Overview Of Estradiol Valerate Injection
Dosage Power Of Estradiol Valerate Injection
Commercial: 10 mg/mL 5 mL Vial (Sesame Oil)
Commercial: 20 mg/mL 5 mL Vial (Sesame Oil)
Commercial: 40 mg/mL 5 mL Vial (Sesame Oil)
Compounded: 40 mg/mL 5 mL Vial (Grapeseed Oil)
Commercial: 20 mg/mL 5 mL Vial (Sesame Oil)
Commercial: 40 mg/mL 5 mL Vial (Sesame Oil)
Compounded: 40 mg/mL 5 mL Vial (Grapeseed Oil)
Generic Details
Estrogens are a group of female sex hormones produced primarily by the ovaries. They are also synthesized at non-gonadal sites including adipose tissue, adrenal glands, bone, liver, and brain. Structurally, they are a class of steroid hormones responsible for normal development and maintenance of the female reproductive system. At puberty, estrogens promote the development of female secondary sex characteristics including breast development, axillary and pubic hair growth, and maintenance of the estrous cycle. Estrogens also influence physiological pathways that contribute to the health of bones, the cardiovascular system, and the nervous system.
There are three types of estrogens in females – estradiol, estrone, and estriol. Of the three forms, E2 or 17β-estradiol is the most potent estrogen. Most importantly, estradiol is the principal estrogen in premenopausal women. Serum estradiol levels vary between 15-350 pg/mL in pre-menopausal women (depending on the stage of the menstrual cycle) and fall to <10 pg/mL in postmenopausal women. This decrease in hormone levels is responsible for vasomotor symptoms of menopause including hot flashes, night sweats, heart palpitations, and changes in blood pressure. Some women opt for hormone therapy to relieve vasomotor symptoms of menopause. Historically, estradiol derived from cow ovaries or from the urine of pregnant mares was used to treat menopausal symptoms. Eventually, the first synthetic estrogen derivative was approved by the US FDA in 1941. Since then, several FDA-approved medications containing estradiol or its synthetic derivatives are available as pills, transdermal patches, transdermal sprays, gels, topical creams, vaginal creams, vaginal inserts, vaginal rings, vaginal tablets, and intramuscular injections. There is no evidence to show that bioidentical hormones or estrogens derived from natural sources are safer or more efficacious than synthetic estrogens. Estradiol valerate is the synthetic esterified pro-drug of estradiol. Inside the body, this pro-drug is cleaved into 17β-estradiol and a fatty acid. Therefore, its biological effects are no different from endogenously circulating estradiol. Esterification provides the benefits of improved drug bioavailability following oral administration, enhanced lipophilicity, and sustained release of estradiol after intramuscular depot injection. Estradiol valerate injection is indicated for the treatment of moderate to severe vasomotor symptoms as well as vulvar or vaginal atrophy associated with menopause. It can also be used to treat hypoestrogenism that occurs as a result of castration or primary ovarian failure. In men, it is indicated for palliative treatment of advanced androgen-dependent prostate cancer. Estrogen therapy is associated with increased risk of cardiovascular disorders including myocardial infarction, stroke, and venous thromboembolism. Long-term estrogen therapy is also associated with an increased risk of endometrial, breast, and ovarian cancer.
There are three types of estrogens in females – estradiol, estrone, and estriol. Of the three forms, E2 or 17β-estradiol is the most potent estrogen. Most importantly, estradiol is the principal estrogen in premenopausal women. Serum estradiol levels vary between 15-350 pg/mL in pre-menopausal women (depending on the stage of the menstrual cycle) and fall to <10 pg/mL in postmenopausal women. This decrease in hormone levels is responsible for vasomotor symptoms of menopause including hot flashes, night sweats, heart palpitations, and changes in blood pressure. Some women opt for hormone therapy to relieve vasomotor symptoms of menopause. Historically, estradiol derived from cow ovaries or from the urine of pregnant mares was used to treat menopausal symptoms. Eventually, the first synthetic estrogen derivative was approved by the US FDA in 1941. Since then, several FDA-approved medications containing estradiol or its synthetic derivatives are available as pills, transdermal patches, transdermal sprays, gels, topical creams, vaginal creams, vaginal inserts, vaginal rings, vaginal tablets, and intramuscular injections. There is no evidence to show that bioidentical hormones or estrogens derived from natural sources are safer or more efficacious than synthetic estrogens. Estradiol valerate is the synthetic esterified pro-drug of estradiol. Inside the body, this pro-drug is cleaved into 17β-estradiol and a fatty acid. Therefore, its biological effects are no different from endogenously circulating estradiol. Esterification provides the benefits of improved drug bioavailability following oral administration, enhanced lipophilicity, and sustained release of estradiol after intramuscular depot injection. Estradiol valerate injection is indicated for the treatment of moderate to severe vasomotor symptoms as well as vulvar or vaginal atrophy associated with menopause. It can also be used to treat hypoestrogenism that occurs as a result of castration or primary ovarian failure. In men, it is indicated for palliative treatment of advanced androgen-dependent prostate cancer. Estrogen therapy is associated with increased risk of cardiovascular disorders including myocardial infarction, stroke, and venous thromboembolism. Long-term estrogen therapy is also associated with an increased risk of endometrial, breast, and ovarian cancer.
