Estradiol Contraindications and Precautions

benzyl alcohol hypersensitivity
breast cancer
cervical cancer
endometrial cancer
endometrial hyperplasia
hepatic disease
hepatocellular cancer
hypercalcemia
intravenous administration
jaundice
myocardial infarction
neonates
ovarian cancer
pregnancy
stroke
thromboembolic disease
thrombophlebitis
uterine cancer
vaginal bleeding
vaginal cancer
asthma
breast-feeding
cardiac disease
cerebrovascular disease
children
contact lenses
coronary artery disease
dementia
depression
diabetes mellitus
elderly
endometriosis
gallbladder disease
hypercholesterolemia
hyperlipoproteinemia
hypertension
hypocalcemia
hypothyroidism
migraine
obesity
pancreatitis
porphyria
renal disease
seizure disorder
surgery
systemic lupus erythematosus (SLE)
thyroid disease
tobacco smoking
uterine leiomyomata

Estradiol Contraindications and Precautions

Certain intramuscular injections of estradiol cypionate or valerate contain benzyl alcohol, and would be contraindicated in those with benzyl alcohol hypersensitivity. Benzyl alcohol is associated with ‘gasping syndrome’ in neonates; there is no known indication for estradiol injections in premature infants. Other estradiol cypionate and valerate injections contain chlorobutanol, a chloral hydrate derivative.

Estradiol cypionate and estradiol valerate are esterified estrogens that are in oil-based injections and are contraindicated for intravenous administration. They are to be administered by the intramuscular route only.

Estrogens are generally contraindicated in patients with known, suspected, or history of breast cancer, except in those patients appropriate for palliative therapy. Estrogen and estrogen/progestin therapy in postmenopausal women has been associated with an increased risk of breast cancer. In the past, high-dose estrogen therapy was used in selected men and postmenopausal women with inoperable, progressive cancer of the breast, but this therapy is rarely used today. Since 1970, numerous epidemiological studies have examined the association of exogenous estrogen and breast cancer. Epidemiologic studies have reported an increased risk of breast cancer in association with increasing duration of postmenopausal treatment with estrogens, with or without progestin. This association was reanalyzed in original data from 51 studies that involved treatment with various doses and types of estrogens, with and without progestin. In the reanalysis, an increased risk of having breast cancer diagnosed became apparent after about 5 years of continued treatment, and subsided after treatment had been discontinued for about 5 years. Some later studies have suggested that treatment with estrogen and progestin increases the risk of breast cancer more than treatment with estrogen alone. In the estrogen-progestin sub-study of the WHI trial , there were more diagnoses of breast cancer in the HRT group compared to the placebo group, with a hazard ratio of 1.24. The breast cancers diagnosed in the HRT group had similar histology and grade to those found in the placebo group, but the women receiving HRT were more likely to be diagnosed with a more invasive cancer (hazard ratio 1.24) that was larger in size (1.7 cm HRT vs. 1.5 cm placebo), node positive (25.9% HRT vs. 15.8% placebo), and diagnosed at a more advanced stage (regional/metastatic 25.4% HRT vs. 16% placebo) compared to those who received placebo. The increased risk of breast cancer became apparent after 4 years on combined HRT. Women reporting prior postmenopausal use of estrogen and/or estrogen with progestin had a higher relative risk for breast cancer associated with combined HRT than those who had never used these hormones. In the estrogen-only sub-study of WHI, NO increased risk of breast cancer in estrogen-treated women compared to placebo was found, even in women who used estrogen replacement therapy for 25 years or longer. In addition to the associated increase risk of breast cancer, at least 1 abnormal mammogram was discovered in a total of 31.5% of women in the HRT group compared to 21.2% of placebo patients, with an absolute increase in abnormal mammograms of about 4% per year in women receiving HRT. Accordingly, after a thorough review of the available data, the World Health Organization International Agency for Research on Cancer (WHO IARC) has classified combined menopausal HRT as carcinogenic to humans; the agency indicates that the risk of breast cancer which is confined mostly to current or recent users increases with duration of use and is higher than the risk in women taking estrogen-only regimens. All women taking estrogen with or without a progestin should receive an annual clinical breast examination, perform monthly self-examinations, and have regular mammograms as recommended by their health care professional.

