Estrogens increase the risk of endometrial cancer. Close clinical surveillance of all women taking estrogens is important. Adequate diagnostic measures, including endometrial sampling when indicated, to rule out malignancy in all cases of undiagnosed persistent or recurring abnormal vaginal bleeding. There is no evidence that the use of "natural" estrogens results in a different endometrial risk profile than synthetic estrogens at equivalent estrogen doses.
Estrogens with and without progestins should not be used for the prevention of cardiovascular disease. The Women's Health Initiative (WHI) study reported increased risks of myocardial infarction, stroke, pulmonary emboli, and deep vein thrombosis in postmenopausal women (50 to 79 years of age) during 5 years of treatment with oral conjugated estrogens (0.625 mg) combined with medroxyprogesterone (2.5 mg), relative to placebo.
The Women's Health Initiative (WHI) study reported increased risks of invasive breast cancer in postmenopausal women (50 to 79 years of age) during 5 years of treatment with oral conjugated estrogens (0.625 mg) combined with medroxyprogesterone (2.5 mg) relative to placebo.
The Women's Health Initiative Memory Study (WHIMS) a substudy of WHI, reported an 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. It is unknown whether this finding applies to younger postmenopausal women or to women taking estrogen alone therapy.
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, estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
General dosing guidelines: When treating symptoms of menopause, hormone therapy should be evaluated routinely for appropriate dose, duration, and route of administration for each individual patient based on treatment goals, risk factors, and overall health (NAMS 2017). Combined estrogen/progestin therapy is indicated for postmenopausal persons with a uterus to decrease the risk of endometrial cancer. Individuals who have had a hysterectomy generally do not need a progestin; however, one may be needed if there is a history of endometriosis. Adjust dose based on patient response.
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. 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 (3 weeks on and 1 week off). 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 menstrual bleeding has not occurred for ≥2 months, cyclic administration can be started at any time. If the patient is menstruating, cyclical administration is started on day 5 of the bleeding.
Vulvar and vaginal atrophy associated with menopause: Oral: 0.3 to ≥1.25 mg/day, initiate at the lowest dose and adjust based on patient response. Administer cyclically (3 weeks on and 1 week off).
Breast cancer, metastatic (appropriately selected patients): Males and postmenopausal females: Oral: 10 mg 3 times/day for at least 3 months
No dosage adjustment provided in manufacturer's labeling; use with caution.
No dosage adjustment provided in manufacturer's labeling; use is contraindicated with hepatic impairment or dysfunction.
Note: Women >65 years of age should be assessed for benefits and risks of treatment; possible adjustments to safer lower-dose and/or route of administration should be considered (ACOG 565 2013; NAMS 2017). The Beers Criteria recommends avoiding systemic estrogen therapy in patients ≥65 years of age (independent of diagnosis or condition) (Beers Criteria [AGS 2019]).
Refer to adult dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Tablet, Oral:
Menest: 0.3 mg, 0.625 mg, 1.25 mg, 2.5 mg [DSC]
No
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral:
Estragyn: 0.3 mg [contains sodium benzoate, tartrazine (fd&c yellow #5)]
Estragyn: 0.625 mg [contains brilliant blue fcf (fd&c blue #1), sodium benzoate, tartrazine (fd&c yellow #5)]
Hazardous agent (NIOSH 2016 [group 2]).
Use appropriate precautions for receiving, handling, administration, and disposal. Gloves (single) should be worn during receiving, unpacking, and placing in storage. NIOSH recommends single gloving for administration of intact tablets or capsules (NIOSH 2016). Assess risk to determine appropriate containment strategy (USP-NF 2017).
