Pharmacological Classifications: Estrogen hormones
General Information: Estradiol is the principal intracellular human estrogen and is substantially more active than its metabolites, estrone and estriol, at the cellular level. Estradiol can be obtained from natural sources or prepared synthetically into a variety of salt forms. Due to almost complete first-pass metabolism, estradiol must be given in a micronized oral dosage form to ensure therapeutic effect. Esterification of estradiol to estradiol cypionate or valerate increases the parenteral duration of action of estradiol to allow for IM administration. Estradiol is used to prevent osteoporosis and relieve symptoms associated with menopause and is also used to treat female hypogonadism and other abnormalities of female gonadotropin dysfunction (see Indications). In selected circumstances, estrogens have been used to treat advanced inoperable breast carcinoma in both sexes or prostatic carcinoma. The FDA began to allow the marketing of various estrogen products in 1938, its first year of organization. Estradiol is available in many dosage forms, including transdermal systems, topical emulsions, topical gels, topical sprays, intravaginal estrogen cream, oral tablets, vaginal rings, and parenteral injections. In accordance with the FDA's guidance to provide efficacious low dose estrogen therapies in alternate drug delivery systems, 2 low-dose estradiol topical gels are available for the treatment of moderate to severe vasomotor symptoms associated with menopause. The Elestrin™ brand of estradiol gel was approved in December 2006 and the Divigel® brand of estradiol gel was approved in June 2007. In July 2007, the FDA approved a topical spray of estradiol (Evamist™).
In regard to the use of estrogen for hormone replacement therapy (HRT), unopposed estrogen has been associated with increased risk of endometrial cancer in women with an intact uterus; concomitant progestin therapy reduces, but does not eliminate, this risk. However, combination HRT therapy may add additional health risks for some women, as evidenced by the HERS trials,1233 the Women's Health Initiative study,4 and other investigations. In particular, the Women's Health Initiative (WHI) study reported an increased risk of myocardial infarction, stroke, dementia, invasive breast cancer, and venous thromboembolism in patients taking combination HRT, and an increased risk of stroke, dementia, and venous thromboembolism in patients taking estrogen only HRT; an increased risk of invasive breast cancer was not evident in women taking estrogen only. Because of these findings, patients should be prescribed estrogen HRT or estrogen-progestin HRT for the shortest duration consistent with the treatment goals. Estrogen HRT, with or without a progestin, is not indicated and should not be used to prevent coronary artery disease or other cardiovascular disease. The risks and benefits of HRT must be determined for a woman individually.
Mechanism of Action: The primary source of estrogens in premenopausal women is the ovary, which normally secretes 0.07 to 0.5 mg of estradiol daily, depending on the phase of the menstrual cycle. Once estrogens enter the cells of responsive tissues (e.g., female organs, breasts, hypothalamus, pituitary), they increase the rate of synthesis of DNA, RNA, and some proteins. The secretion of gonadotropin-releasing hormone by the hypothalamus is reduced during estrogen administration, causing reduction in follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary. Exogenous estrogens elicit all of the actions of endogenous estrogens. Estrogens are responsible for the growth and development of female sex organs and the maintenance of sex characteristics including growth of axillary and pubic hair and shaping of body contours and skeleton. At the cellular level, estrogens increase cervical secretions, cause proliferation of the endometrium, and increase uterine tone. Paradoxically, prolonged administration of estrogen can shrink the endometrium. During the preovulatory or nonovulatory phase of the menstrual cycle, withdrawal of estrogen can initiate menstruation; in the ovulatory phase, the decrease in progesterone secretion is the more significant factor causing menstruation. In post-menopausal use, amenorrhea occurs in most women within several months of oral estrogen use.
Estrogens have a weak anabolic effect and also can affect bone calcium deposition and accelerate epiphysial closure. Estrogens appear to prevent osteoporosis associated with the onset of menopause. Estrogens generally have a favorable effect on blood lipids, reducing LDL- and increasing HDL-cholesterol concentrations on average, by 15%. Serum triglycerides increase with estrogen administration. Estrogens increase the rate of synthesis of many proteins, including thyroid binding globulin and several clotting factors. Estrogens reduce levels of antithrombin III, and increase platelet aggregation. Estrogens also enhance sodium and fluid retention.
