Bi-est Cream

Estradiol is the principal intracellular human estrogen and is substantially more active than its metabolites, estrone and estriol, at the cellular level. Estradiol can be obtained from natural sources or prepared synthetically. There is no evidence that ‘natural’ estrogens are more or less efficacious or safe than ‘synthetic’ estrogens.^[1] Due to almost complete first-pass metabolism, estradiol must be given in a micronized oral dosage form to ensure therapeutic effect. Esterification of estradiol to estradiol cypionate or valerate increases the parenteral duration of action of estradiol to allow for parenteral intramuscular administration. Estradiol is primarily used to prevent osteoporosis and relieve vasomotor and genitourinary symptoms associated with menopause (natural or surgical), for postmenopausal osteoporosis prevention, and is also used to treat female hypogonadism and other abnormalities of female gonadotropin dysfunction. Various estrogen products have been marketed in the U.S. since 1938. Estradiol is available in many dosage forms, including oral tablets, transdermal systems, topical emulsions, topical gels, topical sprays, vaginal creams, vaginal rings, and parenteral depot injections. Vaginal therapies are preferred in postmenopausal women with exclusive genitourinary symptoms, due to lower systemic absorption/exposure with most of these dosage forms.^[1] Many estradiol products have been FDA-approved since the 1990’s, in accordance with the FDA’s guidance to provide efficacious low-dose estrogen therapies in alternate drug delivery systems.

The primary source of estrogens in premenopausal women is the ovary, which normally secretes 0.07 to 0.5 mg of estradiol daily, depending on the phase of the menstrual cycle. Once estrogens enter the cells of responsive tissues (e.g., female organs, breasts, hypothalamus, pituitary), they increase the rate of synthesis of DNA, RNA, and some proteins. The secretion of gonadotropin-releasing hormone by the hypothalamus is reduced during estrogen administration, causing reduction in follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary. Exogenous estrogens elicit all of the actions of endogenous estrogens. Estrogens are responsible for the growth and development of female sex organs and the maintenance of sex characteristics including growth of axillary and pubic hair and shaping of body contours and skeleton. At the cellular level, estrogens increase cervical secretions, cause proliferation of the endometrium, and increase uterine tone. Paradoxically, prolonged administration of estrogen can shrink the endometrium. During the preovulatory or nonovulatory phase of the menstrual cycle, withdrawal of estrogen can initiate menstruation; in the ovulatory phase, the decrease in progesterone secretion is the more significant factor causing menstruation. In post-menopausal use, amenorrhea occurs in most women within several months of oral estrogen use.

Estrogens have a weak anabolic effect and also can affect bone calcium deposition and accelerate epiphysial closure. Estrogens appear to prevent osteoporosis associated with the onset of menopause. Estrogens generally have a favorable effect on blood lipids, reducing LDL- and increasing HDL-cholesterol concentrations on average, by 15%. Serum triglycerides increase with estrogen administration. Estrogens increase the rate of synthesis of many proteins, including thyroid binding globulin and several clotting factors. Estrogens reduce levels of antithrombin III, and increase platelet aggregation. Estrogens also enhance sodium and fluid retention.

Unopposed estrogen has been associated with increased risk of endometrial cancer in menopausal women with an intact uterus; concomitant progestin therapy reduces, but does not eliminate, this risk. However, combination hormone replacement therapy (HRT) may add additional health risks for some women, as evidenced by the HERS trials, the Women’s Health Initiative study and other investigations.^[2][3][4][5] In particular, the Women’s Health Initiative (WHI) study reported an increased risk of myocardial infarction, stroke, dementia, invasive breast cancer, and venous thromboembolism in patients taking combination HRT and an increased risk of stroke, dementia, and venous thromboembolism in patients taking estrogen only HRT; an increased risk of invasive breast cancer was not evident in women taking estrogen only. Because of these findings, patients should be prescribed estrogen HRT or estrogen-progestin HRT for the shortest duration consistent with the treatment goals. Estrogen HRT with or without a progestin is not indicated and should not be used to prevent coronary artery disease or other cardiovascular disease. The risks and benefits of HRT must be determined for a woman individually.

In men with advanced prostate cancer, estrogens exert their effect by inhibition of the hypothalamic-pituitary axis through negative feedback. This results in decreased secretion of luteinizing hormone (LH). Decreased testosterone production from the Leydig cells in the testes occurs, which may decrease tumor growth and lower prostate specific antigen (PSA) levels. Improvement in bone metastasis may also occur. In the past, high-dose estrogen therapy was also used in selected men and postmenopausal women with inoperable, progressive breast cancer. Since the development of selective estrogen receptor modifiers (SERMs), high-dose estrogen therapy for the palliative treatment of breast cancer is rarely used today.

Do not use estradiol products in patients with a known hypersensitivity to any of the specific product ingredients; estradiol is contraindicated in patients with known anaphylactic reactions or history of angioedema to the drug. Cases of both anaphylactic reactions and angioedema have been reported in patients taking estrogens, including estradiol. Events have developed in minutes and have required emergency medical treatment. Exogenous estrogens may also induce or exacerbate symptoms of angioedema, particularly in women with hereditary angioedema, which can be hormonally sensitive.^{[6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]}