MOA
The effects of both endogenous estradiol and synthetic estradiol derivatives are mediated via estrogen receptors. There are two types of estrogen receptors – ERα and ERβ. Located primarily on the nucleus, the two receptor subtypes have distinct tissue expression patterns. ERα is expressed primarily in gonadal organs (uterus, ovaries, prostate, and testes), while ERβ is expressed primarily in non-gonadal tissues (bone marrow, vascular endothelium, lung, bladder, and colon). Estradiol exerts its effects on tissues and organ systems where estrogen receptors are expressed.
Estradiol binds to nuclear receptors to produce a physiological response. The hormone-receptor complex acts as a transcription factor that binds to the promoter region of specific genes and alters their expression in target organs.
Since estradiol is the main estrogen in premenopausal women, its plays an important role in the maintenance of the estrous cycle. Estradiol levels are low at the beginning of the menstrual cycle. As the ovarian follicle matures, it starts producing estradiol. Depending on the phase of the menstrual cycle, 70 – 500 micrograms of estradiol may be secreted by the ovaries The mid-cycle rise in estradiol levels activates a negative feedback mechanism. Increase in estradiol levels inhibit the secretion of follicle stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary gland. This inhibitory mechanism is absent in post-menopausal women given the consistently low levels of circulating estradiol.
Vasomotor symptoms have been reported in 50 to 82 percent of U.S. women experiencing menopause. The exact mechanism responsible for these symptoms is not known. It is hypothesized that a combination of higher FSH levels and low estradiol levels may disrupt thermoregulation, resulting in hot flashes, chills, and night sweats. About 27 to 60 percent of women experiencing menopause also report moderate to severe symptoms of vaginal dryness and vulvovaginal atrophy. Therefore, hormone therapy involving low dose estradiol administered locally or systemically is used to treat moderate to severe vulvovaginal and vasomotor symptoms of menopause.
Postmenopausal osteoporosis affects an estimated 200 million women globally. Estrogens contribute to bone health by maintaining bone mineral density and microarchitecture. Estrogen inhibits bone resorption by increasing the production of calcitonin and reducing sensitivity to parathyroid hormone. Estrogen deficiency during menopause leads to a disproportionate increase in bone resorption over bone formation. This increases bone fragility leading to fractures. Estrogen therapy alone or in combination with a progestogen can improve bone mineral density and reduce the risk of postmenopausal osteoporotic fractures.
The effects of estrogen on the cardiovascular system are mixed. Hormone therapy with estradiol alone or in combination with progestin showed reduction in LDL cholesterol and elevation of HDL cholesterol and triglycerides. These effects may be attributed to estrogen receptor-mediated changes in lipid metabolism in the liver. However, two large randomized controlled trials found conflicting results for the effect of estrogen therapy on cardiovascular disease risk. The HERS trial did not find any significant improvement in cardiovascular disease risk, while the WHI study reported that hormone therapy worsened cardiovascular disease risk. Cardiovascular effects were most evident when estradiol was administered through systemic routes than non-systemically. The risk of cardiovascular disease increases if hormone therapy is initiated by postmenopausal women older than 60 years, or more than 10 years after menopause onset, and with continued long-term use. Therefore, estrogen therapy should be prescribed for the shortest duration based on treatment goals and only after the risks and benefits have been determined for each woman individually.
Chronic unopposed use of estrogens increases the risk of endometrial cancer in a duration and dose-dependent manner. When low-dose estrogen is combined with progestogen, the risk of endometrial cancer is reduced to near placebo levels During the normal menstrual cycle, rise in estrogen levels stimulate growth of the endometrium in anticipation of pregnancy. However, this growth is countered by the rise in progesterone during the luteal phase of the menstrual cycle. Consequently, in women with intact uteri, exogenous estrogens without progestogens cause unabated thickening of the uterine endometrial lining. Some studies suggest that long-term use of systemic estrogen therapy lasting more than 5 years may also increase the risk of breast and ovarian cancer.
In men, estrogen therapy has been evaluated for the treatment of androgen-dependent prostate cancer. Estrogens activate a negative feedback mechanism, inhibiting the release of LH from the anterior pituitary and ultimately lowering testosterone levels. Oral diethylstilbesterol was previously used to treat prostate cancer. However, it was discontinued due to increased cardiotoxicity. Subsequently, low dose estrogen therapy through non-systemic routes such as transdermal patches was tested. It reduced testosterone levels and led to concomitant reduction in prostate-specific antigen.
Estradiol binds to nuclear receptors to produce a physiological response. The hormone-receptor complex acts as a transcription factor that binds to the promoter region of specific genes and alters their expression in target organs.
Since estradiol is the main estrogen in premenopausal women, its plays an important role in the maintenance of the estrous cycle. Estradiol levels are low at the beginning of the menstrual cycle. As the ovarian follicle matures, it starts producing estradiol. Depending on the phase of the menstrual cycle, 70 – 500 micrograms of estradiol may be secreted by the ovaries The mid-cycle rise in estradiol levels activates a negative feedback mechanism. Increase in estradiol levels inhibit the secretion of follicle stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary gland. This inhibitory mechanism is absent in post-menopausal women given the consistently low levels of circulating estradiol.