In men with advanced prostate cancer, estrogens exert their effect by inhibition of the hypothalamic-pituitary axis through negative feedback. This results in decreased secretion of luteinizing hormone (LH). Decreased testosterone production from the Leydig cells in the testes occurs, which may decrease tumor growth and lower prostate specific antigen (PSA) levels. Improvement in bone metastasis may also occur. In the past, high-dose estrogen therapy was also used in selected men and postmenopausal women with inoperable, progressive breast carcinoma. Since the development of selective estrogen receptor modifiers (SERMs), high-dose estrogen therapy for the treatment of breast carcinoma is rarely used today.
Pharmacokinetics: Estradiol products are administered orally, intramuscularly, vaginally, and topically. Affected cytochrome P450 isoenzymes: CYP3A4. In vitro and in vivo studies indicate that estrogens are partially metabolized by CYP3A4.5 Interactions with drugs that are inhibitors or inducers of CYP3A4 are possible.
Route-Specific Pharmacokinetics: Oral Route: Estradiol is extensively metabolized in the GI mucosa during absorption and in the liver. Micronization of oral estradiol tablets slows oral absorption and decreases the first-pass effects in the liver and increases the normally poor bioavailability of estradiol. Absolute bioavailability of micronized estradiol is roughly 5—10% of an administered dose. Following oral administration, estradiol is rapidly transformed by the liver to estrone and estriol, the major circulating forms in the serum, by 17beta-hydroxysteroid dehydrogenase. The estrogens are widely distributed and are strongly protein-bound, primarily to albumin and sex hormone-binding globulin (SHBG). Estradiol, estrone, and estriol undergo glucuronide and sulfate conjugation to a variety of minor metabolites which are excreted primarily in the urine. In vitro and in vivo studies have shown that estrogens are metabolized partially by cytochrome P450 3A4 (CYP3A4). Therefore, inducers or inhibitors of CYP3A4 may affect estrogen drug metabolism. Some biliary excretion and entero-hepatic recycling of estradiol and its metabolites occurs. The plasma half-life of orally administered estradiol is approximately 1—2 hours at steady state; but other circulating estrogens persist longer.
Intramuscular Route: Estradiol cypionate and estradiol valerate: These forms of estradiol are given as a depot injection in oil, which slows absorption after intramuscular injection. Esterification of estradiol to estradiol cypionate or valerate significantly increases the parenteral duration of action compared to aqueous estradiol formulations. Intramuscular administration of the cypionate esters of estradiol have more prolonged actions than the valerate esters, averaging 3—6 weeks and 2—3 weeks, respectively. However, IM dosage intervals are usually every 4 weeks for both cypionate and valerate esters of estradiol for most indications; dosage is adjusted to patient response.
Topical Route: Topical administration of estradiol avoids first-pass metabolism and allows for continuous delivery of the hormone. Estradiol is minimally metabolized in the skin, thus higher therapeutic estradiol serum levels are present, and more closely approximate natural premenopausal concentrations. Estradiol topical emulsion (Estrasorb) utilizes micellar nanoparticle technology for estradiol administration through the skin. Estradiol topical emulsion incorporates 17-beta-estradiol in a soy-based oil formulation, designed to deliver systemic levels of estrogen through the skin. Once in the serum, the distribution, metabolism and excretion of topically administered estradiol occurs through the same pathways as for oral administration.
