Relationship between Exogenous Hormones (HRT), Breast Density and Cancer Risk
HRT, Hormone Replacement Therapy, (estrogen and a progestogen) slows normal breast involution and causes and increase in mammographic density.1-3The increase in density is most commonly diffuse but may be focal or multifocal.4,5Estrogen combined with a progestin has a greater association with breast density than the use of estrogen alone.6-9An increase in breast density is also more commonly observed with continuous use of combined HRT, where both estrogen and a progestin are taken daily, rather than cyclic HRT, where estrogen is used daily but the progestin is only used a part of the month to mimic the menstrual cycle.6-9In addition, the proliferation in women using estrogen and a progestin is localized to the terminal duct lobular unit, which is the site of the development of most breast cancers.10
It is generally agreed that the use of HRT is responsible for an increased breast density and thereby an increased risk of breast cancer. Authors of three large cohort studies have demonstrated a greater breast cancer risk with the use of HRT (estrogen and a progestin) than with the use of estrogen alone (ERT).11-13The estrogen plus progestin arm of the arm of the Women’s Health Initiative (WHI) was halted before study completion because of the increased risk of breast cancer.14Another arm of the WHI compared placebo with conjugated equine estrogen alone in women who undergone a total abdominal hysterectomy. In the 11.8 year follow up of the Estrogen alone trial (seven years of estrogen alone and 4.8 years of subsequent observation) a paradoxical reduction in breast cancer risk reached statistical significance in the total group (RR 0.77, CI 0.62 to 0.95). The protective effect was confined to those without a family history of breast cancer or benign breast disease.15,16
The observational trials reporting an increased risk of breast cancer with long-term use of estrogen alone and the WHI study reporting a reduced risk would seem paradoxical.16-18Data from the Nurses’ Health study suggests that the increased risk only occurs in women using estrogen alone for more than 10 years, particularly in lean women.17,18Comparison of short term estrogen use, which may decrease breast cancer risk by 30% with long-term administration for 10 to 20 years which appears to increase the risk 41 to 77%, suggests an estrogen paradox.17,18An explanation of the estrogen paradox is that estradiol can exert two separate mechanistic effects based on timing: estradiol induced apoptosis short-termand the initiation and promotion of new cancers long-term. Studies have demonstrated that estradiol can induce apoptosis in breast tumors that have been deprived of estradiol over a prolonged period.18,19
Thus, this apparent paradox may be explained: At entry to the WHI estrogen alone study, the average age of the women was 63, 12 years beyond the average age of menopause. Accordingly, women who had never previously taken hormone therapy were in a state of long-term estradiol deprivation, 12 years on average. If these patients had occult undiagnosed tumors estrogen alone may have caused apoptotic cell death in them.
When all of the confounding factors are taken into account the pooled observational data are relatively consistent and suggest that there is an increased risk of breast cancer in women taking estrogen and a progestin for over 5 years and women taking estrogen alone for 10 or more years.
- Kaufman, Z., Garstin, W., Hayes, R., et al. The mammographic parenchymal patterns of women on hormone replacement therapy. Clin Radiol. 1991; 43:389-392.
- Sterns, E. E., Zee B. mammographic density changes in perimenopausal women: is the effect of hormone replacement therapy predictable? Breast Cancer Res Treat2000; 59:125-132.
- Rutter, C. M., Mandelson, M. T., Laya, M. B., Taplin, S. Changes in breast density associated with initiation, discontinuation, and continuing use of hormone replacement therapy. JAMA;2001; 285:171-176.
- McNicholas, M. M., Heneghan, J. P., Milner, M. H., et al. Pain and increased mammographic density in women receiving hormone replacement therapy: a prospective study. AJR Am J Roentgenol. 1994; 163:311-315.
- Stomper, P. C., VanVoorhis, B. J., Ravnikar, V. A., et al. Mammographic changes associated with postmenopausal hormone replacement therapy: a longitudinal study. Radiology. 1990, 174:487-490.
- Berkowitz, J. E., Gatewood, O. M., Goldblum, L. E., Gayler, B. W. hormonal replacement therapy: mammographic manifestations. Radiology. 1990; 174:199-201.
- Persson E. B., Thurfjell, E., Holmberg L. Effect of estrogen and estrogen-progestin replacement regimens on mammographic breast parenchymal density. J Clin Oncol. 1997; 15:3201-3207.
- Laya, M. B., Gallagher, J. C., Schreiman J S., et al. Effect of postmenopausal hormone replacement therapy on mammographic density and parenchymal pattern. Radiology1995; 196:433-437
- Greendale, G. A., Reboussin, B. A. Sie, A., et al. Effects of estrogen and estrogen-progestin on mammographic parenchymal. Ann Internal Med.1999; 130:262-269.
- Hofseth, L. J., Raafat, A. M., Osuch, J. R., et al. hormone replacement therapy with estrogen or estrogen plus medroxyprogesterone acetate is associated with increased epithelial proliferation in the normal postmenopausal breast. J Clin Endocrinol Metab.1999; 84:4559-4565.
- Schairer, C., Lubin, J., Trosi, R., et al. Menopausal estrogen and estrogen-progestin replacement therapy and breast cancer risk. JAMA2000; 283:485-491.
- Persson, I., Welderpass, E., Bergkvist, I., et al. Risks of breast and endometrial cancer after estrogen and estrogen-progestin replacement. Cancer Causes Control1999; 10:253-260.
- Ross, R. K., Paganini-Hill, A, Wan, P. C., Pike, M. C. Effect of hormone replacement therapy on breast cancer risk: estrogen vs. estrogen plus Progestin. J Natl Cancer Inst2000; 92:328-332.
- Rossouw, J. E., Anderson, G. L., Prentice, R. I., et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA2002; 288:321-333.
- Stefanick, M. L., Anderson G. L., Margolis, K. L., et al. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA2006; 295(14):1647-1657.
- Anderson, G. L., Chlebowski, R. t., Aragaki, A. K., et al. conjugated equine estrogens and breast cancer incidence and mortality in postmenopausal women with hysterectomy: extended follow-up of the Women’s Health Initiative randomized placebo controlled trial. Lancet Oncology. 2012; 13(5):476-486.
- Chen, W.Y., Manson J. E., Hankinson, S. E., et al. Unopposed estrogen therapy and the risk of invasive breast cancer. Archives of Internal Medicine. 2006; 166(9): 1027-1032.
- Chen W. Y., et al. Estrogen alone long term nurses health study. Abstract. 2012.
- Song, R. X., Mor, G., Naftolin, F., et al. Effect of long term estrogen deprivation on apoptotic responses of breast cancer cells to 17 beta estradiol. Journal of the National Cancer Institute.2001; 93(22):1714-1723.
- Lewis, S. J., Osipo, C., Meeke, K., Jordan, V.C. Estrogen induced apoptosis in a breast cancer model resistant to long term estrogen withdrawal. Journal of Steroid Chemistry and Molecular Biology. 2005; 94(1-3):131-141.