(ES troe jenz, es TER i fied)
- Esterified Estrogens
- Oestrogens Esterified
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Menest: 0.3 mg, 0.625 mg, 1.25 mg, 2.5 mg [DSC]
Brand Names: U.S.
- Estrogen Derivative
Esterified estrogens contain a mixture of estrogenic substances; the principle component is estrone. Preparations contain 75% to 85% sodium estrone sulfate and 6% to 15% sodium equilin sulfate such that the total is not <90%. Estrogens are responsible for the development and maintenance of the female reproductive system and secondary sexual characteristics. Estradiol is the principle intracellular human estrogen and is more potent than estrone and estriol at the receptor level; it is the primary estrogen secreted prior to menopause. In males and following menopause in females, estrone and estrone sulfate are more highly produced. Estrogens modulate the pituitary secretion of gonadotropins, luteinizing hormone, and follicle-stimulating hormone through a negative feedback system; estrogen replacement reduces elevated levels of these hormones.
Widely distributed; high concentrations in the sex hormone target organs
Hepatic; partial metabolism via CYP3A4 enzymes; estradiol is reversibly converted to estrone and estriol; oral estradiol also undergoes enterohepatic recirculation by conjugation in the liver, followed by excretion of sulfate and glucuronide conjugates into the bile, then hydrolysis in the intestine and estrogen reabsorption. Sulfate conjugates are the primary form found in postmenopausal women.
Primarily urine (as estradiol, estrone, estriol, and their glucuronide and sulfate conjugates)
Bound to sex hormone-binding globulin and albumin
Use: Labeled Indications
Treatment of moderate-to-severe vasomotor symptoms associated with menopause; treatment of moderate-to-severe vulvar and vaginal atrophy associated with menopause; hypoestrogenism (due to hypogonadism, castration, or primary ovarian failure); advanced prostatic cancer (palliation), metastatic breast cancer (palliation) in men and postmenopausal women
Hypersensitivity to estrogens or any component of the formulation; undiagnosed abnormal genital bleeding; DVT or PE (current or history of); active or recent (within 1 year) arterial thromboembolic disease (eg, stroke, MI); carcinoma of the breast (known, suspected or history of), except in appropriately selected patients being treated for metastatic disease; known or suspected estrogen-dependent tumor; hepatic dysfunction or disease; known or suspected pregnancy
Prostate cancer, advanced: Oral: 1.25 to 2.5 mg 3 times/day
Female hypoestrogenism due to hypogonadism: Oral: 2.5 to 7.5 mg/day in divided doses for 20 days followed by a 10-day rest period. Administer cyclically (3 weeks on and 1 week off). If bleeding does not occur by the end of the 10-day period, repeat the same dosing schedule; the number of courses to produce bleeding is dependent upon the responsiveness of the endometrium. If bleeding occurs before the end of the 10-day period, begin an estrogen-progestin cyclic regimen of 2.5 to 7.5 mg/day in divided doses for 20 days; during the last 5 days of estrogen therapy, give an oral progestin. If bleeding occurs before regimen is concluded, discontinue therapy and resume on the fifth day of bleeding.
Female hypoestrogenism due to castration and primary ovarian failure: Oral: 1.25 mg/day, cyclically. Adjust dosage upward or downward, according to the severity of symptoms and patient response. For maintenance, adjust dosage to lowest level that will provide effective control.
Vasomotor symptoms associated with menopause: Oral: 1.25 mg/day administered cyclically (3 weeks on and 1 week off). If patient has not menstruated within the last 2 months or more, cyclic administration is started arbitrary. If the patient is menstruating, cyclical administration is started on day 5 of the bleeding. For short-term use only and should be discontinued as soon as possible. Re-evaluate at 3- to 6-month intervals for tapering or discontinuation of therapy.
Vulvar and vaginal atrophy associated with menopause: Oral: 0.3 to ≥1.25 mg/day, depending on the tissue response of the individual patient. Administer cyclically. For short-term use only and should be discontinued as soon as possible. Re-evaluate at 3- to 6-month intervals for tapering or discontinuation of therapy.
Breast cancer, metastatic (appropriately selected patients): Males and postmenopausal females: Oral: 10 mg 3 times/day for at least 3 months
Refer to adult dosing.