Vaginal Route: Estradiol is well absorbed through the vaginal mucous membranes. Drug delivery from intravaginal ring dosage forms is rapid as evidenced by Tmax values for estradiol of less than 1 hour. Following Cmax, serum estradiol concentrations decrease rapidly such that by 24—48 hours post-application of the dosage form, serum estradiol concentrations are relatively constant through the end of the 3-month dosing interval. The vaginal dosage applied determines systemic hormone exposure; as a result, systemic as well as local tissue effects may occur. Different intravaginal ring devices are not interchangeable due to differences in dosage and efficacy in symptom control. For example, Estring dosages are not effective for addressing vasomotor symptoms; low dose systemic delivery of estradiol from Estring results in mean steady state serum estradiol estimates of 7—8.1 pg/ml; with an estradiol delivery rate of roughly 7.5 mcg/24 hours. Following administration of Femring 0.05 mg/day, the average serum estradiol concentration is 40.6 pg/ml; the corresponding apparent in vivo estradiol delivery rate is 0.052 mg/day. Following administration of Femring 0.10 mg/day, the average serum estradiol concentration is 76 pg/mL; the apparent in vivo delivery rate is 0.097 mg/day. Consistent with the avoidance of first pass metabolism achieved by vaginal estradiol administration, serum estradiol concentrations are slightly higher than estrone concentrations. Once absorbed systemically, the distribution, metabolism and excretion of estradiol delivered via vaginal application occurs via the same pathways as for oral administration.
Indications: Estradiol is indicated for: relief from moderate to severe vasomotor symptoms associated with menopause such as hot flashes, vaginal dryness, burning and irritation; maintenance treatment (as a replacement estrogen) of postmenopausal atrophic vaginitis; various types of ovarian cysts; female hypogonadism as well as other ovarian dysfunction; atrophy of vulva; prevention of osteoporosis in postmenopausal women, and; sometimes as a part of cancer treatment in women and men.
Contraindications and Precautions: Estradiol topical gels and sprays (e.g., Divigel, Elestrin, Estrogel, and Evamist) are alcohol-based. Alcohol-based gels and sprays are potentially flammable. Patients should be advised to avoid fire, flame, or smoking until the gel or spray has dried.
Estradiol cypionate and estradiol valerate are esterified estrogens that are in oil-based injections and are not recommended for intravenous administration. They are to be administered by the intramuscular route only.
Estrogens, including estradiol, are contraindicated in patients with known, suspected, or history of breast cancer. Estrogen and estrogen/progestin therapy in postmenopausal women has been associated with an increased risk of breast cancer.6 All women taking estrogen with or without a progestin should receive an annual clinical breast examination, perform monthly self-examinations, and have regular mammograms as recommended by their health care professional.
Estrogens are not recommended in patients with hypercalcemia associated with tumors or metabolic bone disease because estrogens influence the metabolism of calcium and phosphorus. In particular, severe hypercalcemia may occur in patients with breast cancer with bone metastases.6
Estrogens, including estradiol, should be used cautiously in patients with uterine leiomyomata (fibroids) or endometriosis since they can exacerbate fibroid or endometrial growth. They are contraindicated in the presence of vaginal cancer, cervical cancer, uterine cancer, or other estrogen-responsive tumors.
Estrogens are contraindicated in women with undiagnosed abnormal vaginal bleeding. Women experiencing persistent abnormal vaginal bleeding should receive adequate diagnostic tests to rule out malignancy before being prescribed estrogens.
Estrogens, including estradiol, are contraindicated in the presence of estrogen-responsive tumors. Use of estrogen-only products, in particular for 10 or more years, has been associated with an increased risk of ovarian cancer in some epidemiological studies.7
Estrogens should be used cautiously in patients with acute intermittent, or variegate hepatic porphyria, which can be exacerbated. Exogenous orally administered estrogens may increase the risk of gallbladder disease (e.g., cholestasis, cholelithiasis and cholecystitis) in postmenopausal women.1
Estrogens, including estradiol, are contraindicated in patients with an active or past history of stroke, myocardial infarction, thrombophlebitis, or thromboembolic disease. Should any of these occur or be suspected, discontinue the estrogen immediately.18
Definitive recommendations regarding the use of HRT in patients with systemic lupus erythematosus (SLE) are not available.9
Because certain major surgical procedures are associated with prolonged immobilization or increased risk of thromboembolism, estrogens, including estradiol, should be discontinued several weeks (i.e., 4—6 weeks) prior to major surgery where feasible.
Mood disorders, like depression, may be aggravated in women taking exogenous estrogens. Women with a history of depression may need special monitoring. If significant depression occurs, estradiol should be discontinued.
Use estrogens, including estradiol, with caution in patients with thyroid disease, particularly hypothyroidism.