Breast cancer, metastatic: Treatment of metastatic breast cancer (palliation) in appropriately selected men and postmenopausal women
Hypoestrogenism (female): Treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure
Prostate cancer: Palliative therapy of advanced prostatic carcinoma
Vasomotor symptoms associated with menopause: Treatment of moderate to severe vasomotor symptoms associated with menopause
Vulvar and vaginal atrophy associated with menopause: Treatment of moderate to severe symptoms of vulvar and vaginal atrophy associated with menopause
Limitations of use: When used solely for the treatment of vulvar and vaginal atrophy, topical vaginal products should be considered
Note: The International Society for the Study of Women’s Sexual Health and The North American Menopause Society have endorsed the term genitourinary syndrome of menopause (GSM) as new terminology for vulvovaginal atrophy. The term GSM encompasses all genital and urinary signs and symptoms associated with a loss of estrogen due to menopause (Portman 2014).
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs that have a heightened risk of causing significant patient harm when used in error.
Beers Criteria: Estrogens (oral or topical patch products only), with or without progestins, are identified in the Beers Criteria as a potentially inappropriate medication to be avoided in patients 65 years and older (independent of diagnosis or condition) due to their carcinogenic potential (breast and endometrium) and lack of cardioprotection or cognitive protection in older women. Low-dose intravaginal estrogen (vaginal creams or tablets) are acceptable for dyspareunia, recurrent lower urinary tract infections, and other vaginal symptoms. Of note, women with a history of breast cancer not responding to non-hormonal therapies are advised to discuss the risks/benefits of low dose vaginal estrogen (estradiol less than 25 mcg twice weekly) with their healthcare provider (Beers Criteria [AGS 2019]).
Pharmacy Quality Alliance (PQA): Estrogens (oral, topical patch, and topical gel products only), with or without progestins, are identified as a high-risk medication in patients 65 years and older on the PQA’s, Use of High-Risk Medications in the Elderly (HRM) performance measure, a safety measure used by the Centers for Medicare and Medicaid Services (CMS) for Medicare plans (Ref).
Estragyn: Brand name for estrone vaginal [Canada] and estrogens esterified oral [Canada]
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. 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
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
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). Observational studies noted this risk declines once therapy is discontinued. The WHI study did not observe an increased risk of invasive breast cancer in women with a hysterectomy using CE alone. The risk of breast cancer in postmenopausal patients on hormone therapy may depend upon type of estrogen and/or progestin, dose, timing of therapy initiation, duration of therapy, route of administration, and individual patient characteristics (AACE/ACE [Cobin 2017]; NAMS 2017). Hormone therapy may be associated with increased breast density (NAMS 2017); an increase in abnormal mammogram findings requiring further evaluation has been reported with estrogen alone or in combination with progestin therapy. Estrogen use may 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. Because the WHI memory studies were conducted in women ≥65 years of age, it is unknown if these findings apply to younger postmenopausal women. However, hormone therapy is not recommended at any age to prevent or treat cognitive decline or dementia (AACE [Goodman 2011]; NAMS 2017).
• 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. There is no evidence that the use of natural estrogens results in a different endometrial risk profile than synthetic estrogens at equivalent estrogen doses. The risk of endometrial cancer appears to be dose and duration dependent, greatest with use ≥5 years, and may persist following discontinuation of therapy. The use of a progestin is not generally required when low doses of estrogen are used locally for vaginal atrophy, although long term data (>1 year) supporting this recommendation are lacking (NAMS 2013; NAMS 2017).
• Endometriosis: 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: Available information related to the use of menopausal estrogen or estrogen/progestin therapy and risk of ovarian cancer is inconsistent. If an association is present, the absolute risk is likely rare and may be influenced by duration of therapy (AACE [Goodman 2011]; ES [Stuenkel 2015]; NAMS 2017).
• 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.
Disease-related concerns:
• Asthma: Use caution in patients with asthma; may exacerbate disease.
• Carbohydrate intolerance: May impair glucose tolerance; use caution in patients with diabetes. Prior to therapy, consider age, cardiovascular and metabolic risk factors in patients previously diagnosed with diabetes (AACE/ACE [Cobin 2017]).
• 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 immediately if adverse cardiovascular events occur or are suspected. Due to possible lower risk of thrombotic events, transdermal administration may be preferred for treating vasomotor symptoms of menopause in patients with risk factors for cardiovascular disease (AACE/ACE [Cobin 2017]; ACOG 556 2013; ES [Stuenkel 2015]). Use is contraindicated in women with active DVT, PE, arterial thromboembolic disease (stroke and MI), or a history of these conditions.