Dosing: Renal Impairment
No dosage adjustment provided in manufacturer's labeling; use with caution.
Dosing: Hepatic Impairment
No dosage adjustment provided in manufacturer's labeling; use with caution.
Administer with food at same time each day.
Should be taken with food at same time each day.
Ajmaline: Estrogen Derivatives may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased. Monitor therapy
Anastrozole: Estrogen Derivatives may diminish the therapeutic effect of Anastrozole. Avoid combination
Anthrax Immune Globulin (Human): Estrogen Derivatives may enhance the thrombogenic effect of Anthrax Immune Globulin (Human). Monitor therapy
Anticoagulants: Estrogen Derivatives may diminish the anticoagulant effect of Anticoagulants. More specifically, the potential prothrombotic effects of some estrogens and progestin-estrogen combinations may counteract anticoagulant effects. Management: Carefully weigh the prospective benefits of estrogens against the potential increased risk of procoagulant effects and thromboembolism. Use is considered contraindicated under some circumstances. Refer to related guidelines for specific recommendations. Consider therapy modification
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy
Ascorbic Acid: May increase the serum concentration of Estrogen Derivatives. Monitor therapy
Bosentan: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
C1 inhibitors: Estrogen Derivatives may enhance the thrombogenic effect of C1 inhibitors. Monitor therapy
Cannabis: May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Monitor therapy
Chenodiol: Estrogen Derivatives may diminish the therapeutic effect of Chenodiol. Management: Monitor clinical response to chenodiol closely when used together with any estrogen derivative. Monitor therapy
Corticosteroids (Systemic): Estrogen Derivatives may increase the serum concentration of Corticosteroids (Systemic). Monitor therapy
CYP1A2 Inducers (Moderate): May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Monitor therapy
CYP3A4 Inducers (Moderate): May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
CYP3A4 Inducers (Strong): May increase the metabolism of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification
CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Estrogen Derivatives. Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Estrogen Derivatives. Monitor therapy
Cyproterone: May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Monitor therapy
Dabrafenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Seek alternatives to the CYP3A4 substrate when possible. If concomitant therapy cannot be avoided, monitor clinical effects of the substrate closely (particularly therapeutic effects). Consider therapy modification
Dantrolene: Estrogen Derivatives may enhance the hepatotoxic effect of Dantrolene. Monitor therapy
Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Dehydroepiandrosterone: May enhance the adverse/toxic effect of Estrogen Derivatives. Avoid combination
Enzalutamide: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Concurrent use of enzalutamide with CYP3A4 substrates that have a narrow therapeutic index should be avoided. Use of enzalutamide and any other CYP3A4 substrate should be performed with caution and close monitoring. Consider therapy modification
Exemestane: Estrogen Derivatives may diminish the therapeutic effect of Exemestane. Avoid combination
Hemin: Estrogen Derivatives may diminish the therapeutic effect of Hemin. Avoid combination
Herbs (Estrogenic Properties): May enhance the adverse/toxic effect of Estrogen Derivatives. Monitor therapy
Hyaluronidase: Estrogen Derivatives may diminish the therapeutic effect of Hyaluronidase. Management: Patients receiving estrogens (particularly at larger doses) may not experience the desired clinical response to standard doses of hyaluronidase. Larger doses of hyaluronidase may be required. Consider therapy modification
Immune Globulin: Estrogen Derivatives may enhance the thrombogenic effect of Immune Globulin. Monitor therapy
Indium 111 Capromab Pendetide: Estrogen Derivatives may diminish the diagnostic effect of Indium 111 Capromab Pendetide. Avoid combination
LamoTRIgine: Estrogen Derivatives may decrease the serum concentration of LamoTRIgine. Monitor therapy
Lenalidomide: Estrogen Derivatives may enhance the thrombogenic effect of Lenalidomide. Monitor therapy
Mitotane: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Doses of CYP3A4 substrates may need to be adjusted substantially when used in patients being treated with mitotane. Consider therapy modification
Mivacurium: Estrogen Derivatives may increase the serum concentration of Mivacurium. Monitor therapy
Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective): May enhance the thrombogenic effect of Estrogen Derivatives. Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective) may increase the serum concentration of Estrogen Derivatives. Monitor therapy
Ospemifene: Estrogen Derivatives may enhance the adverse/toxic effect of Ospemifene. Estrogen Derivatives may diminish the therapeutic effect of Ospemifene. Avoid combination