Estrogens can increase the curvature of the cornea and may lead to intolerance of contact lenses. There have been clinical case reports of retinal thrombosis.
Estrogens, including estradiol, are not indicated in neonates, infants, or children because estrogens promote epiphysial closure and may be associated with other adverse events.10
Cases of both anaphylactic reactions and angioedema have been reported in patients taking exogenous estrogens. Events have developed in minutes and have required emergency medical treatment. Therefore, estradiol is contraindicated in patients with known anaphylactic reactions or angioedema to estradiol.511
Estradiol, like other estrogens, is contraindicated for patients with known protein C deficiency, protein S deficiency, or antithrombin deficiency or other known thrombophilic disorders associated with increased risk of venous thrombosis.5
Pregnancy: Estrogens are contraindicated during pregnancy and are labeled as FDA pregnancy risk category X.12 Increased risk of a wide variety of fetal abnormalities, including modified development of sexual organs, cardiovascular anomalies and limb defects, have been reported following the use of estrogens in pregnant women. In any patient in whom pregnancy is suspected, pregnancy should be ruled out before continuing estrogen use. There is no known approved indication for the use of these drugs during pregnancy. In select instances estradiol is used off-label as an adjuvant to clomiphene treatment of infertility (see Dosage), 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;12 the infant may need to be monitored for effects such as breast enlargement, poor appetite, and appropriate growth and weight gain. Less than 10% of an estradiol dose passes into breast milk and most estrogens are reported to be excreted in low amounts in breast milk. Estrogens, including ethinyl estradiol, have been reported to interfere with milk production and duration of lactation in some women, particularly at contraceptive doses of 30 mcg/day ethinyl estradiol (or estrogenic equivalent) or more.13 However, when estrogens are used in doses to establish hormone replacement to provide normal physiologic estrogen levels, the effect on lactation in the female is less clear. The American Academy of Pediatrics has considered most estrogens to be compatible with breast-feeding due to a lack of documented cases of adverse events in infants.14 Estrogens are not approved by the FDA for the treatment of postpartum breast engorgement.
Interactions: NOTE: In vitro and in vivo studies indicate that estrogens are partially metabolized by CYP3A4.15 Interactions with drugs that are inhibitors or inducers of CYP3A4 are possible.
Bromocriptine is used to restore ovulation and ovarian function in amenorrheic women.16 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.17
There have been reports indicating the estrogens and/or progestins in oral contraceptives or non-oral combinatio contraceptives may inhibit the metabolism of cyclosporine.181920 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.2122 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.17 Estrogens have reportedly potentiated the anti-inflammatory effects of hydrocortisone.23 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.17 Ethinyl estradiol has reportedly delayed the clearance of prednisolone.24 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.2526
Estrogens interact with growth hormone (somatropin and somatrem) during pre-puberty by accelerating epiphysial maturation.27
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.22 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).28 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.29 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.30
Raloxifene31 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.32 Increased antidepressant serum concentrations may occur.
There is a possibility of contraceptive failure when bosentan is coadministered with products containing estrogens and/or progestins.35 In addition, bosentan is teratogenic and is contraindicated during pregnancy.35 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.36 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.37
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.38 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;3940414241 barbiturates;43441545 rifampin, rifabutin, or rifapentine.21461545 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.4748 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.49 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.5051 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.52
Grapefruit juice has been reported to decrease estrogen metabolism.17
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.17
Dose adjustments may be needed in some hypothyroid patients receiving exogenous thyroid treatments who initiate estrogen therapy.53
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.54
Estrogens could interfere competitively with the pharmacologic action of the aromatase inhibitors.55565758 Estrogen therapy is not recommended during aromatase inhibitor treatment, due to opposing pharmacologic actions.
Theoretically, the soy isoflavones may compete with or have additive effects with, drugs that have estrogenic activity or which selectively modulate estrogen receptors.6162 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).63 Because of the potential interaction with hormonal contraceptives it is strongly recommended that one of the forms of contraception be non-hormonal.64
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.65
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%.66
A subtherapeutic response to metyrapone can be seen in patients on estrogen therapy.67
The efficacy of estrogens and/or progestins may be reduced when coadministered with aprepitant, fosaprepitant.68
St. John's wort, Hypericum perforatum appears to interact with estrogens and oral contraceptives.69 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:2122 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.