Estradiol products are contraindicated in patients with a known or suspected estrogen-dependent neoplasm, including breast cancer. The use of estrogen-alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms, requiring further evaluation. 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 based on patient age, risk factors, and prior mammogram results.^{[6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]} Since the 1970’s, numerous epidemiological studies have examined the association of estrogens or combined hormone replacement therapy (HRT) and breast cancer (new primary malignancy).^[23] The data available are derived from studies of estrogen-alone or estrogen plus progestin hormonal replacement therapy (HRT). The most important randomized clinical trial providing information about breast cancer in estrogen-alone users is the Womens Health Initiative (WHI) substudy of estrogen-alone therapy. In the WHI estrogen-alone substudy, after an average follow-up of 7.1 years, daily estrogen monotherapy was not associated with an increased risk of invasive breast cancer [relative risk (RR) 0.80].^[24][25] The most important randomized clinical trial providing information about breast cancer in patients taking combined estrogen-progestin HRT regimens is the WHI substudy of estrogen plus a progestin.^[26][5] After a mean follow-up of 5.6 years, the WHI estrogen plus progestin substudy reported an increased risk of invasive breast cancer in women who took daily estrogen plus progestin vs. placebo. In this substudy, prior use of estrogen-alone or estrogen plus progestin therapy was reported by 26 percent of the women. The relative risk of invasive breast cancer was 1.24, and the absolute risk was 41 versus 33 cases per 10,000 women-years, for estrogen-progestin compared with placebo. Among women who reported prior use of hormone therapy, the relative risk of invasive breast cancer was 1.86, and the absolute risk was 46 vs. 25 cases per 10,000 women-years for estrogen-progestin compared with placebo. Among women who reported no prior use of hormone therapy, the relative risk of invasive breast cancer was 1.09, and the absolute risk was 40 vs. 36 cases per 10,000 women-years for estrogen-progestin compared with placebo. In the same WHI substudy, invasive breast cancers were larger, were more likely to be node positive, and were diagnosed at a more advanced stage in the combined HRT group compared with the placebo group. Metastatic disease was rare, with no apparent difference between the 2 groups. Other prognostic factors, such as histologic subtype, grade and hormone receptor status did not differ between the 2 groups.^[26] Consistent with the WHI clinical trial, observational studies have also reported an increased risk of breast cancer for estrogen plus progestin therapy, and a smaller increased risk for estrogen-alone therapy, after several years of use. The risk increased with duration of use, and appeared to return to baseline over about 5 years after stopping treatment (only the observational studies have substantial data on risk after stopping). Observational studies also suggest that the risk of breast cancer was greater, and became apparent earlier, with combined HRT as compared to estrogen-alone therapy. However, these studies have not found significant variation in the risk of breast cancer among different estrogen plus progestin combinations, doses, or routes of administration. While estrogen therapy may be used rarely for the palliative treatment of advanced breast cancer in men and women, estrogen administration may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, use of the drug should be stopped and appropriate measures taken to reduce the serum calcium level.^{[6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]}

Estradiol products are contraindicated in women with estrogen-dependent neoplasms, including ovarian cancer. What is known about the risk of ovarian cancer due to estrogen-containing hormonal replacement therapy (HRT) regimens is derived from data available for estrogen-alone and estrogen plus progestin products. The Women’s Health Initiative (WHI) estrogen plus progestin substudy reported a statistically non-significant increased risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for estrogen plus progestin versus placebo was 1.58 (95% CI 0.77 to 3.24). The absolute risk for estrogen plus progestin versus placebo was 4 versus 3 cases per 10,000 women-years.^[27] A meta-analysis of 17 prospective and 35 retrospective epidemiology studies found that women who used hormonal therapy for menopausal symptoms had an increased risk for ovarian cancer. The primary analysis, using case-control comparisons, included 12,110 cancer cases from the 17 prospective studies. The relative risk associated with current use of hormonal therapy was 1.41 (95% confidence interval [CI] 1.32 to 1.5); there was no difference in the risk estimates by duration of the exposure (less than 5 years [median of 3 years] vs. greater than 5 years [median of 10 years] of use before the cancer diagnosis). 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 exact duration of hormone therapy use associated with an increased risk of ovarian cancer, however, is unknown.^{[6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]}

Estrogen therapy is contraindicated in patients with known estrogen-dependent malignancies. There is an association of unopposed estrogen therapy and endometrial cancer in women with an intact uterus. Adding a progestin to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal vaginal bleeding. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. 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 estrogen therapy is discontinued. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose. With concurrent progestin use (cyclically or continuously), the incidence of endometrial hyperplasia due to estrogen therapy is estimated to be 1% or less.^{[23][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]}

Estrogens are contraindicated in the presence of vaginal cancer, cervical cancer, uterine cancer, or other estrogen-responsive tumors. Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is important; all women receiving estrogen treatment should have an annual pelvic examination and other diagnostic or screening tests, such as cervical cytology, as clinically indicated or as generally recommended based on age, risk factors, and other individual needs. Because estrogens influence the growth of endometrial tissues, use estradiol products cautiously in women with endometriosis or uterine leiomyomata (uterine fibroids). A few cases of malignant transformation of residual endometrial growths have been reported in women treated post-hysterectomy with estrogen-alone therapy. For women known to have residual endometriosis post-hysterectomy, the addition of a progestin should be considered to reduce the risk of endometrial tissue growth.^{[6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]}

Estrogens are contraindicated in patients with an active or past history of thrombophlebitis, thromboembolism, thromboembolic disease, stroke, or myocardial infarction (MI). An increased risk of cerebrovascular disease (stroke) and deep venous thrombosis (DVT) has been reported with unopposed estrogen therapy. An increased risk of thromboembolism, including pulmonary embolism (PE), DVT, stroke and myocardial infarction (MI) has been reported with estrogen plus progestin hormone replacement therapy (HRT). Should any of these events occur or be suspected, discontinue estradiol immediately. Estrogens are also contraindicated for patients with known protein C deficiency, protein S deficiency, or antithrombin deficiency or other known thrombophilic disorders associated with increased risk of venous thrombosis. Other risk factors for arterial vascular disease (e.g., hypertension, diabetes, tobacco smoking, hypercholesterolemia, and obesity) and/or venous thromboembolism (VTE) [e.g., personal history or family history of VTE, obesity, or systemic lupus (SLE)] should be monitored and managed appropriately.^{[6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]} A positive relationship between estrogen use and an increased risk for thromboembolism has been demonstrated. In the WHI estrogen-alone substudy, the risk of VTE (DVT and PE) was increased for women receiving daily unopposed estrogen compared to placebo (30 vs. 22 per 10,000 women-years), although only the increased risk of DVT reached statistical significance (23 vs. 15 per 10,000 women years). The increase in VTE risk was demonstrated during the first 2 years. In the WHI estrogen plus progestin substudy, a statistically significant 2-fold greater rate of VTE was reported in women receiving estrogen plus progestin HRT compared to women receiving placebo (35 vs. 17 per 10,000 women-years). Statistically significant increases in risk for both DVT (26 vs. 13 per 10,000 women-years) and PE (18 vs. 8 per 10,000 women-years) were also demonstrated. The increase in VTE risk was demonstrated during the first year and persisted.^[28][5] Estrogens with or without progestins should not be used for the prevention of cardiac disease or cardiovascular disease (e.g., coronary artery disease). In the Women’s Health Initiative (WHI) estrogen-alone substudy, no overall effect on coronary heart disease (CHD) events (defined as non-fatal MI, silent MI, or CHD death ) was reported in women receiving estrogen-alone compared to placebo. Subgroup analyses of women 50 to 59 years of age suggest a statistically non-significant reduction in CHD events (CE-alone vs. placebo) in women with less than 10 years since menopause (8 vs. 16 per 10,000 women-years). In the WHI estrogen plus progestin substudy, there was a statistically non-significant increased risk of CHD events reported in women receiving daily estrogen plus progestin compared to women receiving placebo (41 vs. 34 per 10,000 women-years). An increase in relative risk was demonstrated in year 1, and a trend toward decreasing relative risk was reported in years 2 through 5.^[5][29] Studies have also shown no cardiovascular benefit to the use of estrogens or estrogen-progestin therapy for secondary prevention in women with documented cardiac disease or CHD.^[2][3] Estrogens also increase the risk for 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 estrogen-alone compared to women in the same age group receiving placebo (45 vs. 33 per 10,000 women-years). The increase in risk was demonstrated in the first year and persisted. Subgroup analyses of women 50 to 59 years of age suggest no increased risk of stroke for those women receiving estrogen-alone versus those receiving placebo (18 vs. 21 per 10,000 women-years). In the WHI estrogen plus progestin substudy, a statistically significant increased risk of stroke was reported in women 50 to 79 years of age receiving estrogen plus progestin HRT compared to women in the same age group receiving placebo (33 vs. 25 per 10,000 women-years). The increase in risk was demonstrated after the first year and persisted. Women over the age of 65 years were at increased risk for non-fatal stroke.^[30][5] Patients with hypertension should be monitored closely for increases in blood pressure if estrogens are administered. In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogen therapy. In a large, randomized, placebo controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen. Estrogens may cause some degree of fluid retention. Women with conditions that might be influenced by this factor, such as a cardiac disease, warrant careful observation when estrogens are prescribed.^{[6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]} In men treated with estrogens for palliation of prostate or breast cancer, estrogens have increased the risk of nonfatal MI, PE, and thrombophlebitis.