• 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.
Special populations:
• Surgical patients: Whenever possible, estrogens should be discontinued at least 4 to 6 weeks prior to elective surgery associated with an increased risk of thromboembolism or during periods of prolonged immobilization.
Other warnings/precautions:
• Duration of use: Extended use of menopausal hormone therapy may be considered for persistent vasomotor symptoms or issues related to quality of life. Menopausal hormonal therapy does not need to be routinely discontinued in women >60 years of age and may continue in women >65 years of age after clinical evaluation and discussion of benefits and risks of treatment. Annual exams should be performed with a review of comorbidities; possible adjustments to safer lower-dose and/or route of administration should be discussed (ACOG 565 2013; NAMS 2017).
• Genitourinary syndrome of menopause: Low-dose vaginal estrogen is preferred over systemic therapy for genitourinary syndrome of menopause in the absence of vasomotor symptoms due to increased efficacy and decreased systemic effects (eg, cardiovascular effects, cancer risk) (Crandall 2018; NAMS 2013; NAMS 2017).
• 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.
• Risks vs benefits: When used for the relief of menopausal symptoms, the benefit-risk of hormone therapy is most favorable if started in patients who have no contraindications to therapy, are <60 years of age, within 10 years of menopause onset, have a favorable lipid profile, and do not have the factor V Leiden genotype or metabolic syndrome. Risk factors for cardiovascular disease should also be considered when evaluating therapy and route of administration (AACE/ACE [Cobin 2017]; NAMS 2017). [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. 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.
Substrate of CYP1A2 (minor), CYP2B6 (minor), CYP2C9 (minor), CYP2E1 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential
Ajmaline: Estrogen Derivatives may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased. Risk C: Monitor therapy
Anastrozole: Estrogen Derivatives may diminish the therapeutic effect of Anastrozole. Risk X: Avoid combination
Anthrax Immune Globulin (Human): Estrogen Derivatives may enhance the thrombogenic effect of Anthrax Immune Globulin (Human). Risk C: Monitor therapy
Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
C1 inhibitors: Estrogen Derivatives may enhance the thrombogenic effect of C1 inhibitors. Risk C: 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. Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Corticosteroids (Systemic): Estrogen Derivatives may increase the serum concentration of Corticosteroids (Systemic). Risk C: Monitor therapy
Cosyntropin: Estrogen Derivatives may diminish the diagnostic effect of Cosyntropin. Management: Discontinue estrogen containing drugs 4 to 6 weeks prior to cosyntropin (ACTH) testing. Risk D: Consider therapy modification
CYP3A4 Inducers (Moderate): May decrease the serum concentration of Estrogen Derivatives. Risk C: Monitor therapy
CYP3A4 Inducers (Strong): May decrease the serum concentration of Estrogen Derivatives. Risk C: Monitor therapy
CYP3A4 Inhibitors (Strong): May increase the serum concentration of Estrogen Derivatives. Risk C: Monitor therapy
Dantrolene: Estrogen Derivatives may enhance the hepatotoxic effect of Dantrolene. Risk C: Monitor therapy
Dehydroepiandrosterone: May enhance the adverse/toxic effect of Estrogen Derivatives. Risk X: Avoid combination
Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy
Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Exemestane: Estrogen Derivatives may diminish the therapeutic effect of Exemestane. Risk X: Avoid combination
Fexinidazole: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk X: Avoid combination
Growth Hormone Analogs: Estrogen Derivatives may diminish the therapeutic effect of Growth Hormone Analogs. Management: Initiate somapacitan at 2 mg once weekly in patients receiving oral estrogens. Monitor for reduced efficacy of growth hormone analogs; increased doses may be required. Risk D: Consider therapy modification
Hemin: Estrogen Derivatives may diminish the therapeutic effect of Hemin. Risk X: Avoid combination