Adverse Reactions/Side Effects: Many of the serious adverse reactions reported with the use of estrogens are similar to those reported with the use of estrogen-containing oral contraceptives. However, the risk of these serious events are typically lower in the postmenopausal use of these drugs, presumably due to the comparatively low estrogen doses used in this population for hormone replacement therapy versus oral contraceptive use in premenopausal women. The use of estrogens, including estradiol, for other indications, like cancer, require higher estrogen doses and thus may be associated with a higher incidence of serious estrogen-related side effects.
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 discharge, vaginal irritation, vaginal candidiasis, vaginitis, cervicitis, or changes in cervical erosion (e.g., cervical ectropion) may appear. 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 post-menopausal women, changes in uterine bleeding patterns will usually taper and stabilize within 3—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 annual pelvic examinations including regular Papanicolaou smears to detect cervical dysplasia.11
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, and follow current recommendations for routine mammography and clinical breast examinations.11
Stomach/abdominal pain or cramps, bloating, nausea, and vomiting are common adverse effects of estrogens such as estradiol. Consider benign hepatic adenoma if abdominal pain/tenderness, abdominal mass, or hypovolemic shock is present, as the 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.70 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.71 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.1112 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.72 Persistent or severe abdominal symptoms should be evaluated by a medical professional.111271
Deep and superficial venous thrombosis, pulmonary embolism, thrombophlebitis, myocardial infarction, and stroke have been reported with estrogens and/or progestin therapy. Immediately discontinue estradiol if myocardial infarction, stroke, pulmonary emboli, or deep vein thrombosis occur or are suspected. Appropriately manage any risk factors for arterial vascular disease and venous thromboembolism such as high blood pressure, diabetes mellitus, tobacco use, hypercholesterolemia, personal history or family history of VTE, obesity, and systemic lupus erythematosus. If feasible, discontinue estrogens at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.1112 Estrogens decrease levels of antithrombin-III and increase the production of blood clotting factors VII, VIII, IX and X. A positive association has been noted between estrogen dosage and thrombotic disorders. Smoking appears to greatly increase the risk of thrombotic events, and women on estrogens should be advised not to smoke. Since 1970, at least 15 studies have evaluated the effect of estrogen use on stroke risk in women.6 Some of these studies showed a slightly increased risk for stroke in estrogen recipients while other studies showed a decreased risk. One analysis calculated the pooled estimate of the relative risk for stroke in estrogen recipients to be 0.96.6 In the Women's Health Initiative (WHI) Trial, an increase in the incidence of strokes were observed in both the estrogen-alone and the estrogen-progestin sub-studies when the active treatment groups were compared to placebo groups. While the details from the estrogen-alone sub-study are preliminary, in the estrogen-progestin sub-study, women in the active treatment group had 8 more strokes per year for every 10,000 women than those taking placebo;8 this increase in risk was observed after the first year and persisted. In addition, in the estrogen-progestin sub-study of WHI8, an increased risk of coronary heart disease (CHD) events (defined as non-fatal MI and CHD death) was observed with estrogen-progestin HRT compared to placebo. The increase in risk was observed in year one and persisted. In postmenopausal women with documented cardiac disease, a controlled clinical trial (i.e., HERS trial)1 demonstrated no cardiovascular benefit to using estrogen-progestin HRT as secondary prevention. During an average follow-up of 4.1 years, treatment did not reduce the overall rate of CHD events in postmenopausal women with established coronary artery disease. There were more CHD events in the HRT-treated group than in the placebo group in year 1, but not during the subsequent years. Over two thousand women from the original HERS trial agreed to participate in an open label extension of HERS, known as HERS II.2 Average follow-up in HERS II was an additional 2.7 years, for a total of 6.8 years overall. Rates of CHD events were comparable among women in the estrogen-progestin HRT group and the placebo group in HERS, HERS II, and overall. In men treated with estrogen for palliation of prostate and breast cancer, estrogens have increased the risks of nonfatal myocardial infarction, pulmonary embolism, and thrombophlebitis. In the WHI trial, an increase in VTE has been observed in women receiving estrogen compared to placebo. In the estrogen-progestin sub-study of WHI,8 a 2-fold greater rate of VTE, including DVT and PE, was observed with combined HRT compared to placebo. The increase in VTE risk was observed during the first year and persisted.
