Correspondence to: Lewis H. Kuller, M.D., Dr.P.H., Department of Epidemiology, University of Pittsburgh, 130 DeSoto Ave., Rm. A527, Crabtree Hall, Pittsburgh, PA 15261 (e-mail: kuller{at}pitt.edu).
The report by Ross et al. (1) in the February 16, 2000, issue of the Journal concludes that a combination of estrogen and progestin increases the risk of breast cancer over time when compared with estrogen alone. A similar conclusion was recently reported in a paper in the Journal of the American Medical Association by Schairer et al. (2). There is little question that hormone therapy, either estrogen or estrogen/progestin, is associated with an increased risk of breast cancer especially with long-term use (3). However, papers contrasting estrogen therapy with estrogen/progestin therapy have a serious use bias.
When comparing estrogens alone versus estrogen/progestin, the use indication for either therapy must be similar. Estrogen therapy alone is used for women who have had an artificial menopause (i.e., removal of the ovaries and uterus). Such women may be at a lower baseline risk of breast cancer for the following reasons: 1) Because of the oophorectomy and the resulting decreased estrogen levels, these women may remain at a lower risk until the time they are placed on hormone therapy; and 2) the reasons for the hysterectomy or oophorectomy, including aberrant menstrual cycles and/or decreased ovarian function during their premenopausal years place these women at lower risk for postmenopausal breast cancer.
Women on estrogen/progestin usually have an intact uterus, have started on hormone therapy after naturally becoming menopausal, and may be at higher background risk of breast cancer than women who were placed on estrogen therapy alone. Women on estrogen/progestin therapy tend to be better educated, may be older at first pregnancy, and are less likely to be premenopausally obese.
A proper comparison is the relative and absolute risks of breast cancer between estrogen users and control women, i.e., hysterectomy and/or oophorectomy, and women with an intact uterus who are on combination estrogen/progestin versus those with an intact uterus who are not on therapy. The most important comparison is absolute risk and relative risk by duration of exposure in the four arms. Adjustment for oophorectomy or hysterectomy is unlikely to be successful, since very few women would be on long-term estrogen use with an intact uterus. Furthermore, such women must have a unique characteristiceither they do not adhere to the estrogen therapy or they have characteristics that result in either lower estrogen levels or a lack of tissue sensitivity (i.e., they do not develop uterine hyperplasia on long-term estrogen therapy).
The papers in the Journal and the Journal of the American Medical Association have, unfortunately, generated a great deal of interest in the media and, possibly, in the interpretation that estrogens alone are safer than estrogen/progestin (4). This interpretation may be the case but, certainly, the data to date do not support this conclusion. The results from the Women's Health Initiative, especially the long-term follow-up, including women on estrogen, estrogen/progestin, and placebo therapy will probably provide the only data to test the hypothesis of the risks and benefits of estrogen or estrogen/progestin therapy.
REFERENCES
1
Ross RK, Paganini-Hill A, Wan PC, Pike MC. Effect of hormone replacement therapy on breast cancer risk: estrogen versus estrogen plus progestin. J Natl Cancer Inst 2000;92:32832.
2
Schairer C, Lubin J, Troisi R, Sturgeon S, Brinton L, Hoover R. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA 2000;283:48591.
3 Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52 705 women with breast cancer and 108 411 women without breast cancer. Lancet 1997;350:104759.[Medline]
4
Willett WC, Colditz G, Stampfer M. Postmenopausal estrogensopposed, unopposed, or none of the above [editorial]. JAMA 2000;283:5345.
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