRT of either type and was greatest in the E plus; P group. Lobules were relatively large and less compact in this group and the acini had larger lumens, similar to what is seen during the luteal phase in cycling women. Progesterone receptorndash;positive cells were 3-fold more frequent in ducts and TDLU of the E-alone group than in the no-HRT group. The addition of progestin lowered progesterone receptor levels. Estrogen receptorndash;positive cells were similarly frequent in all groups.Fig. 1. Epithelial proliferation indices in normal breast tissue of postmenopausal women and cycling premenopausal women. The number under each bar represents the number of individuals for whom ducts or TDLU could be analyzed. ast;, P equals; .002ndash;.0001 that the percentages of PCNA- (A) and Ki67- (B) positive cells in the TDLU of the E plus; P group were significantly greater than in TDLU of no-HRT or E-alone groups; dagger;, P equals; .007ndash;.002 that the percentages of PCNA-positive cells in the TDLU or ducts of the E group or ducts of the E plus; P group were significantly greater than in the TDLU or ducts of the no-HRT group; Dagger;, P .05 that the percentages of PCNA- and Ki67-positive cells in the TDLU of the luteal-phase group were significantly greater than in the TDLU of the follicular-phase group; sect;, P .05 that the percentages of PCNA- and Ki67-positive cells were greater in TDLU than in the ducts of the same group. Used with permission. Hofseth LJ et al. J Clin Endocrinol Metab 1999;84colon;4559ndash;4565. copy; The Endocrine Society.Combined estrogen/progestin HRT is associated with increased epithelial-cell proliferation in the TDLU of the postmenopausal breast, and there is evidence that more marked changes accompany longer-term treatment. It is possible that different progestins have disparate effects on breast tissue.J Clin Endocrinol Metab 1999;84colon;4559ndash;4565