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 edema formation would be detrimental.1112 In the PEPI trial, postmenopausal women 45—65 years of age randomized to any hormone replacement therapy regimen experienced increases in both systolic and diastolic blood pressure of 3—5% after the first year of treatment, but the increases were not statistically different from placebo.73
Headache has been noted with use of estrogens such as estradiol. A severe headache 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 sudden onset of migraine. If examination reveals a serious event, estrogens should be permanently discontinued.1112 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.
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. These patches 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.1112 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 post-marketing include, paresthesias, skin discoloration/pigmentation, and swelling.74 To help reduce the chance of skin redness or skin irritation, wait at least one week before the patient reuses a skin site for application.75 Estradiol topical emulsions and sprays have been associated with pruritus or skin irritation during clinical trials.6676 During post-marketing 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.76
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. If examination reveals papilledema, visual loss, or retinal vascular lesions, permanently discontinue estrogens.1112 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.1112 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.77
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 earlypregnancy.1112 Estrogens are known to cause teratogenesis 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.
Unopposed estrogen therapy, including estradiol, can promote endometrial hyperplasia in approximately 10% of patients with an intact uterus and can increase the risk of endometrial cancer. Also, endometriosis may be exacerbated with estrogen administration such as estradiol. A few cases of malignant transformation of residual endometrial implants have been reported in women treated with estrogen alone therapy after hysterectomy. Consider the addition of progestin for patients known to have residual endometriosis after hysterectomy. When estrogen is prescribed for a postmenopausal woman with a uterus, a progestin should also be initiated to reduce the risk of endometrial cancer. Studies of the addition of progestin for 10 or more days of a cycle of estrogen administration or daily with estrogen in a continuous regimen have reported a lowered incidence of endometrial hyperplasia than would be induced by estrogen treatment alone. When progestin therapy is taken for < 10 days per month, the risk of endometrial cancer is increased; however, if the progestin is taken daily in combination with estrogen, the risk of endometrial cancer is similar to that in women who have never used HRT. Further, use the lowest effective estrogen and progestin dose, if applicable, for the shortest duration consistent with treatment goals and risks for the individual woman. Closely monitor patients with an intact uterus for signs of endometrial cancer including utilization of appropriate diagnostic measures to rule out malignancy in the event of persistent or recurring abnormal vaginal bleeding. The use of unopposed estrogens in women who have a uterus is associated with an increased risk of endometrial cancer. The reported endometrial cancer risk among unopposed estrogen users is about 2- to 12- fold greater than in nonusers 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 one year. The greatest risk appears associated with prolonged use, with increased risks of 15- to 24-fold for five to ten years or more, and this risk has been shown to persist for at least 8 to 15 years after estrogen therapy is discontinued. No evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens of equivalent estrogen dose exists.1112 At diagnosis, endometrial cancers in estrogen recipients are generally of an earlier stage and a lower grade and show less myometrial invasion than tumors in women who have not used estrogen. Survival is also better in estrogen recipients than in women who have not received estrogen and develop endometrial cancers. Thus, while the risk of endometrial cancer increases with increased duration of estrogen use, the risk of dying does not.6