Hyaluronidase: Estrogen Derivatives may diminish the therapeutic effect of Hyaluronidase. Risk C: Monitor therapy
Hydrocortisone (Systemic): Estrogen Derivatives may increase the serum concentration of Hydrocortisone (Systemic). Estrogen Derivatives may decrease the serum concentration of Hydrocortisone (Systemic). Risk C: Monitor therapy
Immune Globulin: Estrogen Derivatives may enhance the thrombogenic effect of Immune Globulin. Risk C: Monitor therapy
Indium 111 Capromab Pendetide: Estrogen Derivatives may diminish the diagnostic effect of Indium 111 Capromab Pendetide. Risk X: Avoid combination
Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Risk C: Monitor therapy
LamoTRIgine: Estrogen Derivatives may decrease the serum concentration of LamoTRIgine. Risk C: Monitor therapy
Lenalidomide: Estrogen Derivatives may enhance the thrombogenic effect of Lenalidomide. Risk C: Monitor therapy
Melatonin: Estrogen Derivatives may increase the serum concentration of Melatonin. Risk C: Monitor therapy
Mivacurium: Estrogen Derivatives may increase the serum concentration of Mivacurium. Risk C: 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. Risk C: Monitor therapy
Ospemifene: Estrogen Derivatives may enhance the adverse/toxic effect of Ospemifene. Estrogen Derivatives may diminish the therapeutic effect of Ospemifene. Risk X: Avoid combination
Pomalidomide: Estrogen Derivatives may enhance the thrombogenic effect of Pomalidomide. Risk C: Monitor therapy
Protease Inhibitors: May decrease the serum concentration of Estrogen Derivatives. Protease Inhibitors may increase the serum concentration of Estrogen Derivatives. Risk C: Monitor therapy
ROPINIRole: Estrogen Derivatives may increase the serum concentration of ROPINIRole. Risk C: Monitor therapy
Succinylcholine: Estrogen Derivatives may increase the serum concentration of Succinylcholine. Risk C: Monitor therapy
Tacrolimus (Systemic): Estrogen Derivatives may increase the serum concentration of Tacrolimus (Systemic). Risk C: Monitor therapy
Thalidomide: Estrogen Derivatives may enhance the thrombogenic effect of Thalidomide. Risk C: Monitor therapy
Thyroid Products: Estrogen Derivatives may diminish the therapeutic effect of Thyroid Products. Risk C: Monitor therapy
Tranexamic Acid: Estrogen Derivatives may enhance the thrombogenic effect of Tranexamic Acid. Risk X: Avoid combination
Ursodiol: Estrogen Derivatives may diminish the therapeutic effect of Ursodiol. Risk C: Monitor therapy
Folic acid absorption may be decreased.
Estrogens esterified are contraindicated for use during pregnancy.
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.
Estrogens are present in breast milk.
Estrogen has been shown to decrease the quantity and quality of human milk. The manufacturer recommends caution be used if administered to a breastfeeding woman.
Females: Prior to therapy, baseline risk for breast cancer and CVD. During therapy, age appropriate breast and pelvic exams; blood pressure; unscheduled bleeding lasting >6 months for endometrial pathology (sooner in patients who are obese, diabetic, or have a history of endometrial cancer); serum triglycerides (2 weeks after starting therapy in patients with baseline level >200 mg/dL); TSH (6 to 12 weeks after starting oral therapy in patients taking thyroid replacement) (ES [Stuenkel 2015]).
Menopausal symptoms: Efficacy beginning 1 to 3 months after starting therapy, then every 6 to 12 months as appropriate. Duration of treatment should be evaluated at least annually (ES [Stuenkel 2015]).
Note: Monitoring of FSH and serum estradiol is not useful when managing vasomotor symptoms or GSM.
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.
Absorption: Readily
Distribution: Widely distributed; high concentrations in the sex hormone target organs
Protein binding: Bound to sex hormone-binding globulin and albumin
Metabolism: 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.
Excretion: Primarily urine (as estradiol, estrone, estriol, and their glucuronide and sulfate conjugates)
Tablets (Menest Oral)
0.3 mg (per each): $2.20
0.625 mg (per each): $3.13
1.25 mg (per each): $4.37
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