Estrogens are not recommended in patients with hypercalcemia associated with tumors or metabolic bone disease because estrogens influence the metabolism of calcium and phosphorus. In particular, severe hypercalcemia may occur in patients with breast cancer with bone metastases. If hypercalcemia occurs, the drug should be discontinued and measures taken to reduce the serum calcium level. Estrogens should also be used with caution in individuals with severe hypocalcemia.

Since 1970, at least 35 epidemiological studies have examined the association of exogenous estrogen and endometrial cancer in women with an intact uterus. These studies were summarized in a review published in 1992 of hormonal replacement therapy in postmenopausal women. The majority of these studies have shown an increased risk of endometrial cancer in women who have received exogenous estrogens without concomitant progestin. Histologic and clinical data, as well as limited epidemiologic data suggest that the addition of a progestin to estrogen therapy offsets the risk of endometrial carcinoma caused by exogenous estrogen. With concurrent progestin use, the incidence of endometrial hyperplasia due to estrogens is estimated to be 1% or less. The best available epidemiological evidence is from one case-control study that showed no increased risk for endometrial cancer when progestins were used with estrogen for at least 10 days/month. Accordingly, the WHO IARC has classified combined menopausal HRT as carcinogenic to humans when progestins are taken for < 10 days/month; the agency also indicates that when progestins are taken daily, the risk of endometrial cancer is similar to that in women who have never used hormonal therapy. Because of the risk of endometrial cancer, women taking exogenous estrogen who are experiencing persistent abnormal vaginal bleeding should receive adequate diagnostic tests to rule out malignancy. Estrogens are contraindicated in patients with preexisting endometrial hyperplasia.

Estrogens are relatively contraindicated in patients with uterine leiomyomata (fibroids) or endometriosis since they can exacerbate fibroid or endometrial growth. They are also contraindicated in the presence of vaginal cancer, cervical cancer, uterine cancer, or other estrogen-responsive tumors. Estrogens should not be administered to women with undiagnosed abnormal vaginal bleeding. Women experiencing persistent abnormal vaginal bleeding should receive adequate diagnostic tests to rule out malignancy before being prescribed estrogens. All women receiving estrogen treatment should have an annual pelvic examination which includes a Papanicolaou smear to screen for cervical dysplasia.

Estrogens are contraindicated in the presence of estrogen-responsive tumors. Use of estrogen-only products, in particular for 10 or more years, has been associated with an increased risk of ovarian cancer in some epidemiological studies. Other studies did not show a significant association. Data are insufficient to determine whether there is an increased risk with combined estrogen/progestin therapy in postmenopausal women.

Estrogens are contraindicated during pregnancy and are labeled FDA pregnancy risk category X. Increased risk of a wide variety of fetal abnormalities, including modified development of sexual organs, cardiovascular anomalies and limb defects, have been reported following the use of estrogens in pregnant women. In any patient in whom pregnancy is suspected, pregnancy should be ruled out before continuing estrogen use. There is no known approved indication for the use of these drugs during pregnancy. In select instances estradiol or ethinyl estradiol is used off-label as an adjuvant to clomiphene treatment of infertility, or in donor oocyte program procedures in assisted reproduction technology (ART) under the direction of ART specialists.

Estrogens, including ethinyl estradiol, have been reported to interfere with milk production and duration of lactation in some women. Less than 10% of an estradiol dose passes into breast milk. The American Academy of Pediatrics has considered estradiol to be usually compatible with breast-feeding due to a lack of documented cases of adverse events. However, estrogens should be used in lactation only when clearly indicated. Caution should be used if breast-feeding is continued while the mother is on estrogens; the infant may need to be monitored for appropriate nutrition and weight gain. Estrogens are not approved by the FDA for the treatment of postpartum breast engorgement.

