Relationship Between Estrogen Levels, Use of Hormone Replacement Therapy, and Breast Cancer

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Abstract
We sought to determine the strength of the evidence suggesting that estrogen and postmenopausal replacement hormones play a role in the development of breast cancer. We reviewed the existing English language literature in MEDLINE® on hormones and breast cancer, including reports on cell proliferation and endogenous hormone levels, as well as epidemiologic studies of the relationship between the use of postmenopausal hormones and the risk of breast cancer in women. A factor that increases the probability that cancer will develop in an individual has been defined as a cancer cause. The Hill criteria for demonstrating a link between environmental factors and disease were used to review the evidence for a causal relationship between female hormones and breast cancer. We found evidence of a causal relationship between these hormones and breast cancer, based on the following criteria: consistency, dose-response pattern, biologic plausibility, temporality, strength of association, and coherence. The magnitude of the increase in breast cancer risk per year of hormone use is comparable to that associated with delaying menopause by a year. The positive relationship between endogenous hormone levels in postmenopausal women and risk of breast cancer supports a biologic mechanism for the relationship between use of hormones and increased risk of this disease. The finding that the increase in risk of breast cancer associated with increasing duration of hormone use does not vary substantially across studies offers further evidence for a causal relationship. We conclude that existing evidence supports a causal relationship between use of estrogens and progestins, levels of endogenous estrogens, and breast cancer incidence in postmenopausal women. Hormones may act to promote the late stages of carcinogenesis among postmenopausal women and to facilitate the proliferation of malignant cells. Strategies that do not cause breast cancer are urgently needed for the relief of menopausal symptoms and the long-term prevention of osteoporosis and heart disease. [J Natl Cancer Inst 1998;90:814–23]