If feasible, estradiol therapy should be discontinued at least 4 to 6 weeks before any surgery associated with an increased risk of thromboembolism, or during any periods of prolonged immobilization. The decision on when to resume estrogens after such procedures or conditions would be based on the perceived additional thromboembolic risk from estrogen use and the need for estrogen therapy; resume only after the patient is fully ambulatory. In addition, women taking estradiol should be advised to move about periodically during travel involving prolonged immobilization.^{[6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]}

Estrogens are contraindicated during pregnancy. There is no known approved indication for the use of estrogens during pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins from oral contraceptives inadvertently during early pregnancy.^{[6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]} Estradiol and other estrogens freely cross the placenta to the fetus. 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 continued use of estrogens in pregnant women. In any patient in whom pregnancy is suspected, pregnancy should be ruled out before continuing estrogen use.^[12] In select instances estradiol has been 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; however, treatment is discontinued when pregnancy ensues.^[31]

Caution should be used if a breast-feeding mother is receiving estradiol for hormone replacement. Estrogen administration to nursing women is generally avoided during lactation as estrogens have been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving estradiol and other estrogens.^{[6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][32][22]} Estrogens are not approved by the FDA for the treatment of postpartum breast engorgement.^[12]

Estrogens are contraindicated in the presence of hepatocellular cancer, hepatic adenoma, or in severe hepatic disease of any type. Estrogens may be poorly metabolized in women with impaired liver function. For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, caution should be exercised, and in the case of recurrence, estrogens should be discontinued. Estrogens should also be used cautiously in patients with acute intermittent, or variegate hepatic porphyria, which can be exacerbated. Estrogens have been reported during trials to increase the risk of gallbladder disease (e.g., cholestasis, cholelithiasis and cholecystitis) by roughly 2- to 4-fold in postmenopausal women; use with caution in patients with a history of gallbladder disease.^{[6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]}

Patients with systemic lupus erythematosus (SLE) may have increased risk for thromboembolism and should be managed appropriately when estrogen therapy is considered.^{[6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]} 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, including estradiol, 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.^[33][34]

In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Consider discontinuation of estradiol treatment if pancreatitis occurs.^{[6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]}

Retinal vascular thrombosis has been reported in women receiving estrogens. Any visual disturbance should be examined by an ophthalmologist. Discontinue the estrogen pending examination if there is sudden partial or complete loss of vision, or a sudden onset of proptosis, diplopia, or migraine with visual changes. If examination reveals papilledema or retinal vascular lesions, estrogens should be permanently discontinued.^{[6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]}Estrogen therapy may cause an exacerbation of migraine or a change in headache patterns and should be used with caution in women with migraine. Patients who complain of migraine with focal neurologic visual changes should be evaluated, and in some patients, such changes may indicate cerebrovascular events. Estrogens can increase the curvature of the cornea and may lead to intolerance of contact lenses.

Patients with risk factors for arterial vascular disease (e.g., diabetes mellitus), which may increase the risk for thromboembolism, should be monitored and managed appropriately during estradiol therapy. Patients with diabetes mellitus should be observed for changes in glucose tolerance when initiating or discontinuing estrogen therapy, since estrogen therapy may exacerbate diabetes. Altered glucose tolerance secondary to decreased insulin sensitivity has been reported.^{[6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]}

Use estradiol 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.^{[6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]}

Because estrogens may cause fluid retention, conditions that might be affected by fluid retention, such as heart disease or renal disease, require careful observation. Estrogen therapy may also cause an exacerbation of asthma, seizure disorder, and hepatic hemangiomas in some patients and should be used with caution in women with these conditions.^{[6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]}

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, estradiol should be discontinued.

Estrogen therapy should be used with caution in women with hypoparathyroidism as estrogen-induced hypocalcemia may occur.^{[6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]}

Hormone replacement therapy (HRT), both estrogen/progestin combination therapy and estrogen alone therapy, has been found to fail to prevent mild cognitive impairment (memory loss) and to increase the risk of dementia in geriatric women 65 years and older.^{[6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]} Administration of HRT should generally be avoided in women 65 years of age and older, and HRT should not be used to prevent or treat dementia or preserve cognition (memory). Overall risk vs. benefit should be considered along with the goals of use of HRT for the individual patient when considering whether to continue HRT in a geriatric woman over 65 years of age.^[35][36][1] According to the Beers Criteria, oral and topical patch, or other systemic forms of estrogens, with or without progestins are considered potentially inappropriate medications (PIMs) for use in geriatric patients and should be avoided due to evidence of carcinogenic potential (i.e., breast and endometrium) and lack of cardiovascular or cognitive protective effects in older women. Additionally, the Beers expert panel recommends avoiding oral or transdermal estrogen in elderly women with any type of urinary incontinence due to the potential for aggravation of incontinence. The Beers expert panel considers use of intra-vaginal preparations acceptable for the management of dyspareunia, lower urinary tract infections, and other vaginal/vulvar symptoms. In addition, evidence suggests that vaginal estrogens are safe and effective for the treatment of vaginal dryness; women with a history of breast cancer who do not respond to non-hormonal therapies are advised to discuss the risks and benefits of low-dose vaginal estrogen (estradiol less than 25 mcg twice weekly) with their healthcare provider.^[37] The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents of long-term care facilities (LTCFs). According to the OBRA guidelines, assessment of the underlying causes and identification of the type/category of urinary incontinence needs to be documented prior to or soon after initiating treatment with a medication to manage urinary incontinence (e.g., estrogen replacement agents). These medications have specific and limited indications based on the cause and categorization of incontinence. Patients should be assessed periodically for medication effects on urinary incontinence as well as lower urinary tract symptoms and treatment tolerability. The Guidelines caution that oral estrogen products may cause systemic side effects and increased risks (e.g., DVT, breast cancer), and topical agents may be preferred.^[38]