Estrogens are relatively contraindicated in patients with acute intermittent, or variegate hepatic porphyria, which can be exacerbated. Exogenous orally administered estrogens may increase the risk of gallbladder disease (e.g., cholestasis, cholelithiasis and cholecystitis) in postmenopausal women. Based on evidence from the HERS trial, the risk of gallbladder disease may be more prevalent in those postmenopausal women with established coronary heart disease who receive oral estrogens. Similar increases in gallbladder disease have not been reported with transdermally administered estradiol, perhaps due to the fact that estradiol does not appear to increase saturation of cholesterol in the bile when administered by this route. Patients with familial hyperlipoproteinemia may develop elevations in triglycerides while taking exogenous estrogens which may predispose them to pancreatitis; caution is warranted in these individuals. Estrogens are contraindicated in the presence of hepatocellular cancer, hepatic adenoma, jaundice, or in severe hepatic disease of any type.

In some patients, blood pressure may increase during therapy with estrogen therapy. Patients with hypertension should be monitored closely for increases in blood pressure if estrogens are administered. Because estrogens may cause fluid retention, conditions that might be affected by this factor, such as asthma, heart disease, renal disease, migraine, or seizure disorder require careful observation.

Although the effects appear to be minimal in most patients receiving hormone replacement therapy with estrogens or estrogen-progestin combinations; altered glucose tolerance secondary to decreased insulin sensitivity has been reported. Patients with hyperglycemia or diabetes mellitus should be observed for changes in glucose tolerance when initiating or discontinuing estrogen therapy.

Estrogen therapies have been associated with an increased risk of cerebrovascular disease (i.e., stroke), venous thrombosis (venous thromboembolism or VTE) and pulmonary embolism, and the addition of a progestin to estrogen therapy adds an increased risk of cardiovascular events such as myocardial infarction. Estrogens are contraindicated in patients with an active or past history of stroke, thrombophlebitis, or thromboembolic disease. Should any of these occur or be suspected, discontinue the estrogen immediately. A positive relationship between estrogen dosage and blood clotting has been demonstrated. Estrogens decrease levels of antithrombin-III and increase the production of blood clotting factors VII, VIII, IX and X. Because tobacco smoking increases the risk of DVT, myocardial infarction, and other thromboembolic disease, estrogen-containing treatment should be used cautiously in smokers. Risk is especially high for female cigarette smokers 35 years of age or older. Patients should be advised not to smoke. Risk factors for cardiac disease (e.g., hypertension, diabetes mellitus, tobacco use, hypercholesterolemia, and obesity) should be managed appropriately. In the estrogen sub-study of the WHI trial, estrogen alone does not affect (either increase or decrease) heart disease, although an increase in the number of strokes and VTE were been observed in women receiving estrogen HRT compared to placebo. In the estrogen-progestin sub-study of WHI, an increased risk of coronary heart disease (CHD) events (defined as non-fatal MI and CHD death) and stroke, and a 2-fold greater rate of VTE, including DVT and PE, were observed with estrogen-progestin HRT compared to placebo. The increase in risk was observed in year one and persisted. In postmenopausal women with documented cardiac disease, a controlled clinical trial (i.e., HERS trial) demonstrated no cardiovascular benefit to using estrogen-progestin HRT as secondary prevention. During an average follow-up of 4.1 years, treatment did not reduce the overall rate of CHD events in postmenopausal women with established coronary artery disease. There were more CHD events in the HRT-treated group than in the placebo group in year 1, but not during the subsequent years. Over two thousand women from the original HERS trial agreed to participate in an open label extension of HERS, known as HERS II. Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the estrogen-progestin HRT group and the placebo group in HERS, HERS II, and overall. In men treated with estrogen for palliation of prostate and breast cancer, estrogens have increased the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis.

