Controversial issues in climacteric medicine II. Hormone replacement therapy and cancer. International Menopause Society Expert Workshop. 9-12 June 2001, Opera del Duomo, Pisa, Italy.
Sex steroids are not known to damage DNA directly. They can stimulate or inhibit cell proliferation, and thus can modulate tumor developmental progression. Sex steroid-related tumors in women are represented by breast cancer and endometrial cancer, and a possible relationship exists between sex steroids and both ovarian and colon cancer. Among current ERT users or those who stopped use 1-4 years previously, the relative risk of having breast cancer diagnosed increases by a factor of 1.023 for each year of hormone use. This increase is comparable with the effect on breast cancer of delaying menopause, and seems to be largely limited to lean women. The breast cancers diagnosed during ERT are more likely to contain ER and are less aggressive. Some reports indicate no increase in breast cancer mortality in HRT users. Recent data suggest that an estrogen-progestin regimen may increase breast cancer risk beyond that associated with estrogen alone. However, the effect of progestogens on the breast awaits further clarification. ERT/HRT is generally considered to be contraindicated in breast cancer patients, as no firm data are yet available from randomized clinical trials. Despite the potential risks, ERT/HRT could be considered for breast cancer patients suffering from menopausal symptoms resistant to alternative treatments, after completely informed consent is given, particularly in women with ER--(hormone-resistant) cancers. Unopposed estrogen therapy is known to increase endometrial cancer risk, and is appropriate only for hysterectomized women. To negate the excess risk of endometrial hyperstimulation, an adequate progestin dose must be given in a continuous combined regimen or for an appropriate number of days in sequential regimens (10 days or more for some progestogens or 12 days or more for other progestogens). An appropriate combination of estrogen and progestin does not appear to increase, and may even decrease, the risk of endometrial cancer. HRT is generally considered to be contraindicated in endometrial cancer patients. Despite the potential risks, HRT could be considered for patients suffering from menopausal symptoms resistant to alternative treatments, after completely informed consent is given. Available data suggest a reduced risk of colorectal adenoma and colon cancer in current users of HRT, but definitive studies are still needed. There is no contraindication to HRT prescription in colon cancer survivors. Consistent epidemiological data describe a decreased incidence of ovarian cancer with oral contraceptive use during the reproductive years. Studies on HRT and risk of epithelial ovarian cancer have produced conflicting results but most data seem to exclude a strong association. While no data contraindicate HRT use in epithelial ovarian cancer survivors, current studies do not allow us to exclude the possibility that estrogens alone could stimulate ovarian cancer growth in a small fraction of patients. Additional studies are required. It is important to consider that not all estrogens and progestins are used with the same dosage, route of administration (oral, transdermal and for estradiol intranasal) and, mostly, different estrogens do not show the same bioavailability and tissue effects. The available data do not allow to discriminate for all these variables and therefore it is inappropriate to consider jointly all forms of hormonal therapy. This issue is considered as an important area for future evaluation and research. The International Menopause Society is in the process of drawing up specific recommendations for further research in the field of HRT and cancer.
Genazzani
A R
AR
Department of Gynecology and Obstetrics, University of Pisa, Via Roma 35, 56126 Italy.
Gadducci
A
A
Gambacciani
M
M
D001943:Breast Neoplasms / Q000139:chemically induced; D003110:Colonic Neoplasms / Q000139:chemically induced; D016889:Endometrial Neoplasms / Q000139:chemically induced; D015914:Estrogen Replacement Therapy / Q000009:adverse effects*; D005260:Female; D006801:Humans; D008545:Melanoma / Q000139:chemically induced; D008593:Menopause; D009369:Neoplasms / Q000139:chemically induced*; D010051:Ovarian Neoplasms / Q000139:chemically induced; D012878:Skin Neoplasms / Q000139:chemically induced