Vasomotor symptoms have been reported in 50 to 82 percent of U.S. women experiencing menopause. The exact mechanism responsible for these symptoms is not known. It is hypothesized that a combination of higher FSH levels and low estradiol levels may disrupt thermoregulation, resulting in hot flashes, chills, and night sweats. About 27 to 60 percent of women experiencing menopause also report moderate to severe symptoms of vaginal dryness and vulvovaginal atrophy. Therefore, hormone therapy involving low dose estradiol administered locally or systemically is used to treat moderate to severe vulvovaginal and vasomotor symptoms of menopause.
Postmenopausal osteoporosis affects an estimated 200 million women globally. Estrogens contribute to bone health by maintaining bone mineral density and microarchitecture. Estrogen inhibits bone resorption by increasing the production of calcitonin and reducing sensitivity to parathyroid hormone. Estrogen deficiency during menopause leads to a disproportionate increase in bone resorption over bone formation. This increases bone fragility leading to fractures. Estrogen therapy alone or in combination with a progestogen can improve bone mineral density and reduce the risk of postmenopausal osteoporotic fractures.
The effects of estrogen on the cardiovascular system are mixed. Hormone therapy with estradiol alone or in combination with progestin showed reduction in LDL cholesterol and elevation of HDL cholesterol and triglycerides. These effects may be attributed to estrogen receptor-mediated changes in lipid metabolism in the liver. However, two large randomized controlled trials found conflicting results for the effect of estrogen therapy on cardiovascular disease risk. The HERS trial did not find any significant improvement in cardiovascular disease risk, while the WHI study reported that hormone therapy worsened cardiovascular disease risk. Cardiovascular effects were most evident when estradiol was administered through systemic routes than non-systemically. The risk of cardiovascular disease increases if hormone therapy is initiated by postmenopausal women older than 60 years, or more than 10 years after menopause onset, and with continued long-term use. Therefore, estrogen therapy should be prescribed for the shortest duration based on treatment goals and only after the risks and benefits have been determined for each woman individually.
Chronic unopposed use of estrogens increases the risk of endometrial cancer in a duration and dose-dependent manner. When low-dose estrogen is combined with progestogen, the risk of endometrial cancer is reduced to near placebo levels During the normal menstrual cycle, rise in estrogen levels stimulate growth of the endometrium in anticipation of pregnancy. However, this growth is countered by the rise in progesterone during the luteal phase of the menstrual cycle. Consequently, in women with intact uteri, exogenous estrogens without progestogens cause unabated thickening of the uterine endometrial lining. Some studies suggest that long-term use of systemic estrogen therapy lasting more than 5 years may also increase the risk of breast and ovarian cancer.
In men, estrogen therapy has been evaluated for the treatment of androgen-dependent prostate cancer. Estrogens activate a negative feedback mechanism, inhibiting the release of LH from the anterior pituitary and ultimately lowering testosterone levels. Oral diethylstilbesterol was previously used to treat prostate cancer. However, it was discontinued due to increased cardiotoxicity. Subsequently, low dose estrogen therapy through non-systemic routes such as transdermal patches was tested. It reduced testosterone levels and led to concomitant reduction in prostate-specific antigen.
Clinical Pharmacokinetics
Except for absorption, the pharmacokinetics of exogenous estradiol is similar to endogenous estradiol.
Absorption: Alkyl esters of estradiol such as estradiol valerate, cypionate, and benzoate are long-acting estrogens. Absorption is altered based on the type of formulation and route of administration. Following intravenous administration of estradiol valerate, maximum plasma concentrations of 17β-estradiol were detected within 15 min of injection. However, when estradiol valerate in an oily solution was administered intramuscularly, maximum 17β-estradiol concentrations were reached after 3 – 5 days. Thus, a single intramuscular depot injection consisting of an estradiol alkyl ester in an oil solution is absorbed over several weeks.
Distribution: Approximately 95 to 98 percent of estradiol is transported in blood by binding to plasma proteins. Estradiol circulating in blood is bound loosely to albumin or tightly to sex hormone binding globulin. Due to its lipophilic nature, free estradiol readily diffuses across the plasma membrane of cells. Downstream estrogen signaling is activated in target organs expressing ERα and ERβ receptors.
Metabolism: Estradiol undergoes differential metabolism based on the various routes of administration. Orally administered estradiol has low bioavailability as it undergoes extensive first pass metabolism. Using other routes of administration (intravenous, intramuscular, transdermal, etc.) can help avoid the first pass effect. Following absorption into the body, exogenous estrogens that are not bound to plasma proteins undergo metabolic interconversions similar to endogenous estrogens. Estradiol is reversibly converted to estrone by the enzyme 17β-hydroxysteroid dehydrogenase. Estradiol and estrone are irreversibly hydroxylated to estriol and catechol estrogens by the cytochrome P450 (CYP) enzymes CYP1A1, CYP1B1, CYP1A2, and CYP3A4. The parent estrogens and catechol estrogens are further conjugated to glucuronides and sulfates by hepatic enzymes.