Approximately 85% of patients diagnosed with systemic lupus erythematosus (SLE) are females, giving support to the notion that hormonal influences, especially estrogen, contribute to the pathophysiology of SLE. Accordingly, hormone replacement therapy (HRT) has been reported to induce, unmask, and exacerbate lupus; case reports, anecdotal data, and the prospective Nurses Health Study indicate that a temporal relationship between HRT and lupus exist. However, several retrospective studies dispute a relationship between estrogens and lupus, and the SELENA trial, a large prospective, randomized clinical trial evaluating the safety of estrogen therapy (both as oral contraceptives and HRT in postmenopausal women) in patients with SLE has been completed and is being analyzed. Determining the risk of estrogen therapy in SLE patients is important as postmenopausal women with lupus can benefit from HRT; not only does it offer relief from postmenopausal symptoms (vasomotor symptoms, genital symptoms, and emotional lability), but it has the additional benefit of protecting patients from bone fracture and postmenopausal or drug-induced (i.e., chronic corticosteroid or cyclophosphamide therapy) osteoporosis. Women with hypercoagulable states are at increased risk of venous thromboembolism when taking HRT; given the increased prevalence of hypercoagulable states in patients with SLE (in particular antiphospholipid antibodies), the use of HRT in this population may be even more risky as the incidence of strokes, heart attacks, and blood clots is increased in general in women taking HRT. Unfortunately, definitive recommendations regarding the use of HRT in patients with SLE are not available. The results of the SELENA trial should provide evidence regarding the use of HRT in this population.

Because certain major surgical procedures are associated with prolonged immobilization or increased risk of thromboembolism, estrogens should be discontinued several weeks (i.e., 4 - 6 weeks) prior to major surgery where feasible. The decision on when to resume estrogens after such procedures would be based on the perceived additional thromboembolic risk from estrogen use and the need for estrogen therapy.

Mood disorders, like depression, may be aggravated in women taking exogenous estrogens. Women with a history of depression may need special monitoring. If significant depression occurs, the hormone replacement therapy should be discontinued.

Use estrogens with caution in patients with thyroid disease, particularly hypothyroidism. Estrogens can increase thyroid-binding globulin (TBG) levels. Patients with normal thyroid function can compensate for the increased TBG by making more thyroid hormone, thus maintaining free T4 and T3 serum concentrations in the normal range. Patients dependent on thyroid hormone replacement therapy who are also receiving estrogens may require increased doses of their thyroid replacement therapy. These patients should have their thyroid function monitored in order to maintain their free thyroid hormone levels in an acceptable range.

Estrogens can increase the curvature of the cornea and may lead to intolerance of contact lenses. There have been clinical case reports of retinal thrombosis. Any change in vision or visual acuity should be examined by an ophthalmologist. Hormonal agents should be discontinued in patients developing any unexplained visual disturbance.

Estrogens are relatively contraindicated in children because estrogens promote epiphysial closure. Use with caution in those patients in whom bone growth is not complete. In young children, overdoses of estrogens have not been reported to cause serious ill effects. However, nausea is common. Vaginal withdrawal bleeding may occur in female children exposed to estrogens in large doses.

Estrogen/progestin combination therapy fails to prevent mild cognitive impairment (memory loss) and may increase the risk of dementia in women 65 years and older. The WHIMS study, an ancillary study of the WHI trial to assess the effects of estrogen/progestin therapy on cognitive function in elderly women (65 years of age or older), found that patients receiving either active treatment or placebo had similar rates of developing mild cognitive impairment. Also, patients receiving estrogen/progestin combination therapy were more likely than patients receiving placebo to be diagnosed with dementia. The applicability of this finding to women who use estrogen alone or to the typical user of HRT (i.e., younger, symptomatic women taking hormone replacement therapy to relieve menopausal symptoms) is unclear. Administration of estrogen/progestin combination therapy should be avoided in women 65 years of age and older and estrogen/progestin combination therapy should not be used to prevent or treat dementia or preserve cognition (memory).

Estradiol Contraindications and Precautions

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