Estradiol is contraindicated in individuals with previous experience of anaphylactic reactions or angioedema in relation to estradiol products and further use is not advised. Previous reported cases show that the patient response can occur in minutes and may require immediate medical intervention. Individuals with hereditary angioedema may experience more intense symptoms.
Estradiol products are contraindicated in neoplasms which include breast, ovarian, and endometrial cancers that are estrogen-dependent. Abnormal mammograms have been observed for women using estrogen-alone or estrogen-progestin treatment. Monthly breast self-examination and annual clinical assessment is recommended when undergoing hormonal therapy. Regular mammograms are also advised. The link between HRT and breast cancer has been examined. The Womens Health Initiative (WHI) clinical trial is a benchmark randomized study that provides valuable insights into the interaction of breast cancer and hormonal therapy. An increased risk of breast cancer was not observed in patients receiving daily estrogen-only treatment vs. placebo after a mean follow-up of 7.1 years [relative risk (RR) 0.80]. However, an elevated risk of invasive breast cancer was observed when undergoing daily estrogen-progestin treatment vs. placebo after an average follow-up of 5.6 years [relative risk (RR) 1.24]. The risk of invasive breast cancer was observed to be elevated in women with previous hormonal therapy [relative risk (RR) 1.86] undergoing estrogen-progestin treatment. The relative risk was lower [relative risk (RR) 1.09] for individuals undergoing the same treatment but had no prior hormonal therapy. Invasive breast cancers were observed to be larger, increased probability to be node positive, and were diagnosed at a more advanced stage in the HRT cohort vs. placebo. Likelihood of metastasis is slim. Histologic subtype, grade and hormone receptor status did not differ between the two cohorts. Other observational studies are in congruent with the WHI study in terms of reporting the differing risks of invasive breast cancer with respect to the distinct hormonal treatments. The influence of other factors such as route of administration, dose, and types of estrogen-progestin treatment on the risk of invasive breast cancer is yet to be elucidated. In the rare case in which estrogen is used as palliative treatment for advanced breast and bone cancers, it should be noted that hypercalcemia may ensue and treatment should cease if this occurs, and counteracting measures be implemented to restore calcium levels. In the same benchmark study, a statistically non-significant result was observed for an increased risk of ovarian cancer when patients receiving estrogen-progestin treatment were compared to placebo after a mean follow-up of 5.6 years [relative risk (RR) 1.58] . However, an increased risk of ovarian cancer was associated with women utilising hormonal therapy for menopausal symptoms after meta-analysis of 17 prospective and 35 retrospective epidemiology studies. The relative risk associated with current use of hormonal therapy was 1.41 (95% confidence interval [CI] 1.32 to 1.5). The relative risk associated with combined current and recent use (discontinued use within 5 years before cancer diagnosis) was 1.37 (95% CI 1.27 to 1.48), and the elevated risk was significant for both estrogen-alone and estrogen plus progestin products. The link between risk and duration of HRT use is yet to be reported.
Unopposed estrogen treatment is linked with endometrial hyperplasia in women with an intact uterus which may potentially result in the development of endometrial cancer. The addition of progestin has been shown to decrease the risk of endometrial hyperplasia. Cases of endometrial hyperplasia have been reported postmarketing in estrogen-alone users. The risk of endometrial cancer is reported to be approximately 2–12 greater in comparison to non-users and appears dependent on duration of treatment and on estrogen dose although several studies show no significant increased risk associated with use of estrogens for less than 1 year. Extended use impacts greatly with increased risks of 15- to 24-fold for 5–10 years or potentially more with effects still observed after the treatment has ceased. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of comparable dosage. Increased risk of ovarian cancer is also associated with HRT use. Furthermore, estrogens are contraindicated in the presence of vaginal cancer, cervical cancer, uterine cancer, or other estrogen-responsive tumors. Strict monitoring is recommended for all individuals on hormonal therapy which includes participation in clinical screening and examinations as needed. Caution is advised.
Some cardiovascular events have been associated with estrogen use. They include deep and superficial venous thrombosis, pulmonary embolism, thrombophlebitis, myocardial infarction, and stroke. Individuals should cease treatment and seek a qualified healthcare practitioner if symptoms are observed. Estrogen therapy is not suggested for use in individuals with confirmed thrombophilic diseases such as protein C deficiency, protein S deficiency as the risk of venous thrombosis is elevated. Attention to other risk factors is also paramount. Furthermore, a link between estrogen use and an elevated risk of thromboembolism has been shown. In the WHI study, patients receiving daily estrogen monotherapy displayed increased risk of venous thromboembolism vs. the placebo cohort. Furthermore, patients receiving estrogen-progestin displayed a statistically 2-fold increase in the risk of VTE vs. placebo. Estrogens with or without progestins is not recommended as a preventative measure for cardiac or cardiovascular disease. Estrogen was associated with an increased risk for stroke in patients (50–79 years old) receiving either daily estrogen monotherapy or combined estrogen-progestin combination treatment vs. placebo. Increased blood pressure has been observed in a few patients with hypertension and requires close monitoring although a large, randomized, placebo-controlled clinical trial, did not observe alterations in blood pressure with estrogen administration. Estrogen therapy may result in sodium and fluid retention and susceptible individuals should be identified and closely monitored when receiving estrogen treatment. In male breast or prostate cancer patients treated with estrogens for palliative care, increased risk of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitiss has been observed. For scheduled surgeries with risk of thromboembolism, estradiol treatment should not be administered within 4–6 weeks of the surgery. This also applies to individuals with prolonged inactivity. Return to treatment will be considered after assessment of all risk factors.