Pitolisant: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Combined use of pitolisant with a CYP3A4 substrate that has a narrow therapeutic index should be avoided. Other CYP3A4 substrates should be monitored more closely when used with pitolisant. Consider therapy modification
Pomalidomide: May enhance the thrombogenic effect of Estrogen Derivatives. Management: Canadian pomalidomide labeling recommends caution with use of hormone replacement therapy and states that hormonal contraceptives are not recommended. US pomalidomide labeling does not contain these specific recommendations. Consider therapy modification
ROPINIRole: Estrogen Derivatives may increase the serum concentration of ROPINIRole. Monitor therapy
Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Somatropin: Estrogen Derivatives may diminish the therapeutic effect of Somatropin. Shown to be a concern with oral hormone replacement therapy in postmenopausal women. Management: Monitor for reduced growth hormone efficacy. A larger somatropin dose may be required to reach treatment goal. This interaction does not appear to apply to non-orally administered estrogens (e.g., transdermal, vaginal ring). Consider therapy modification
St John's Wort: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Management: Consider an alternative for one of the interacting drugs. Some combinations may be specifically contraindicated. Consult appropriate manufacturer labeling. Consider therapy modification
Succinylcholine: Estrogen Derivatives may increase the serum concentration of Succinylcholine. Monitor therapy
Teriflunomide: May decrease the serum concentration of CYP1A2 Substrates (High risk with Inducers). Monitor therapy
Thalidomide: Estrogen Derivatives may enhance the thrombogenic effect of Thalidomide. Monitor therapy
Theophylline Derivatives: Estrogen Derivatives may increase the serum concentration of Theophylline Derivatives. Exceptions: Dyphylline. Monitor therapy
Thyroid Products: Estrogen Derivatives may diminish the therapeutic effect of Thyroid Products. Monitor therapy
Tipranavir: Estrogen Derivatives may enhance the dermatologic adverse effect of Tipranavir. The combination of tipranavir/ritonavir and ethinyl estradiol/norethindrone was associated with a high incidence of skin rash. Tipranavir may decrease the serum concentration of Estrogen Derivatives. Management: Women using hormonal contraceptives should consider alternative, non-hormonal forms of contraception. Consider therapy modification
Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy
Ursodiol: Estrogen Derivatives may diminish the therapeutic effect of Ursodiol. Monitor therapy
Reduced response to metyrapone test.
Frequency not defined.
Cardiovascular: Cerebrovascular accident, edema, hypertension, local thrombophlebitis, myocardial infarction, pulmonary embolism, retinal thrombosis, venous thromboembolism
Central nervous system: Chorea, dementia (exacerbation), depression, dizziness, exacerbation of epilepsy, headache, irritability, migraine, mood disorder, nervousness
Dermatologic: Chloasma, erythema multiforme, erythema nodosum, pruritus, loss of scalp hair, skin rash, urticaria
Endocrine & metabolic: Change in libido, exacerbation of porphyria, fibrocystic breast changes, galactorrhea, hirsutism, hypocalcemia, menstrual disease (alterations in frequency and flow of menstrual patterns), premenstrual-like syndrome, weight gain, weight loss
Gastrointestinal: Abdominal cramps, bloating, carbohydrate intolerance, gallbladder disease, nausea, pancreatitis, vomiting
Genitourinary: Breakthrough bleeding, breast hypertrophy, breast tenderness, change in cervical ectropion, change in cervical secretions, cystitis-like syndrome, dysmenorrhea, endometrial hyperplasia, nipple discharge, vulvovaginal candidiasis, vaginitis
Hematologic & oncologic: Endometrial carcinoma, hemorrhagic eruption, malignant neoplasm of breast, malignant neoplasm of ovary, uterine fibroids (increased size)
Hepatic: Cholestatic jaundice, exacerbation of hepatic hemangioma (enlargement)
Hypersensitivity: Anaphylactoid reaction, anaphylaxis, angioedema
Neuromuscular & skeletal: Arthralgia, leg cramps
Ophthalmic: Contact lens intolerance, change in corneal curvature (steepening)
Respiratory: Exacerbation of asthma
Concerns related to adverse effects:
• Breast cancer: [US Boxed Warning]: Based on data from the Women’s Health Initiative (WHI) studies, an increased risk of invasive breast cancer was observed in postmenopausal women using conjugated estrogens (CE) in combination with medroxyprogesterone acetate (MPA). This risk may be associated with duration of use and declines once combined therapy is discontinued (Chlebowski, 2009). The risk of invasive breast cancer was decreased in postmenopausal women with a hysterectomy using CE only, regardless of weight. However, the risk was not significantly decreased in women at high risk for breast cancer (family history of breast cancer, personal history of benign breast disease) (Anderson, 2012). An increase in abnormal mammogram findings has also been reported with estrogen alone or in combination with progestin therapy. Estrogen use may also lead to severe hypercalcemia in patients with breast cancer and bone metastases; discontinue estrogen if hypercalcemia occurs.