Numerous epidemiologic studies have examined the effects of estrogen HRT and estrogen-progestin HRT on the development of secondary malignancy (e.g., breast cancer, ovarian cancer) in postmenopausal women. Estradiol is contraindicated for use by patients with known or suspected estrogen-dependent neoplasia. The Women's Health Initiative (WHI) Trial has reported slight increased risks of breast cancer in women taking estrogen-progestin HRT but not estrogen only HRT.878 After a mean follow-up of 5.6 years during the clinical trial, the overall relative risk of invasive breast cancer was 1.24 (95% CI, 1.01—1.54). From observational studies, the risk appeared to return to baseline in about five years after stopping treatment.1112 The WHO IARC, classifies combined menopausal HRT as carcinogenic to humans; in current and recent users, the risk of breast cancer increases with duration of use and is higher in women taking combined HRT verus estrogen-only therapy. In a substudy of WHI, estrogen plus progestin increased the risk of ovarian cancer. After an average follow-up of 5.6 years, the relative risk for ovarian cancer for estrogen plus progestin versus placebo was 1.58 (95% CI, 0.77—3.24). In some epidemiologic studies, the use of estrogen alone, in particular for ten or more years, has been associated with an increased risk of ovarian cancer. Other epidemiologic studies have not found these associations. Lastly, hepatocellular carcinoma has been reported in women taking estrogen-containing oral contraceptives. The relationship of liver cancer to HRT is not known at this time. The WHI study used oral conjugated estrogens combined with medroxyprogesterone acetate. Other doses of conjugated estrogens with medroxyprogesterone acetate, and other combinations and dosage forms of estrogens and progestins were not studied in the WHI clinical trials and, in the absence of comparable data, these risks should be assumed to be similar. Because of these risks, prescribe estrogens with or without progestins at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman. All women need yearly breast examinations by a healthcare provider and monthly breast self-examinations. In addition, schedule mammography examinations based on patient age, risk factors, and prior mammogram results.1112
Dementia has been reported with estrogens such as estradiol and/or progestin therapy. Using estrogens with progestins may increase the risk of impaired cognition or dementia. For example, the Women’s Health Initiative Memory Study (WHIMS) reported increased risk of developing probable dementia in postmenopausal women 65 years of age or older during 4 years of treatment with oral conjugated estrogens plus medroxyprogesterone acetate relative to placebo. Specifically, the relative risk of probable dementia for the hormone group versus placebo was 2.05 (95% CI, 1.21—3.48) and was similar for women with and without histories of menopausal hormone use before WHIMS. Differences between groups became apparent in the first year of treatment. Ninety percent of the cases of probable dementia occurred in the 54% of women who were older than 70 years. Alzheimer’s disease was the most common classification of probable dementia in both groups. The applicability of the increased risk of developing probable dementia to younger postmenopausal women or to women taking estrogen therapy alone is unknown.11127980
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.81
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.1112
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.71
A few cases of inadvertent ring insertion into the urinary bladder, which may require surgical removal, have been reported for women using vaginal rings. Adherence of the vaginal ring insert to the vaginal or bladder wall making removal of the ring difficult has been reported. Vaginal or bladder wall ulceration or erosion may occur; vaginal pain upon removal or difficulty removing the vaginal ring should be evaluated by a medical professional. Also, carefully evaluate persistent unexplained urinary symptoms such as bladder discomfort. If erosion or ulceration occur, consider temporarily discontinuing the vaginal ring containing estradiol until healing is complete.71
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.
This list may not include all possible adverse reactions or side effects. Call your health care provider immediately if you are experiencing any signs of an allergic reaction: skin rash, itching or hives, swelling of the face, lips, or tongue, blue tint to skin, chest tightness, pain, difficulty breathing, wheezing, dizziness, red, a swollen painful area/areas on the leg.
How is this medication best taken? This medicine is applied at the same time every day (preferably in the morning) to clean, dry, intact skin of the upper shoulders or arms. Follow the directions on the prescription label. If you take a bath or shower in the morning, apply the medicine after the bath or shower. If you use deodorants or antiperspirants, use them at least 2 minutes before applying this medicine. Allow the skin to dry a few minutes before putting on clothing. Wash your hands after use. Avoid bathing or swimming for at least 2 hours after you apply the medicine. Avoid contact with others, children, and pets with skin that has been treated. Transdermal hormone creams may cause harmful effects to people and animals who touch your skin in the area where you applied it. Talk to your pediatrician regarding the use of this medicine in children. Special care may be needed.
What do I do if I miss a dose? If you miss a dose, take it as soon as you remember. If it is almost time for your next dose, skip the missed dose. Take your next regularly scheduled dose. Do not take two doses at the same time.
Storage: Keep in original closed container in a dark, cool, and dry place away from children. Discard unneeded medicine.
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