Estrogens can diffuse unopposed from the placenta to the fetus. Estrogen prescription is not recommended during pregnancy. For women that unknowingly use estrogen- or progestin-containing products, the risk of birth defect in their children is not increased or minimal. Some studies have reported that the continuous use of estrogens by pregnant women may elevate the risk of developing fetal anomalies such as limb defects, cardiovascular and sexual organs development abnormalities. Estradiol has been used in conjunction with clomiphene in specific cases to treat infertility, or in donor oocyte procedures. Subsequently estradiol administration is stopped upon the development of pregnancy. There is evidence that estrogen therapy may reduce breast milk levels and quality and is not recommended for use in breast-feeding women. There is also no FDA approval for use as a therapeutic intervention for postpartum engorgement.
Estrogen use is not recommended for individuals with liver-related malignancies or diseases. Liver impairment is associated with poor estrogen metabolism. In addition, individuals with history of cholestatic jaundice are advised to exercise caution. This advice also applies to individuals with variegate hepatic porphyria and a history of gall bladder disease. Patients with systemic lupus erythematosus (SLE) are advised to exercise caution with regards to the use of estrogen therapy due to an increased risk for thromboembolism. Estrogen and potentially other hormones are suspected to have a role in the pathophysiology of SLE since the majority of individuals diagnosed with this condition are women. The literature contains contradicting results with one study reporting a link between HRT and lupus, and others with distinct conclusions. It will be important to elucidate the mechanism of this interaction as estrogen therapy is known to be beneficial in managing symptoms of menopause in postmenopausal women. In addition, there is an increased risk of venous thromboembolism women with hypercoagulable states when undergoing HRT. This state is common in SLE patients and may result in a rise of strokes, heart attacks, and blood clots cases in individuals receiving HRT. 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 analysed. This would aid in gaining more understanding.
In women with a history of hypertriglyceridemia, estrogen treatment is potentially linked with increased plasma triglycerides culminating in pancreatitis. Therapy should be stopped if this develops.
Some cases have reported retinal vascular thrombosis with estrogen use. Cease therapy upon the onset of severe headache or partial/complete loss of vision and seek a qualified healthcare practitioner. If the clinical assessment indicates papilledema or retinal vascular lesions, then estrogen use should be permanently stopped. Estrogens can increase the curvature of the cornea and may lead to intolerance of contact lenses.
The risk of thromboembolism may be increased in patients predisposed to arterial vascular disease and are receiving estradiol treatment and thus monitoring is required. Judicious use of estradiol is advised for thyroid disease patients especially individuals with hypothyroidism as estrogens may elevate the concentration of thyroid-biding globulin (TBG). Individuals with functioning thyroid can counteract this by increasing the production of thyroid hormones. For individuals without this capacity and require exogenous thyroid hormone supplements, an elevated dose may be required and should be monitored.
Estrogen therapy may result in fluid retention and affect certain individuals. Aggravation of conditions such as asthma, seizure disorder, and hepatic hemangiomas has also been reported and cautious use of estrogen therapy is advised. Similarly, exacerbation of mood disorders has been linked to estrogen treatment and requires close monitoing. If mood disturbances persist, the treatment should be stopped.
Hormone therapy treatment is not recommended to women aged ≥ 65 years old due to an increased risk of dementia. Other potential estrogen-related effects for this age group include an increased risk of developing breast cancer and other malignancies, through oral, trasndermal, and other systemic administration of estrogen therapy according to the Beers Criteria. Estrogen vaginal administration is considered safe and effective for treating menopausal symptoms including vaginal dryness and other vagina/vulvar symptoms. Individuals with urinary incontinence should avoid estrogen treatment to avoid possible exacerbation.
Data depicting the safety and efficacy of estrogen is not established in neonates, children or infants. This hormone promotes epiphyseal closure and bone maturation. Nausea and vaginal withdrawal bleeding (in female children) has been associated with high doses. Estrogen treatment has also been administered to promote puberty in some adolescents.
Esterified estrogens e.g. estradiol cypionate and estradiol valerate should be administered intramuscularly. Intravenous administration may cause serious adverse effects. Estradiol topical gels and sprays contain alcohol and are potentially a fire hazard. Hence flammable conditions such as fire, flame, or smoking should be avoided during application.
There is potential of accidental exposure of estrogen treatment to others and awareness is necessary. For example in 2010, the FDA reported an advisory notice for Evamist brand topical spray secondary exposure through skin contact. Safety data sheets should be checked. Adverse events such as premature puberty, nipple swelling and breast development in females and breast enlargement in males have been reported. Reports of pet exposure were also reported with nipple enlargement and/or vulvar swelling observed. The risk of exposure to others can be mitigated by avoiding contact with the treated section or by covering up the area. Upon accidental exposure, the contaminated area should be washed with water and soap. If symptoms of exposure manifest, a healthcare practitioner should be sought.