The safety and efficacy of estrogens have not been established in neonates, infants or children. Estrogens are not indicated in children because estrogens promote epiphysial closure. In young children, overdose 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 therapy has been used for the induction of puberty in adolescents with some forms of pubertal delay; however, if estrogen is administered to adolescent patients whose bone growth is not complete, these patients should be monitored periodically for bone maturation and effects on epiphyseal centers.^{[6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]}

Estradiol cypionate and estradiol valerate are esterified estrogens that are in oil-based injections; intravenous administration should be avoided as injection by this route may result in serious adverse effects. These injections are to be administered by the intramuscular route only.^[19][20]

Estradiol is available in many topical dosage forms, including transdermal systems, topical emulsions, topical gels, and topical sprays. Estradiol topical gels and sprays are alcohol-based and thus are potentially flammable. Patients should be advised to avoid fire, flame, or smoking until the gel or spray has dried after application.^{[21][7][6][16]} Patients should be advised to carefully read and follow administration directions in order to avoid accidental exposure of estradiol hormone to others, including children and pets. In July 2010, the FDA released an advisory notice warning of inadvertent exposure to Evamist brand topical spray through skin contact with patients using the product. Adverse events including premature puberty, nipple swelling and breast development in females, and breast enlargement in males were reported. Reports of pet exposure were also reported; signs of exposure in pets may include mammary/nipple enlargement and vulvar swelling. To reduce the risk of exposure, patients applying this product should avoid contact of the treated area to children and pets. If direct contact cannot be avoided, the treated area should be covered with a garment. If inadvertent exposure occurs, the skin of the child or pet should be washed immediately with soap and water.^[39] Patients should be aware that if a child under their care shows signs of exposure including breast development or other sexual changes, the child should be examined by a healthcare professional. Once exposure is removed, symptoms of exposure should resolve.^[7]

A variety of endocrine and urogenital effects can occur during therapy with estradiol. Changes in sexuality include libido increase or libido decrease. Positive changes in libido may occur as a result of improvements in vulvar and vaginal atrophy in postmenopausal women. Vaginal changes such as discharge or irritation, vaginitis, cervicitis, or changes in cervical erosion (e.g., cervical ectropion) may appear. Vulvovaginal or vaginal candidiasis or other mycotic infections may occur infrequently with systemic or vaginal estrogen therapy. In a clinical trial of postmenopausal women to compare estradiol vaginal tablets to placebo, vulvovaginal mycotic infection occurred in 8% of estradiol-treated patients vs. 3% with placebo.^[9] Estrogens may also cause enlargement of uterine leiomyomatas (fibroids), if present. A cystitis like syndrome has also been reported. Changes in vaginal bleeding pattern and abnormal withdrawal bleeding or flow, breakthrough bleeding, spotting, and dysmenorrhea have been noted with estrogens and/or progestins and are commonly reported. In postmenopausal women, changes in uterine bleeding patterns will usually taper and stabilize within 3 to 6 months of beginning cyclic or continuous HRT combinations. Amenorrhea is desirable in many postmenopausal women and not considered to be an adverse effect of estrogen therapy. However, when estrogens are used for the treatment of hypogonadism in premenopausal females, continued amenorrhea may signal a lack of response to estrogen therapy. Unusual vaginal bleeding, menorrhagia, or spotting that persists beyond 6 months in any woman on estrogen therapy should be evaluated by a health care professional. For women who have a uterus, adequate diagnostic measures such as endometrial sampling, when indicated, should be undertaken to rule out malignancy in cases of undiagnosed persistent or recurring abnormal vaginal bleeding. Women who take estrogens should follow current recommendations for periodic pelvic examinations, including Papanicolaou smears when indicated to detect cervical dysplasia.^[12]

Mastalgia (breast pain) is a common adverse effect of estrogens such as estradiol. Breast tenderness, breast enlargement, breast discharge, galactorrhea, and fibrocystic breast changes have been reported with estrogens and/or progestin therapy. Gynecomastia may occur in men on estrogen therapy. Patients should report breast changes, lumps, or breast discharge to their health care professionals. All women should receive yearly breast examinations by a healthcare provider and perform monthly breast self-examinations. In addition, mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results.^[12]

Stomach/abdominal pain or cramps, bloating, nausea, and vomiting are common side effects of estrogens such as estradiol; these effects may attenuate with continued treatment. Diarrhea is infrequent with estradiol use. For example, in a clinical trial comparing estradiol vaginal tablet 10 mcg to placebo, diarrhea occurred in 5% of treated postmenopausal women vs. 0% of those receiving placebo.^[9] Consider benign hepatic adenoma if gastrointestinal symptoms such as abdominal pain/tenderness, abdominal mass, or hypovolemic shock are present, as an adenoma may rupture and cause intraabdominal hemorrhage. Benign hepatic adenomas appear to be associated with the use of oral contraceptives, and enlargement of hepatic hemangiomas has been reported with estrogen and/or progestin therapies. Pancreatitis and colitis have also been reported; high dose estrogens have been associated with ischemic colitis (bowel ischemia) with mesenteric vein thrombus secondary to hypercoagulability a reported potential mechanism.^[95] In patients with preexisting hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis and other complications. Additionally, GI obstruction of the bowel has been reported in patients using the estradiol vaginal ring.^[11] Estrogens enhance hepatic lipoprotein uptake and inhibit bile acid synthesis, resulting in increased concentration of cholesterol in the bile which can lead to cholelithiasis, biliary obstruction, and cholestasis. Cholestatic jaundice and an increased incidence of gallbladder disease have also been reported. A 2- to 4-fold increase in the risk of gallbladder disease requiring surgery (e.g., cholecystitis) in postmenopausal women receiving estrogens has been reported. Estrogens may be poorly metabolized in patients with impaired liver function. For patients with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, use estradiol cautiously. If cholestatic jaundice recurs, discontinue the estrogen.^[8][12] Rare adverse reactions include hepatitis (and elevated hepatic enzymes). Estrogens may induce peliosis hepatis, a very rare consequence of taking estrogens and combined oral contraceptives that is characterized by the presence of blood-filled spaces.^[96] Persistent or severe abdominal symptoms should be evaluated by a medical professional.^[8][11][12]

