In 1975, two published case-control studies showed an increased occurrence of endometrial cancer in postmenopausal women taking estrogens65,66 (see Chap. 223). The occurrence of endometrial cancer appeared to be not only dose related but also duration related. It was possible to identify the estrogen-endometrial cancer relationship because the latency period between initial estrogen ingestion and the onset of the endometrial cancer was as short as 2 years. Some studies have suggested that after the estrogens are discontinued, the added risk disappears within 6 months. Estrogens seem to be associated with low-grade endometrial cancers; that is, although cancer is a frightening disease, perhaps prescribing estrogens does not increase the endometrial cancer mortality rate in women. Successful treatment, however, may require hysterectomy and possibly radiation therapy.67

It remained a paradox for a long time why older women given low-dose estrogens should develop endometrial cancer while younger women who are producing greater endogenous estrogen during pregnancy or taking high-estrogen birth control pills do not develop the disease. The explanation appears to be that the estrogens initially were given to postmenopausal women in an unopposed fashion, that is, without progesterone. This speculation led investigators to add a progestin to the prescribed estrogens given to older women, which lowered the incidence of endometrial cancer and of endometrial hyperplasia (considered a precursor of endometrial cancer). The progestins, used for at least 10 days a month within the estrogen regimen, may act by decreasing the estrogen receptors as well as by converting estradiol to estrone, which is a less potent estrogen.68

Breast cancer, which affects >10% of women in the United States, is a much more serious disease than endometrial cancer. Besides being common, breast cancer has a high mortality rate. This disease is frequently disfiguring and emotionally very disturbing. Whether estrogens actually cause breast cancer is presently unknown. Although some studies have found no increased risk of breast cancer.69 Other large studies found excess risk among long-term users.70 This observation was confirmed by the Nurses’ Health Study, which analyzed 1935 cases of breast cancer prospectively seen during 725,000 person-years of observation.71 They found that the risk of death due to breast cancer in women who had taken estrogen for five or more years was increased 45%. Other studies are in agreement.71a This conclusion is consistent with available animal data suggesting that breast cancer can be induced with high-dose estrogens (see Chap. 222). Also, estrogens can maintain breast tumor growth in tissue culture. They also found that the addition of a progestin to estrogen treatment did not influence the increased risk of breast cancer seen with long-term estrogen use.71 Interestingly, hormone replacement therapy reduces the sensitivity of mammography.71b