Special Warnings: General: Combined Estrogen and Progestin Therapy: There are additional and/or increased risks that may be associated with the use of combination estrogen-plus-progestin therapy compared with using estrogen-alone regimens. These include an increased risk of myocardial infarction, pulmonary embolism, invasive breast cancer and ovarian cancer.
Cardiovascular risk: ET has been reported to increase the risk of stroke and deep venous thrombosis (DVT).
Patients who have risk factors for thrombotic disorders should be kept under careful observation.
Patients who are at risk of developing migraines with aura may be at risk of ischemic stroke and should be kept under careful observation.
Stroke: In the WHI estrogen-alone-substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving daily CE (0.625 mg) compared to women receiving placebo (45 vs. 33 per 10,000 women-years). The increase in risk was demonstrated in year one and persisted.
Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving CE (0.625 mg) versus those receiving placebo (18 versus 21 per 10,000 women-years).
Should a stroke occur or be suspected, estrogens should be discontinued immediately (see Pharmacology: Pharmacodynamics under Actions).
Venous thromboembolism (VTE): In the estrogen-alone substudy of WHI, the increased risk of deep venous thrombosis (DVT) was reported to be statistically significant (23 vs. 15 per 10,000 person-years). The risk of pulmonary embolism (PE) was reported to be increased, although it did not reach statistical significance. The increase in venous thromboembolism (VTE,DVT and PE) risk was demonstrated during the first two years (30 vs. 22 per 10,000 person-years).
Should a VTE occur or be suspected, estrogens should be discontinued immediately (see Pharmacology: Pharmacodynamics under Actions).
If visual abnormalities develop, discontinue estrogens pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine. If examination reveals papilledema or retinal vascular lesions, estrogens should be withdrawn. Retinal vascular thrombosis has been reported in patients receiving estrogens with or without progestins.
If feasible, estrogens should be discontinued at least four to six weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.
Malignant Neoplasms: Endometrial cancer: The use of unopposed estrogens in women with an intact uterus has been associated with an increased risk of endometrial cancer (see Pharmacology: Pharmacodynamics under Actions and Exacerbation of other conditions as follows).
The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-fold greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for 5 to 10 years or more, and this risk has been shown to persist for at least 8 to 15 years after ET is discontinued. Adding a progestin to post-menopausal estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer (see General as previously mentioned).
Clinical surveillance of all women taking estrogen or estrogen-plus-progestin combinations is important. Adequate diagnostic measures should be undertaken to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal uterine bleeding.
Breast Cancer: Studies involving the use of estrogens by post-menopausal women have reported inconsistent results on the risk of breast cancer. The most important randomized clinical trial providing information about this issue is the Women's Health Initiative (WHI) (see Pharmacology: Pharmacodynamics under Actions). In the estrogen-alone substudy of WHI, after an average of 7.1 years of follow-up, CE (0.625 mg daily) was not associated with an increased risk of invasive breast cancer.
Some observational studies have reported an increased risk of breast cancer for estrogen-alone therapy after several years of use. The risk increased with duration of use, and appeared to return to baseline within approximately five years after stopping treatment (only the observational studies have substantial data on risk after stopping).
The use of estrogen has been reported to result in an increase in abnormal mammograms requiring further evaluation.
Ovarian cancer: In some epidemiologic studies, the use of estrogen therapy has been associated with an increased risk of ovarian cancer over multiple years of use. Other epidemiologic studies have not found these associations.
Dementia: The estrogen-alone arm of the Women's Health Initiative Memory Study (WHIMS), an ancillary study of WHI that enrolled post-menopausal women between the ages of 65-79 reported a relative risk (HR) of probable dementia for conjugated estrogens alone versus placebo of 1.49 [HR 1.49 (95% CI 0.83-2.66)] (see Pharmacology: Pharmacodynamics under Actions).
It is unknown whether these findings apply to younger post-menopausal women.
Gallbladder Disease: A 2 to 4-fold increase in the risk of gallbladder disease requiring surgery in women receiving ET has been reported.
Hypercalcemia: Administration of estrogens may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If this occurs, the drug should be stopped and appropriate measures taken to reduce the serum calcium level.
Palliative therapy in men: Large doses of estrogen (5 mg conjugated estrogens per day), comparable to those used to treat cancer of the prostate and breast, have been shown in a large prospective clinical trial in men to increase the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis.
Immune System: Angioedema: Exogeneous estrogens may induce or exacerbate symptoms of angioedema, particularly in patients with hereditary angioedema.
Fluid retention: Because estrogens may cause some degree of fluid retention, patients with conditions, which might be influenced by this factor, such as cardiac or renal dysfunction, warrant careful observation when estrogens are prescribed.
Hypertriglyceridemia: In the Health and Osteoporosis, Progestin and Estrogen (HOPE) Study, the mean percent increases from baseline in serum triglycerides after one year of treatment with CE 0.625 mg, 0.45 mg 0.3 mg and placebo were 34.2, 30.2, 25.0, and 10.8, respectively.
Caution should be exercised in patients with pre-existing hypertriglyceridemia since rare cases of large increases of plasma triglycerides leading to pancreatitis have been reported with estrogen therapy in this population.
Impaired liver function and history of cholestatic jaundice: For patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised and in the case of recurrence, medication should be discontinued. Estrogens may be poorly metabolized in patients with impaired liver function.
Elevated blood pressure: In a small number of case reports, substantial increases in blood pressure during ET have been attributed to idiosyncratic reactions to estrogens. In a large, randomized, placebo-controlled clinical trial a generalized effect of ET on blood pressure was not seen.
Exacerbation of other conditions: Estrogen therapy may cause an exacerbation of asthma, epilepsy, migraine with or without aura, otosclerosis, porphyria, systemic lupus erythematosus, and hepatic hemangiomas, and should be used with caution in women with these conditions.
Endometriosis may be exacerbated with administration of estrogen therapy. A few cases of malignant transformation of residual endometrial implants have been reported in women treated post-hysterectomy with estrogen-alone therapy. For women known to have residual endometriosis post-hysterectomy, the addition of progestin should be considered.
Hypocalcemia: Estrogens should also be used with caution in individuals with disease that can predispose to severe hypocalcemia.
Hypothyroidism: Estrogen administration leads to increased thyroid-binding globulin (TBG) levels. Patients dependent on thyroid hormone therapy, who are receiving estrogens, may require increased doses of their thyroid replacement therapy. These women should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range (see Interactions).
Laboratory monitoring: Estrogen administration should be guided by clinical response rather than by hormone levels (e.g., estradiol, FSH).
Effects on Ability to Drive and Use Machines: No studies on the effect of ability to drive or use machines have been performed.