Deep and superficial venous thrombosis, pulmonary embolism, thrombophlebitis, myocardial infarction, and stroke have been reported with estrogens and/or progestin therapy. The use of estrogens in postmenopausal women, with or without a progestin, carries a risk for thromboembolism, and cardiovascular events such as myocardial infarction (MI) or stroke. Detailed information regarding what is known about thromboembolic and cardiovascular risk in postmenopausal women is available in the boxed warnings and precautions section of the product labeling for the products, as these risks must be considered prior to use of HRT in women, and with consideration to age and other risk factors for these events. Risks vary with the use of estrogen-alone vs. use of estrogen with progestin therapy. Should any of these events occur or be suspected, discontinue the estrogen or estrogen-progestin therapy immediately.^{[6][7][8][10][11][13][12][14][15][16][17][18][19][20][21][22]}

Estrogens such as estradiol can cause sodium and fluid retention, resulting in peripheral edema or mild weight gain. They should be prescribed cautiously to patients in whom the presence of edema would be detrimental. In addition, estrogens can slightly increase blood pressure, occasionally causing hypertension; data indicate in most patients the change is not clinically significant. In a small number of case reports, substantial increases in blood pressure have been attributed to idiosyncratic reactions to estrogens such as estradiol. In a large, randomized, placebo-controlled clinical trial, a generalized effect of estrogens on blood pressure was not seen.^[8][12] In the PEPI trial, postmenopausal women 45 to 65 years of age randomized to any hormone replacement therapy regimen experienced increases in both systolic and diastolic blood pressure of 3% to 5% after the first year of treatment, but the increases were not statistically different from placebo.^[97] Monitor blood pressure at regular intervals with estrogen use.

Headache, with no other symptoms, has been noted with use of estrogens such as estradiol, including with vaginal therapy. For example, headache (5% to 7%) was the most common side effect noted with use of an estradiol vaginal insert for dyspareunia. Headache with no other symptoms occurred at an average incidence range of 5% to 21% with various systemic and transdermal estradiol treatments in postmenopausal women. A severe headache with focal neurologic changes may be a warning sign of a serious adverse event such as a stroke or retinal problems (e.g., thrombosis) in the eye. Discontinue the estrogen pending examination if there is sudden partial or complete loss of vision or new, severe, sudden onset of headache or migraine with focal neurologic changes. If examination reveals a serious event, estrogens should be permanently discontinued.^[8][12] The relationship of headache, specifically migraine headache, and the administration of estrogens is not clearly defined. A number of changes can occur when a woman initiates HRT and include 1) migraines can appear for the first time, 2) a change in frequency, severity and duration of migraine headaches may be seen, or 3) an improvement or decrease in the occurrence of migraine headaches. Such adverse events are not frequent. When initiating estrogens, such as estradiol, an individual’s headache pattern should be observed and, if migraines worsen, consider discontinuing therapy.

Mental depression, nervousness or anxiety, mood disturbances such as emotional lability and irritability have been reported with estrogens such as estradiol and/or progestin therapy.^[8][12] Complaints of insomnia or fatigue may be associated with the underlying menopausal complaints or may be associated with treatment. Women with a history of depression may need special monitoring. If significant depression occurs, estradiol should be discontinued.

A variety of dermatologic or allergic reactions have been reported with use of estrogens, such as estradiol. Melasma, in the form of tan or brown patches, may develop on the forehead, cheeks, temples and upper lip; melasma may persist after the drug is discontinued. In some cases, estrogens may induce or aggravate an existing acne vulgaris. Erythema multiforme, erythema nodosum, hemorrhagic eruption, loss of scalp hair (alopecia), hirsutism, pruritus, maculopapular rash, urticaria, angioedema, and anaphylactoid reactions have been reported with estrogens and/or progestins.^[8][12] Estradiol transdermal systems may cause localized bleeding, hematoma (bruising), burning, skin irritation, xerosis, eczema, edema, erythema, inflammation, pain, vesicular rash, or rash (unspecified). Other dermal reactions reported postmarketing with estradiol transdermal systems include, paresthesias, skin discoloration or pigmentation changes, and swelling.^[17] To help reduce the chance of skin redness or skin irritation, wait at least 1 week before the patient reuses a skin site for transdermal patch application.^[13] Estradiol topical emulsions and sprays have also been associated with pruritus or skin irritation during clinical trials.^[98][7] During postmarketing surveillance, estradiol spray (Evamist) has been associated with nipple and areola skin discoloration, usually occurring on the same side as the inner arm where the product was applied; xerosis has also been reported.^[7] Vaginal therapy with estradiol may cause localized itching or irritation; in one clinical trial during use of 10 mcg vaginal tablets, vulvovaginal pruritus occurred in 8% of treated patients compared to 2% of those receiving placebo.^[9]

Some women taking estrogens, including estradiol, notice tenderness, swelling, or minor bleeding of their gums, which may lead to gingivitis. Proper attention to oral care and regular dental visits are recommended.

Retinal thrombosis has been reported in patients receiving estrogens such as estradiol. Discontinue medication pending examination if there is sudden visual impairment either partial or complete or a sudden onset of proptosis, diplopia, or migraine with focal neurologic changes. If examination reveals papilledema, visual loss, or retinal vascular lesions, permanently discontinue estrogens.^[8][12] Exogenous estrogen use can cause a conical cornea to develop from steepening or increased curvature of the cornea, caused by thinning of the stroma. Patients with contact lenses may develop intolerance to their lenses.

Reduced carbohydrate tolerance and potentially hyperglycemia has been reported with estrogens and/or progestin therapy. Cautious use of estrogens such as estradiol in patients with diabetes is advised, as estrogens may cause an exacerbation of diabetes mellitus.^[8][12]Limited clinical studies of estrogen regimens have not noted significant alterations in glucose metabolism in healthy post-menopausal women. Further, in women without diabetes, estrogens appear to have little to no effect on fasting blood glucose.^[99]

Leg muscle cramps, arthralgia, and hypocalcemia have been reported with estrogen and/or progestin therapy.^[8][12] Back pain has been reported within an overall incidence range of 3.3% to 11% with various estradiol formulations, including oral, transdermal, topical and vaginal products.