Excretion: Estriol is the major estrogen metabolite excreted in urine, along with glucuronide and sulfate conjugates.
Absorption: Alkyl esters of estradiol such as estradiol valerate, cypionate, and benzoate are long-acting estrogens. Absorption is altered based on the type of formulation and route of administration. Following intravenous administration of estradiol valerate, maximum plasma concentrations of 17β-estradiol were detected within 15 min of injection. However, when estradiol valerate in an oily solution was administered intramuscularly, maximum 17β-estradiol concentrations were reached after 3 – 5 days. Thus, a single intramuscular depot injection consisting of an estradiol alkyl ester in an oil solution is absorbed over several weeks.
Distribution: Approximately 95 to 98 percent of estradiol is transported in blood by binding to plasma proteins. Estradiol circulating in blood is bound loosely to albumin or tightly to sex hormone binding globulin. Due to its lipophilic nature, free estradiol readily diffuses across the plasma membrane of cells. Downstream estrogen signaling is activated in target organs expressing ERα and ERβ receptors.
Metabolism: Estradiol undergoes differential metabolism based on the various routes of administration. Orally administered estradiol has low bioavailability as it undergoes extensive first pass metabolism. Using other routes of administration (intravenous, intramuscular, transdermal, etc.) can help avoid the first pass effect. Following absorption into the body, exogenous estrogens that are not bound to plasma proteins undergo metabolic interconversions similar to endogenous estrogens. Estradiol is reversibly converted to estrone by the enzyme 17β-hydroxysteroid dehydrogenase. Estradiol and estrone are irreversibly hydroxylated to estriol and catechol estrogens by the cytochrome P450 (CYP) enzymes CYP1A1, CYP1B1, CYP1A2, and CYP3A4. The parent estrogens and catechol estrogens are further conjugated to glucuronides and sulfates by hepatic enzymes.
Excretion: Estriol is the major estrogen metabolite excreted in urine, along with glucuronide and sulfate conjugates.
Precautions
Estrogen therapy has been shown to increase the risk of dementia and cardiovascular events including myocardial infarction, stroke, and venous thromboembolism. Prolonged use of estrogens without progestins significantly increases the risk of endometrial cancer in a time and dose-dependent manner. Long-term systemic estrogen therapy may also increase the risk of breast and ovarian cancer, especially in women aged over 60 years with underlying genetic and environmental risk factors.
Pregnancy
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. 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. 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.
Breast-Feeding
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. Estrogens are not approved by the FDA for the treatment of postpartum breast engorgement.
Drug Interactions
NOTE: In vitro and in vivo studies indicate that estrogens are partially metabolized by CYP3A4. Interactions with drugs that are inhibitors or inducers of CYP3A4 are possible.
Bromocriptine is used to restore ovulation and ovarian function in amenorrheic women. 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.
There have been reports indicating the estrogens and/or progestins in oral contraceptives or non-oral combinatio contraceptives may inhibit the metabolism of cyclosporine. 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. 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. Estrogens have reportedly potentiated the anti-inflammatory effects of hydrocortisone. 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. Ethinyl estradiol has reportedly delayed the clearance of prednisolone. 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.
Estrogens interact with growth hormone (somatropin and somatrem) during pre-puberty by accelerating epiphysial maturation.
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. 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). 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. 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.
Raloxifene 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. 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.
There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. In addition, bosentan is teratogenic and is contraindicated during pregnancy. 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. 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.
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. 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. 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. 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. 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. 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.
Grapefruit juice has been reported to decrease estrogen metabolism.
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.
Dose adjustments may be needed in some hypothyroid patients receiving exogenous thyroid treatments who initiate estrogen therapy.
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.
Estrogens could interfere competitively with the pharmacologic action of the aromatase inhibitors. 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.
Theoretically, the soy isoflavones may compete with or have additive effects with, drugs that have estrogenic activity or which selectively modulate estrogen receptors. 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). Because of the potential interaction with hormonal contraceptives it is strongly recommended that one of the forms of contraception be non-hormonal.
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.
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%.
A subtherapeutic response to metyrapone can be seen in patients on estrogen therapy.
The efficacy of estrogens and/or progestins may be reduced when coadministered with aprepitant, fosaprepitant.
St. John’s wort, Hypericum perforatum appears to interact with estrogens and oral contraceptives. 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.
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.
Bromocriptine is used to restore ovulation and ovarian function in amenorrheic women. 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.
There have been reports indicating the estrogens and/or progestins in oral contraceptives or non-oral combinatio contraceptives may inhibit the metabolism of cyclosporine. 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. 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. Estrogens have reportedly potentiated the anti-inflammatory effects of hydrocortisone. 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. Ethinyl estradiol has reportedly delayed the clearance of prednisolone. 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.
Estrogens interact with growth hormone (somatropin and somatrem) during pre-puberty by accelerating epiphysial maturation.
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. 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). 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. 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.
Raloxifene 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. 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.
There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins. In addition, bosentan is teratogenic and is contraindicated during pregnancy. 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. 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.