• Dementia: [US Boxed Warning]: Estrogens with or without progestin should not be used to prevent dementia. In the Women’s Health Initiative Memory Study (WHIMS), an increased incidence of dementia was observed in women ≥65 years of age taking CE alone or in combination with MPA.
• Endometrial cancer: [US Boxed Warning]: The use of unopposed estrogen in women with an intact uterus is associated with an increased risk of endometrial cancer. The addition of a progestin to estrogen therapy may decrease the risk of endometrial hyperplasia, a precursor to endometrial cancer. Adequate diagnostic measures, including endometrial sampling if indicated, should be performed to rule out malignancy in postmenopausal women with undiagnosed abnormal vaginal bleeding. Estrogens may exacerbate endometriosis. Malignant transformation of residual endometrial implants has been reported posthysterectomy with unopposed estrogen therapy. Consider adding a progestin in women with residual endometriosis posthysterectomy.
• Inherited thrombophilia: Women with inherited thrombophilias (eg, protein C or S deficiency) may have increased risk of venous thromboembolism (DeSancho, 2010; van Vlijmen, 2011).
• Lipid effects: Estrogen compounds are generally associated with lipid effects such as increased HDL-cholesterol and decreased LDL-cholesterol. Triglycerides may also be increased; use with caution in patients with familial defects of lipoprotein metabolism.
• Ovarian cancer: Postmenopausal estrogen therapy and combined estrogen/progesterone therapy may increase the risk of ovarian cancer; however, the absolute risk to an individual woman is small. Although results from various studies are not consistent, risk does not appear to be significantly associated with the duration, route, or dose of therapy. In one study, the risk decreased after 2 years following discontinuation of therapy (Mørch, 2009). Although the risk of ovarian cancer is rare, women who are at an increased risk (eg, family history) should be counseled about the association (NAMS, 2012).
• Retinal vascular thrombosis: Estrogens may cause retinal vascular thrombosis; discontinue if migraine, loss of vision, proptosis, diplopia, or other visual disturbances occur; discontinue permanently if papilledema or retinal vascular lesions are observed on examination.
• Asthma: Use caution in patients with asthma; may exacerbate disease.
• Carbohydrate intolerance: May have adverse effects on glucose tolerance; use caution in women with diabetes.
• Cardiovascular disease: [US Boxed Warning]: Estrogens with or without progestin should not be used to prevent cardiovascular disease. Using data from the Women’s Health Initiative (WHI) studies, an increased risk of deep vein thrombosis (DVT) and stroke has been reported with CE and an increased risk of DVT, stroke, pulmonary emboli (PE) and myocardial infarction (MI) has been reported with CE with MPA in postmenopausal women. Additional risk factors include diabetes mellitus, hypercholesterolemia, hypertension, SLE, obesity, tobacco use, and/or history of venous thromboembolism (VTE). Adverse cardiovascular events have also been reported in males taking estrogens for prostate cancer. Risk factors should be managed appropriately; discontinue use if adverse cardiovascular events occur or are suspected.
• Diseases exacerbated by fluid retention: Use with caution in patients with diseases which may be exacerbated by fluid retention, including cardiac or renal dysfunction.
• Epilepsy: Use caution with epilepsy; may exacerbate disease.
• Gallbladder disease: Use of postmenopausal estrogen may be associated with an increased risk of gallbladder disease requiring surgery.