Hormone replacement therapy (HRT), both estrogen/progestin combination therapy and estrogen alone therapy, fails to prevent mild impaired cognition (memory loss) and is positively associated with the risk of developing dementia in women 65 years and older; do not use HRT to prevent or treat dementia or preserve cognition (memory).^{[6][7][8][10][11][13][12][14][15][16][17][18][19][20][21][22]} When data from the 2 populations in the WHIMS estrogen-alone and estrogen plus progestin ancillary studies were pooled as planned in the WHIMS protocol, the reported overall relative risk for probable dementia was 1.76 (95% CI 1.19 to 2.60, p = 0.005). Since both ancillary studies were conducted in women 65 to 79 years of age, it is unknown whether these findings apply to younger postmenopausal women.^[35][36][1] In the Women’s Health Initiative Memory Study (WHIMS) estrogen plus progestin ancillary study, a population of 4,532 postmenopausal women 65 to 79 years of age was randomized to daily estrogen plus progestin or placebo. After an average follow-up of 4 years, 40 women in the estrogen plus progestin group and 21 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for estrogen plus progestin vs. placebo was 2.05 (95% CI, 1.21 to 3.48). The absolute risk of probable dementia for estrogen plus progestin vs. placebo was 45 vs. 22 cases per 10,000 women-years.^[35] In the WHIMS estrogen-alone ancillary study of WHI, a population of 2,947 hysterectomized women 65 to 79 years of age was randomized to daily estrogen-alone or placebo. After an average follow-up of 5.2 years, 28 women in the estrogen-alone group and 19 women in the placebo group were diagnosed with probable dementia. The relative risk of probable dementia for estrogen-alone vs. placebo was 1.49 (95% CI, 0.83 to 2.66). The absolute risk of probable dementia for estrogen-alone versus placebo was 37 vs. 25 cases per 10,000 women-years.^[36]

In women with a history of cardiovascular disease, the use of estrogen and progestin combination therapy increases the risk of developing urinary incontinence. Patients in the HERS study who did not have urinary incontinence prior to the studies initiation were observed to determine if hormone replacement therapy was helpful in preventing urinary incontinence. The study found that women who received estrogen/progestin therapy were almost twice as likely as patients receiving placebo to develop urge incontinence and 3 times as likely to develop stress incontinence after 1 year of treatment. At 4 years, the effect of hormone replacement therapy became even more pronounced, increasing the risk to 3.23 for urge incontinence and to 4.81 for stress incontinence. The applicability of these findings to women who use estrogen alone with estradiol is unclear.^[100]

Estradiol vaginal ring inserts do not dissolve, and remain inserted into the vaginal for prolonged periods. Toxic-shock syndrome (TSS) has been reported in women using vaginal rings containing estradiol. TSS is a rare but life threatening complication of bacterial infection; often it results from toxins produced by Staphylococcus aureus bacteria, but may also be caused by toxins from group A streptococcus. Examples of signs/symptoms of TSS include fever, nausea, vomiting, diarrhea, muscle pain, dizziness, fainting, or a sunburn-rash on the face and body. Patients experiencing any of these effects should be instructed to contact their prescriber immediately.^[11][10]

Vaginal estradiol products may cause localized vaginal pruritus/itching or rarely, vaginal irritation. In a clinical trial comparing estradiol vaginal tablet inserts 10 mcg to placebo, vulvovaginal pruritus occurred in 8% of treated patients vs. 2% of patients receiving placebo.^[9] Vaginal ring inserts with estradiol do not dissolve, and remain inserted for prolonged treatment durations. Sometimes, these insertions lead to complications with the ring device. A few cases of inadvertent ring insertion into the urinary bladder or adherence to the bladder wall, which may require surgical removal, have been reported for women using vaginal ring inserts. Adherence of the vaginal rings to the vaginal wall, making removal of the ring difficult, has been reported; some cases have required surgical removal. Vaginal or bladder wall ulceration or erosion may occur with use of the vaginal rings. Symptoms of vaginal erosion and vaginal ulceration have included vaginal pain or irritation, erythema, abrasion, and/or spotting. Vaginal pain upon removal or difficulty removing the vaginal ring should be evaluated by a medical professional. If erosion or ulceration occur, consider temporarily discontinuing the vaginal ring until healing is complete.^[11][10] Also, carefully evaluate unusual vaginal discharge, vaginal pain, or persistent unexplained urinary symptoms such as bladder discomfort in patients using vaginal estradiol products.

There is an association of unopposed estrogen therapy and endometrial hyperplasia in women with an intact uterus. Unopposed estrogen therapy can promote endometrial hyperplasia in approximately 10% of patients with an intact uterus, and thus increase the risk of endometrial cancer. Adding a progestin to estrogen therapy has been shown to reduce, but not eliminate, the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. With concurrent progestin use (cyclically or continuously), the incidence of endometrial hyperplasia due to estradiol is estimated to be 1% or less. Sequential combined or continuous transdermal estrogen-progestin therapy is as effective as oral combined therapy in preventing the development of endometrial hyperplasia. Vaginal use of estrogen does result in systemic absorption, and cases of endometrial hyperplasia have been reported postmarketing in estrogen-alone users. Clinical surveillance of all women using estrogen-alone or estrogen plus progestin therapy is important. Adequate diagnostic measures, including directed or random endometrial sampling when indicated, should be undertaken to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal vaginal bleeding. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12-times greater than in non-users, and appears dependent on duration of treatment and on estrogen dose. Most studies show no significant increased risk associated with use of estrogens for less than 1 year. 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 estrogen therapy is discontinued. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose.^{[6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][101][102][103][23][5][22]}

Numerous epidemiologic studies have examined the effects of estrogen and estrogen-progestin hormone replacement therapy (HRT) on the development of new primary malignancy (e.g., breast cancer, endometrial cancer, ovarian cancer) in postmenopausal women. Detailed clinical study information regarding what is known about cancer risk in postmenopausal women is available in the boxed warnings and precautions section of the product labeling for the products, as these risks must be considered prior to use of HRT in women, and with consideration to age and other risk factors for these events. The risk for endometrial cancer is increased in women who take unopposed estrogen. Adding a progestin to estrogen therapy has been shown to reduce, but not eliminate, the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. The Women’s Health Initiative (WHI) estrogen plus progestin study reported increased risks of invasive breast cancer in patients taking combined estrogen-progestin HRT vs. placebo. The potential risk of breast cancer may increase with longer duration of use. Women who used hormonal therapy for menopausal symptoms also had an increased risk for ovarian cancer, but data are still uncertain if risk is associated with a specific duration of use.^{[5][25][104][1][6][7][8][10][11][13][12][14][15][16][17][18][19][20][21][22]}

Estrogen administration such as estradiol may lead to severe hypercalcemia in patients with breast cancer and bone metastases. If hypercalcemia occurs, discontinue estradiol and take appropriate measures to reduce the serum calcium concentration.^[8][12]

Estradiol cypionate or estradiol valerate injections may cause an injection site reaction, which may include erythema and mild pain and rarely may cause sterile abscess. Never inject these injections intravenously, they are for intramuscular use only. These injections are formulated in oil, and inadvertent intravenous administration may result in pulmonary oil microembolism and serious morbidity.^[19][20]

Estradiol is contraindicated for use during known or suspected pregnancy. Little or no increased risk of birth defects appears to exist in children born to women who have used estrogens and progestins from oral contraceptives inadvertently during early pregnancy.^[8][12]Estrogens are known to cause teratogenesis with continued use during pregnancy. 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. The use of diethylstilbestrol, DES is well known for creating disturbances in the reproductive systems of both male and female offspring; similar disturbances are reported to occur in female offspring of rats exposed to estradiol during gestation. In any patient in whom pregnancy is suspected, pregnancy should be ruled out before continuing estradiol use.