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. 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. 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. 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. 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. 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.
Grapefruit juice has been reported to decrease estrogen metabolism.
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.
Dose adjustments may be needed in some hypothyroid patients receiving exogenous thyroid treatments who initiate estrogen therapy.
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.
Estrogens could interfere competitively with the pharmacologic action of the aromatase inhibitors. 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.
Theoretically, the soy isoflavones may compete with or have additive effects with, drugs that have estrogenic activity or which selectively modulate estrogen receptors. 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). Because of the potential interaction with hormonal contraceptives it is strongly recommended that one of the forms of contraception be non-hormonal.
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.
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%.
A subtherapeutic response to metyrapone can be seen in patients on estrogen therapy.
The efficacy of estrogens and/or progestins may be reduced when coadministered with aprepitant, fosaprepitant.
St. John’s wort, Hypericum perforatum appears to interact with estrogens and oral contraceptives. 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.
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.
Estradiol Valerate Injection Side Effects & Reactions
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. 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.
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.
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. 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. 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. 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.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. 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. Persistent or severe abdominal symptoms should be evaluated by a medical professional.
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.
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. 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. 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. 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. 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. 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. 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. Estradiol topical emulsions and sprays have also been associated with pruritus or skin irritation during clinical trials. 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. 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.
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. 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. 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.
Leg muscle cramps, arthralgia, and hypocalcemia have been reported with estrogen and/or progestin therapy. 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). 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. 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. 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.
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.
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.
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. 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. 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.
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.
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.
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.
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. 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.
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.
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. 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. 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. 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.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. 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. Persistent or severe abdominal symptoms should be evaluated by a medical professional.
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.
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. 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. 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. 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. 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. 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. 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. Estradiol topical emulsions and sprays have also been associated with pruritus or skin irritation during clinical trials. 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. 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.
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. 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. 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.
Leg muscle cramps, arthralgia, and hypocalcemia have been reported with estrogen and/or progestin therapy. 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). 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. 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. 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.
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.
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.
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. 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. 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.
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.
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.
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.
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. 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.
How To Store
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.
Where to Buy Arousal Cream in Florida?
You can order Estradiol Valerate Injection from MediLab’s compounding pharmacy in the following Florida regions:
| North Florida | South Florida | ||
|---|---|---|---|
| Jacksonville | Miami | West Palm Beach | Weston |
| Pensacola | Hialeah | Pompano Beach | Delray Beach |
| Tallahassee | Fort Lauderdale | Davie | Homestead |
| Ocala | Port St. Lucie | Miami Beach | Tamarac |
| Gainesville | Pembroke Pines | Plantation | Sarasota |
| Fort Walton Beach | Hollywood | Sunrise | Wellington |
| Panama City | Miramar | Boca Raton | Jupiter |
| Palm Coast | Coral Springs | Deerfield Beach | Margate |
| Dunnellon | Miami Gardens | Boynton Beach | Coconut Creek |
| Naples | Lauderhill | Broward | |
| Spring hill | Orlando | ||
References [Click to open/close]
- Cui, J., Shen, Y. & Li, R. Estrogen synthesis and signaling pathways during aging: From periphery to brain. Trends in Molecular Medicine vol. 19 197–209 (2013).
- ESTF – Clinical: Estrogens, Estrone (E1) and Estradiol (E2), Fractionated, Serum. https://www.mayocliniclabs.com/test-catalog/Clinical+and+Interpretive/84230.
- Stefanick, M. L. Estrogens and progestins: background and history, trends in use, and guidelines and regimens approved by the US Food and Drug Administration. (2005) doi:10.1016/j.amjmed.2005.09.059.
- Menopause: Medicines to Help You | FDA. https://www.fda.gov/consumers/free-publications-women/menopause-medicines-help-you#estonly.
- Düsterherg, B., Schmidt-Gollwitzer, M. & Hümpel, M. Pharmacokinetics and biotransformation of estradiol valerate in ovariectomized women. Horm. Res. Paediatr. 21, 145–154 (1985).
- fda & cder. DELESTROGEN® (estradiol valerate injection, USP).
- Pinkerton, J. A. V. et al. The 2017 hormone therapy position statement of the North American Menopause Society. Menopause vol. 24 728–753 (2017).
- Findlay, J. K., Liew, S. H., Simpson, E. R. & Korach, K. S. Estrogen signaling in the regulation of female reproductive functions. Handbook of Experimental Pharmacology vol. 198 29–35 (2010).
- Management of menopausal symptoms. Obstet. Gynecol. 123, 202–216 (2014).
- Thurston, R. C. & Joffe, H. Vasomotor Symptoms and Menopause: Findings from the Study of Women’s Health across the Nation. Obstetrics and Gynecology Clinics of North America vol. 38 489–501 (2011).
- Santoro, N. & Komi, J. Prevalence and impact of vaginal symptoms among postmenopausal women. J. Sex. Med. 6, 2133–2142 (2009).
- Johnell, O. & Kanis, J. A. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos. Int. 17, 1726–1733 (2006).
- Hulley, S. et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. J. Am. Med. Assoc. 280, 605–613 (1998).