• Hepatic dysfunction: Estrogens are poorly metabolized in patients with hepatic dysfunction. Use caution with a history of cholestatic jaundice associated with prior estrogen use or pregnancy. Discontinue if jaundice develops or if acute or chronic hepatic disturbances occur. Use is contraindicated with hepatic disease.
• Hepatic hemangiomas: Use with caution in patients with hepatic hemangiomas; may exacerbate disease.
• Hypocalcemia: Use with caution in patients with severe hypocalcemia.
• Migraine: Use caution with migraine; may exacerbate disease.
• Porphyria: Use with caution in patients with porphyria; may exacerbate disease.
• SLE: Use with caution in patients with SLE; may exacerbate disease.
Concurrent drug therapy issues:
• Thyroid replacement therapy: Estrogens may increase thyroid-binding globulin (TBG) levels leading to increased circulating total thyroid hormone levels. Women on thyroid replacement therapy may require higher doses of thyroid hormone while receiving estrogens.
• Pediatric: Prior to puberty, estrogens may cause premature closure of the epiphyses, premature breast development in girls or gynecomastia in boys. Vaginal bleeding and vaginal cornification may also be induced in girls.
• Surgical patients: Whenever possible, estrogens should be discontinued at least 4-6 weeks prior to elective surgery associated with an increased risk of thromboembolism or during periods of prolonged immobilization.
• Laboratory changes: The use of estrogens and/or progestins may change the results of some laboratory tests (eg, coagulation factors, lipids, glucose tolerance, binding proteins). The dose, route, and the specific estrogen/progestin influences these changes. In addition, personal risk factors (eg, cardiovascular disease, smoking, diabetes, age) also contribute to adverse events; use of specific products may be contraindicated in women with certain risk factors.
• Risks vs benefits: [US Boxed Warning]: Estrogens with or without progestin should be used for the shortest duration possible at the lowest effective dose consistent with treatment goals. Before prescribing estrogen therapy to postmenopausal women, the risks and benefits must be weighed for each patient. Women should be informed of these risks and benefits, as well as possible effects of progestin when added to estrogen therapy. Patients should be reevaluated as clinically appropriate to determine if treatment is still necessary. Available data related to treatment risks are from Women’s Health Initiative (WHI) studies, which evaluated oral CE 0.625 mg with or without MPA 2.5 mg relative to placebo in postmenopausal women. Other combinations and dosage forms of estrogens and progestins were not studied. Outcomes reported from clinical trials using CE with or without MPA should be assumed to be similar for other doses and other dosage forms of estrogens and progestins until comparable data becomes available.
• Vulvar and vaginal atrophy use: Moderate-to-severe symptoms of vulvar and vaginal atrophy include vaginal dryness, dyspareunia, and atrophic vaginitis. When used solely for the treatment of vulvar and vaginal atrophy, topical vaginal products should be considered.
Routine physical examination that includes blood pressure and Papanicolaou smear, breast exam, mammogram. Monitor for signs of endometrial cancer in female patients with uterus. Adequate diagnostic measures, including endometrial sampling, if indicated, should be performed to rule out malignancy in all cases of undiagnosed abnormal vaginal bleeding. Monitor for loss of vision, sudden onset of proptosis, diplopia, migraine; signs and symptoms of thromboembolic disorders; glycemic control in patients with diabetes; lipid profiles in patients being treated for hyperlipidemias; thyroid function in patients on thyroid hormone replacement therapy.
Menopausal symptoms; vulvar and vaginal atrophy: Assess need for therapy at 3- to 6-month intervals
In general, the use of estrogen and progestin as in combination hormonal contraceptives have not been associated with teratogenic effects when inadvertently taken early in pregnancy. This product is contraindicated for use during pregnancy.
• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience hair loss, leg cramps, abdominal cramps, bloating, nausea, vomiting, or dark patches on face. Have patient report immediately to prescriber signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), signs of liver problems (dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or jaundice), signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), edema, angina, shortness of breath, coughing up blood, severe headache, severe dizziness, passing out, vision changes, bulging eyes, contact lens discomfort, lump in breast, breast soreness or pain, nipple discharge, vaginal bleeding, vaginitis, depression, mood changes, or memory impairment (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
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More about esterified estrogens
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- Drug class: estrogens
Other brands: Menest