Estrogens are contraindicated during pregnancy. There is no known approved indication for the use of estrogens during pregnancy. There appears to be little or no increased risk of birth defects in children born to women who have used estrogens and progestins from oral contraceptives inadvertently during early pregnancy.^{[6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22]} Estradiol and other estrogens freely cross the placenta to the fetus. 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 continued use of estrogens in pregnant women. In any patient in whom pregnancy is suspected, pregnancy should be ruled out before continuing estrogen use.^[12] In select instances estradiol has been 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; however, treatment is discontinued when pregnancy ensues.^[31]

Caution should be used if a breastfeeding mother is receiving estradiol for hormone replacement. Estrogen administration to nursing women is generally avoided during lactation as estrogens have been shown to decrease the quantity and quality of breast milk. Detectable amounts of estrogens have been identified in the milk of mothers receiving estradiol and other estrogens.^{[6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][32][22]} Estrogens are not approved by the FDA for the treatment of postpartum breast engorgement.^[12]

Interactions: NOTE: In vitro and in vivo studies indicate that estrogens are partially metabolized by CYP3A4.^[40] Interactions with drugs that are inhibitors or inducers of CYP3A4 are possible.

Bromocriptine is used to restore ovulation and ovarian function in amenorrheic women.^[41] Estrogens can cause amenorrhea and, therefore, counteract the desired effects of bromocriptine. Concurrent use is not recommended.

Estrogens can increase calcium absorption. In general, the interaction between calcium salts and estrogen is beneficial and is used to therapeutic advantage in postmenopausal women who have osteoporosis. However, this interaction may not be advantageous in patients predisposed to hypercalcemia or nephrolithiasis.^[42]

There have been reports indicating the estrogens and/or progestins in oral contraceptives or non-oral combinatio contraceptives may inhibit the metabolism of cyclosporine.^[43][44][45] Delayed cyclosporine clearance and elevated cyclosporine concentrations can lead to seizures, nephrotoxicity and/or hepatotoxicity. Additionally, estrogens are metabolized by CYP3A4; cyclosporine may increase plasma concentrations of estrogens and cause estrogen-related side effects such as nausea and breast tenderness.^[46][47] If oral contraceptives, non-oral combination contraceptives, estrogens, or progestins are initiated or discontinued, the patient’s cyclosporine concentrations should be monitored closely. Additionally, patients should be monitored for estrogenic side effects if these drugs are used concomitantly.

Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known.^[42] Estrogens have reportedly potentiated the anti-inflammatory effects of hydrocortisone.^[48] Patients should be monitored for increased corticosteroid effects if estrogens, oral contraceptives, or non-oral combination contraceptives are used with hydrocortisone.

Estrogens have been associated with elevated serum concentrations of corticosteroid binding globulin (CBG), leading to increased total circulating corticosteroids, although the free concentrations of these hormones may be lower; the clinical significance is not known.^[42] Ethinyl estradiol has reportedly delayed the clearance of prednisolone.^[49] Patients should be monitored for increased corticosteroid effects if estrogens, oral contraceptives, or non-oral combination contraceptives are used with prednisolone.

Concomitant use of dantrolene and estrogens may increase the risk of developing hepatotoxicity. While a definite drug interaction with dapsone and estrogen therapy has not yet been established, caution should be observed if the two drugs are to be given concomitantly. Hepatotoxicity has occurred more often, for example, in women over 35 years of age receiving concomitant estrogen therapy.^[50][51]

Estrogens interact with growth hormone (somatropin and somatrem) during pre-puberty by accelerating epiphysial maturation.^[52]

Estrogens increase the hepatic synthesis of prothrombin and factors VII, VIII, IX, and X and decrease antithrombin III; estrogens also increase norepinephrine-induced platelet aggregability.^[47] A positive relationship between hormone replacement therapy and the risk of thromboembolic disease has been demonstrated in the Women’s Health Initiative Trials (WHI trials).^[53] The US FDA has suggested class labeling of HRT products in accordance with this data. HRT products are generally contraindicated in patients with a current history of stroke, cerebrovascular disease, coronary artery disease, coronary thrombosis, thrombophlebitis (including pulmonary embolism and DVT), thromboembolic disease or valvular heart disease with complications. Concurrent use of HRT in female patients receiving anticoagulation therapy with warfarin is generally avoided. If concurrent use of an estrogen or estrogen-progestin containing HRT cannot be avoided in a pateint taking warfarin, carefully monitor for signs and symptoms of thromboembolic complications. If such occur, the estrogen or estrogen-progestin containing HRT regimen should be discontinued. HRT is not expected to significantly alter the INR or to affect the metabolism of warfarin.^[54] Dosage adjustment of warfarin should be based on the prothrombin time or INR value.

The use of estrogens, including oral contraceptives, with tamoxifen is controversial and is generally considered contraindicated in most, but not all, circumstances.^[55]

Raloxifene^[56] exerts its effects by blocking estrogen receptors. Since raloxifene and estrogens are pharmacological opposites, it would be illogical to coadminister them.

The oxidative metabolism of tricyclic antidepressants may be decreased by estrogens.^[57] Increased antidepressant serum concentrations may occur.

Cimetidine has been reported to reduce the hepatic clearance of estradiol; this interaction may partially explain the association between cimetidine therapy and gynecomastia.^[58][59]

There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins.^[60] In addition, bosentan is teratogenic and is contraindicated during pregnancy.^[60] Effective contraception through additional forms of contraception must be practiced.

An alternative method or an additional method of contraception should be utilized during modafinil therapy and continued for one month after modafinil discontinuation.^[61] Similarly, a decrease in estrogen concentrations, and thus efficacy, may occur if modafinil is used in patients taking estrogens. Dosage adjustments may be necessary.