- Granfone, A. et al. Effects of estrogen replacement on plasma lipoproteins and apolipoproteins in postmenopausal, dyslipidemic women. Metabolism 41, 1193–1198 (1992).
- 15.Walsh, B. W. et al. Effects of Postmenopausal Estrogen Replacement on the Concentrations and Metabolism of Plasma Lipoproteins. N. Engl. J. Med. 325, 1196–1204 (1991).
- Palmisano, B. T., Zhu, L. & Stafford, J. M. Role of estrogens in the regulation of liver lipid metabolism. in Advances in Experimental Medicine and Biology vol. 1043 227–256 (Springer New York LLC, 2017).
- Grady, D. et al. Cardiovascular disease outcomes during 6.8 years of hormone therapy: Heart and estrogen/progestin replacement study follow-up (HERS II). J. Am. Med. Assoc. 288, 49–57 (2002).
- Manson, J. A. E. et al. Estrogen plus progestin and the risk of coronary heart disease. N. Engl. J. Med. 349, 523–534 (2003).
- Weiderpass, E. et al. Risk of endometrial cancer following estrogen replacement with and without progestins. J. Natl. Cancer Inst. 91, 1131–1137 (1999).
- Furness, S., Roberts, H., Marjoribanks, J. & Lethaby, A. Hormone therapy in postmenopausal women and risk of endometrial hyperplasia. Cochrane Database Syst. Rev. (2012) doi:10.1002/14651858.cd000402.pub4.
- Marjoribanks, J., Farquhar, C., Roberts, H., Lethaby, A. & Lee, J. Long-term hormone therapy for perimenopausal and postmenopausal women. Cochrane Database of Systematic Reviews vol. 2017 (2017).<.li>
- Langley, R. E. et al. Early hormonal data from a multicentre phase II trial using transdermal oestrogen patches as first-line hormonal therapy in patients with locally advanced or metastatic prostate cancer. BJU Int. 102, 442–445 (2008).
- O’Connell, M. B. Pharmacokinetic and Pharmacologic Variation Between Different Estrogen Products. J. Clin. Pharmacol. 35, 18S-24S (1995).
- McManus, J. M. et al. Rapid and structure-specific cellular uptake of selected steroids. PLoS One 14, e0224081 (2019).
- Longcope, C. et al. The metabolism of estradiol; oral compared to intravenous administration. J. Steroid Biochem. 23, 1065–1070 (1985).
- Samavat, H. & Kurzer, M. S. Estrogen metabolism and breast cancer. Cancer Letters vol. 356 231–243 (2015).
- Elestrin (estradiol topical gel) package insert. Somerset, NJ: Meda Pharmaceuticals Inc; 2017 Nov.
- Evamist (estradiol transdermal spray) package insert. Minneapolis, MN: Perrigo Pharmaceuticals; 2017 Nov.
- Estrace cream (estradiol vaginal cream) package insert. Irvine, CA; Allergan USA, Inc; 2017 Nov.
- Vagifem (estradiol vaginal insert) package insert. Plainsboro, NJ: Novo Nordisk Inc.; 2017 Nov.
- Estring (estradiol vaginal ring) package insert. New York, NY: Pharmacia and Upjohn Co, division of Pfizer; 2017 Nov.
- Femring (estradiol acetate vaginal ring) package insert. Irvine, CA: Allergan USA, Inc.; 2017 Nov.
- Estrace (estradiol tablet) package insert. Irvine, CA; Allergan USA, Inc; 2016 Dec.
- Alora (estradiol transdermal system twice weekly) package insert. Irvine, CA: Allergan USA Inc.; 2017 Nov.
- Climara (estradiol transdermal system weekly) package insert. Whippany NJ: Bayer HealthCare Pharmaceuticals; 2017 Aug.
- Menostar (estradiol transdermal system) package insert. Whippany, NJ: Bayer Healthcare Pharmaceuticals, Inc.; 2017 Nov.
- Estrogel (estradiol gel for topical use) package insert. Herndon, VA: ASCEND Therapeutics US, LLC; 2017 Nov.
- Vivelle-Dot (estradiol transdermal system twice weekly) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2017 Nov.
- Minivelle (estradiol transdermal system twice weekly) package insert. Miami, FL: Noven Pharmaceuticals Inc.; 2017 Nov.
- Delestrogen (estradiol valerate in oil) injection package insert. Chestnut Ridge, NY; Par Pharmaceutical, Inc.: 2017 Nov.
- Depo-Estradiol (estradiol cypionate injection 5 mg/mL) package insert. New York, NY: Pfizer: 2016 Nov.
- Divigel (estradiol topical gel) package insert. Bridgewater, NJ: Vertical Pharmaceuticals, LLC; 2018 Aug.
- Imvexxy (estradiol vaginal insert) package insert. Boca Raton, FL: TherapeuticsMD, Inc.; 2018 May.
- Nassar J, Tadros T, Adda-Herzog E, et al. Steroid hormone pretreatments in assisted reproductive technology. Fertil Steril. 2016;106:1608-1614. Epub 2016 Oct 25. Review.
