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Therapy with estrogens should be administered cautiously in patients with preexisting hypercalcemia, renal dysfunction, or metabolic bone diseases that are associated with hypercalcemia. High dosages of estrogens may be used for the palliative treatment of inoperable, metastatic breast cancer, but only in appropriately selected men and postmenopausal women. Patients with diabetes mellitus should be monitored more closely during therapy with estrogens and/or progestogens, and adjustments made accordingly in their antidiabetic regimen. Moreover, estrogens (and also progestogens) may elevate blood pressure and worsen the hypertension, thus compounding the risk. In addition, noncontraceptive use of estrogens in young women (particularly smokers) may substantially increase the risk of nonfatal myocardial infarction. Estrogens should be avoided in patients with a history of thrombotic and thromboembolic disorders associated with estrogen use, except when used in the treatment of breast or prostatic malignancy. A hematologic concern has been the risk of thromboembolism associated with exogenous estrogens. Therapy with estrogens should be administered cautiously in patients with liver disease. In addition, exogenous estrogens may exert cardioprotective effects by causing favorable changes in lipid profiles. The Toronto Breast Cancer Study has reported that women who receive unopposed conjugated estrogens for less than 15 years are not at increased risk of breast cancer. In addition, estrogens have increased the size of preexisting uterine leiomyomata. A large study (n = 16,608 postmenopausal women) of conjugated equine estrogens and medroxyprogesterone was terminated in 2002 due to the increased risk of coronary heart disease, stroke, and pulmonary embolism. Because the dose of exogenous estrogens is low in most commercially available preparations, the risk of thromboembolism is minimal for most women. Hematologic side effects have included the risk of thromboembolism that is associated with the use of exogenous estrogens. CardiovascularThe manufacturer recommends close observation if conjugated estrogens must be used in patients who may be particularly sensitive to fluid retention because of underlying asthma, epilepsy, migraine, heart disease, and renal dysfunction. In addition, combinations of high-dose conjugated estrogens and progestin have been reported to increase ventilation and increase the hypoxic ventilatory response. In that study, an increase in the risk of breast cancer for women who used conjugated estrogens for more than 15 years was not ruled out. Exogenous estrogens may exert cardioprotective effects due to favorable changes in lipid profiles, however, beneficial effects may be partially or completely offset by alterations in lipid profiles induced by exogenous progestins. While the role of progestogens in the development of thromboembolic events associated with hormonal therapy is often unclear and thought to be secondary to that of estrogens, it may not be insignificant. However, the estrogens in oral contraceptive combinations exert opposing effects. The increased risk of breast cancer due to use of estrogens is controversial. Increased sulfobromophthalein retention has been reported with the use of estrogen-containing oral contraceptives and may be expected with larger doses of estrogens. CardiovascularThe reported effects of estrogens on cardiovascular activity are variable. Therapy with estrogens should be administered cautiously in patients with preexisting hypertension.


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