Phenytoin: pregnancy has been reported during therapy with estrogens, oral contraceptives, non-oral combination contraceptives, or progestins in patients receiving phenytoin concurrently.^[62]

An alternate or additional form of contraception should be considered in patients prescribed concomitant therapy with enzyme-inducing anticonvulsants, or higher-dose hormonal regimens may be indicated where acceptable or applicable. Epileptic women taking both anticonvulsants (AEDs) and Oral Contraceptives (OCs) may be at higher risk of folate deficiency secondary to additive effects on folate metabolism; if oral contraceptive failure occurs, the additive effects could potentially heighten the risk of neural tube defects in pregnancy.^[63] The alternative or additional contraceptive agent may need to be continued for one month after discontinuation of the interacting medication.

Estrogens and progestins are both susceptible to drug interactions with hepatic enzyme inducing drugs such as the carbamazepine family; barbiturates; rifampin, rifabutin, or rifapentine.^{[64][65][66][67][66][68][69][40][70][46][71][40][70]} Concurrent administration of said drugs with estrogens, oral contraceptives, non-oral combination contraceptives, or progestins may increase the hormone’s elimination.

Concomitant use of griseofulvin and oral contraceptives has been reported to reduce the efficacy of the oral contraceptive and cause breakthrough bleeding.^[72][73] An alternate or additional form of contraception should be used during concomitant treatment and should be continued for 1 month after griseofulvin discontinuation.

Topiramate can increase the clearance of ethinyl estradiol and compromise the efficacy of estrogens or progestins used for contraception or hormone replacement therapies.^[74] Dosages of the products may need adjustment; the manufacturer of topiramate recommends that an oral contraceptive containing 50 mcg of ethinyl estradiol be used. Different or additional forms of contraception may also be needed.

Based on very limited data, it appears felbamate can accelerate the clearance of the estrogen component of some oral contraceptives.^[75][76] Additionally, patients taking non-oral combination contraceptives or estrogens or progestins for hormone replacement therapy may also experience reduced clinical efficacy; dosage adjustments may be necessary.

Nevirapine may decrease plasma concentrations of oral contraceptives, non-oral combination contraceptives, and other hormones, including estrogens and progestins.^[77]

Grapefruit juice has been reported to decrease estrogen metabolism.^[42]

Patients receiving antidiabetic agents should be closely monitored for signs indicating loss of diabetic control or hypoglycemia when therapy with any of these agents is instituted or discontinued.^[42]

Dose adjustments may be needed in some hypothyroid patients receiving exogenous thyroid treatments who initiate estrogen therapy.^[78]

It appears that the simultaneous administration of estrogens and mineral oil, as a laxative, may decrease the absorption of the estrogens, resulting in lower estrogen plasma concentrations.^[79]

Estrogens could interfere competitively with the pharmacologic action of the aromatase inhibitors.^{[80][81][82][83]} Estrogen therapy is not recommended during aromatase inhibitor treatment, due to opposing pharmacologic actions.

Estrogens and combined hormonal and oral contraceptives may counteract the effectiveness of ursodeoxycholic acid, ursodiol.^[84][85]

Theoretically, the soy isoflavones may compete with or have additive effects with, drugs that have estrogenic activity or which selectively modulate estrogen receptors.^[86][87] Soy isoflavones should be used with caution in patients taking estrogens, since the effects of combining soy isoflavone dietary supplements with estrogens are not clear.

Bexarotene: it is recommended that two reliable forms of contraception be used simultaneously, unless abstinence is the chosen method, during oral bexarotene therapy (see Bexarotene Contraindications).^[88] Because of the potential interaction with hormonal contraceptives it is strongly recommended that one of the forms of contraception be non-hormonal.^[89]

Nefazodone: estrogenic-related side effects (e.g., nausea, breast tenderness) may potentially increase when nefazodone is coadministered with either estrogens or combined hormonal contraceptives, including oral contraceptives.^[90]

Application of sunscreen 10 minutes prior to the application of estradiol topical emulsion (i.e., Estrasorb) increases the exposure to estradiol by approximately 35%. Application of sunscreen 25 minutes after the application of estradiol topical emulsion (Estrasorb) increases the exposure to estradiol by approximately 15%.^[91]

A subtherapeutic response to metyrapone can be seen in patients on estrogen therapy.^[92]

The efficacy of estrogens and/or progestins may be reduced when coadministered with aprepitant, fosaprepitant.^[93]

St. John’s wort, Hypericum perforatum appears to interact with estrogens and oral contraceptives.^[94] One report noted intermenstrual bleeding after the concurrent use of St. John’s wort in 8 premenstrual women who had been on oral contraceptives for long durations of time.

Erythromycin, amiodarone, systemic azole antifungals (fluconazole, itraconazole, ketoconazole, miconazole, posaconazole, and voriconazole), clarithromycin, conivaptan, danazol, dalfopristin,dasatinib, delavirdinine, diltiazem, duloxetine, fluvoxamine, imatinib, mifepristone, RU-486, propoxyphene, telithromycin, troleandomycin, verapamil, zafirlukast, zileuton: these compounds may increase plasma concentrations of estrogens and cause estrogen-related side effects.^[46][47]

Interactions between anti-retroviral protease inhibitors and estrogens or progestins are complex. It may be prudent to use caution and careful monitoring during coadministration of fosamprenavir or other retrovirals with estrogens or progestins.

Store this medication at 68°F to 77°F (20°C to 25°C) and away from heat, moisture and light. Keep all medicine out of the reach of children. Throw away any unused medicine after the beyond use date. Do not flush unused medications or pour down a sink or drain.

1. The 2017 hormone therapy position statement of The North American Menopause Society. Menopause. 2017 Jun 22. [Epub aheadof print]
2. The Heart and Estrogen/progestin Replacement Study (HERS) Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998;280:605-13.
3. Grady D, Herrington D, Bittner V, et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002;288:49-57.
4. Hulley S, Furberg C, Barrett-Connor E, et al. Noncardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and Estrogen/progestin Replacement Study follow-up (HERS II). JAMA 2002;288:58-66.
5. Rossouw JE, Anderson GL, Prentice RL, et al. The Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative ra
6. Elestrin (estradiol topical gel) package insert. Somerset, NJ: Meda Pharmaceuticals Inc; 2017 Nov.
7. Evamist (estradiol transdermal spray) package insert. Minneapolis, MN: Perrigo Pharmaceuticals; 2017 Nov.
8. Estrace cream (estradiol vaginal cream) package insert. Irvine, CA; Allergan USA, Inc; 2017 Nov.
9. Vagifem (estradiol vaginal insert) package insert. Plainsboro, NJ: Novo Nordisk Inc.; 2017 Nov.
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