- Tankeyoon M, Dusitsin N, Chalapati S, et al. Effects of hormonal contraceptives on milk volume and infant growth. WHO Special Programme of Research, Development and Research Training in Human Reproduction, Task Force on Oral Contraceptives. Contr
- Elestrin™ (estradiol) package insert. San Antonio,TX: DPT Laboratories, Ltd.; 2006 Dec.
- Parlodel (bromocriptine) package insert. East Hanover, NJ: Novartis Pharmaceutical Corporation, Inc.; 2003 Mar.
- US Food and Drug Administration (FDA). Draft guidance for industry labeling for noncontraceptive estrogen drug products. Document No. 5670. Division of Dockets Management (HFA-305), Food and Drug Administration, Rockville, MD; Issued February, 2004.
- Maurer G. Metabolism of cyclosporine. Transplant Proc 1985;17(S1):19—26.
- Deray G, le Hoang P, Cacoub P, et al. Oral contraceptive interaction with cyclosporin. Lancet 1987;1:158—9.
- Deray G, Le Hoang P, Cacoub P, et al. Oral contraceptive interaction with cyclosporin. Lancet 1987;1:158—9.
- Hansten P, Horn J. The Top 100 Drug Interactions: A Guide to Patient Management. includes table of CYP450 and drug transporter substrates and modifiers (appendices). H & H Publications, LLP 2014 edition.
- Premarin® (conjugated estrogens, equine) package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2003 Jul.
- Spangler AS, Antoniades HN, Sotman SL, et al. Enhancement of the anti-inflammatory action of hydrocortisone by estrogen. J Clin Endocrinol Metab 1969;29:650—5.
- Seidegard J, Simonsson M, Edsbacker S. Effect of an oral contraceptive on the plasma levels of budesonide and prednisolone and the influence on plasma cortisol. Clin Pharmacol Ther 2000;67:373—81.
- Chan CH. Dantrolene sodium and hepatic injury. Neurology 1990;40:1427—32.
- Dantrium capsules (dantrolene sodium) package insert. Rochester, MI: JHP Pharmaceuticals; 2012 Jul.
- Humatrope™ (somatropin);package insert. Indianapolis, IN: Eli Lilly and Company; 2003 Jul. 59.Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women’s Health Initiative randomized controlled trial. JAMA. 2002;288(3):321-333.
- McLintock LA, Dykes A, Tait RC, et al. Interaction between hormone replacement therapy preparations and oral anticoagulant therapy. BJOG 2003;110:777-9.
- Nolvadex® (tamoxifen) package insert. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2004 Aug.
- Evista® (raloxifene) package insert. Indianapolis, IN: Eli Lilly and Company; 2007 Jul.
- Somani SM, Khurana RC. Mechanism of estrogen-imipramine interaction. JAMA 1973;223:560.
- Galbraith RA, Michnovicz JJ. The effects of cimetidine on the oxidative metabolism of estradiol. N Engl J Med 1989; 321:270—274.
- Michnovicz JJ, Galbraith RA. Cimetidine inhibits catechol estrogen metabolism in women. Metabolism 1991;40:170—4.
- package insert. South San Francisco, CA: Actelion Pharmaceuticals US, Inc.; 2007 Feb.
- Provigil® (modafinil) package insert. West Chester, PA: Cephalon, Inc; 2004 Feb.
- Dilantin® Kapseals® (extended phenyotin sodium capsules, USP) package insert. Morris Plains, NJ: Parke Davis; 1999 Aug
- Lewis DP, VanDyke DC, Stumbo PJ, et al. Drug and environmental factors associated with adverse pregnancy outcomes Part 1: Antiepileptic drugs, contraceptives, smoking and folate. Ann Pharmacother 1998;32:802—17.
- Carbatrol® (carbamazepine) package insert. Wayne, PA. Shire US Inc; 2006 Jul.
- Tegretol® (carbamazepine) package insert. East Hanover, NJ. Novartis Pharmaceuticals; 2003 Sept.
- Crawford P. Interactions between antiepileptic drugs and hormonal contraception. CNS Drugs. 2002;16:263—72.
- Trileptal® (oxcarbazepine) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2005 Dec
- Berman ML, Green OC. Acute stimulation of cortisol metabolism by pentobarbital in man. Anesthesiology 1971;34:365—9.
- Phenobarbital Tablets, USP package insert. Elizabeth, NJ: Purepac Pharmaceuticals; 2000 Oct.
- Endometrin® (progesterone) package insert. Hunt Valley, MD: Pharmaceutics International, Inc.; 2007 Jun.
- Kyriazopoulou V, Parparousi O, Vagenakis A. Rifampicin-induced adrenal crisis in addisonian patients receiving corticosteroid replacement therapy. J Clin Endocrinol Metab 1984;59:1204—6.
- Dickinson BD, Altman RD, Nielsen NH, Sterling ML, for the Council on Scientific Affairs, American Medical Association (AMA). Drug interactions between oral contraceptives and antibiotics. Obstet Gynecol 2001;98:853—60. Review.
- Gris-Peg® (griseofulvin ultramicrosize) package insert. Farmingdale, NY: Pedinol Pharmacal, Inc.; 1996 Aug.
- Topamax® (topiramate) package insert. Raritan, NJ: Ortho-McNeil Pharmaceutical, Inc.; 2005 June.
- Felbatol® (felbamate) package insert. Somerset, NJ: MedPointe Pharmaceuticals; 2002 Dec.
- Saano V, Glue P, Banfield CR, et al. Effects of felbamate on the pharmacokinetics of a low-dose combination oral contraceptive. Clin Pharmacol Ther. 1995;58:523—31.
- Viramune® (nevirapine) package insert. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc.; 2008 Jun.
- Levothroid (levothyroxine sodium tablet) package insert. Shenandoah, IA: Lloyd Pharmaceutical; 2011 June.
- Curry CE, Butler DM. Constipation. In: Handbook of Nonprescription Drugs. 12th ed., Washington, DC, American Pharmaceutical Association. 2000:285, 273—300.
- Arimidex® (anastrozole) package insert. Wilmington DE: AstraZeneca Pharmaceuticals LP; 2002 Oct.
- Aromasin® (exemestane) package insert. Kalamazoo MI: Pharmacia & Upjohn Company; 2005 Oct.
- Femara® (letrozole) package insert. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2003 Feb.
- Teslac (testolactone) package insert. Princeton, NJ: Mead-Johnson Oncology Products, Bristol-Myers Squibb, Co.; 1998 Dec.
- Urso 250 / Urso Forte (ursodiol) package insert. Birmingham AL: Axcan Scandipharm Inc.; 2013 June.
- Actigall (ursodiol) package insert. Morristown,NJ: Watson Pharmaceuticals Inc. Oct 2014.
- Tham DM, et al. Clinical review 97: Potential health benefits of dietary phytoestrogens: a review of the clinical, epidemiological, and mechanistic evidence. J Clin Endocrinol Metab 1998;83:2223-2235.
- Zava DT, Dollbaum CM, Blen M. Estrogen and Progestin Bioactivity of Foods, Herbs, and Spices. Proc Soc Exp Biol Med.1998; 217:369-378.
- Targretin® gel (bexarotene gel) package insert. San Diego CA: Ligand Pharmaceuticals Inc.; 2002 Feb.
- Targretin® (bexarotene capsules) package insert. San Diego CA: Ligand Pharmaceuticals Inc.; 2003 April.
- Adson DE, Kotlyar M. A probable interaction between a very low-dose oral contraceptive and the antidepressant nefazodone: a case report. J Clin Psychopharmacol 2001;21:618—9.
- Estrasorb™ (estradiol topical emulsion) package insert. Columbia, MD: Novavax, Inc.; 2003 Oct.
- Metopirone® (metyrapone USP) package insert. East Hanover NJ: Novartis; 2005 Aug.
- Emend® capsules (aprepitant) package insert. Whitehouse Station, NJ: Merck & Co., Inc.; 2007 Nov.
- Henderson L, Yue QY, Bergquist C, et al. St John’s wort (Hypericum perforatum): drug interactions and clinical outcomes. Br J Clin Pharmacol 2002;54:349—56.
- Cappell MS. Colonic toxicity of administered drugs and chemicals. Am J Gastroenterol 2004;99:1175-90.
- Radzikowska E, Maciejewski R, Janicki K, et al. The relationship between estrogen and the development of liver vascular disorders. Ann Univ Mariae Curie Sklodowska Med. 2001;56:189-93.
- The Writing Group for the PEPI Trial. Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. JAMA 1995;273:199-208.
- Estrasorb (estradiol topical emulsion) package insert. Florham Park, NJ: Exeltis USA, Inc.; 2017 Nov. 105.Quasense (levonorgestrel and ethinyl estradiol) package insert. Corona, CA: Watson Laboratories, Inc.; 2017 Aug.
- Shumaker SA, Legault C, Rapp SR, et al. Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women. The Women’s Health Initiative Memory Study: A randomized controlled trial (WHIMS). JAMA 2003;289:
- Shumaker SA, Legault C, Kuller L, et al. Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women’s health initiative memory study. JAMA 2004;291:2947-58.
- The 2017 hormone therapy position statement of The North American Menopause Society. Menopause. 2017 Jun 22. [Epub ahead of print]
- Steiner JE, Subak L, Grady D, et al. Hormone therapy for prevention of urinary incontinence: the HERS Study. Obstet Gynecol 2003;101(Suppl):S10.
- Premarin tablets (conjugated estrogens, equine) package insert. Philadelphia, PA: Wyeth Pharmaceuticals Inc.; 2017 Nov.
- Cenestin tablets (synthetic conjugated estrogens) package insert. North Wales, PA: Teva Women’s Health; 2017 Nov.
- Enjuvia tablets (synthetic conjugated estrogens, B) tablets package insert. North Wales, PA: Teva Women’s Health, Inc.; 2017 Nov.
- Grady D, Rubin SM, Petitti DB, et al. Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992;117:1016-37.
- 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
- Stefanick ML, Anderson GL, Margolis KL, et al. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA 2006;295:1647-57.
- Lacey JV, Mink PJ, Lubin JH, et al. Menopausal hormone replacement therapy and risk of ovarian cancer. JAMA 2002;288:334-341.