Version May 2024
There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestogen to estrogen therapy has been shown to reduce the risk of endometrial hyperplasia, which may be a precursor to endometrial cancer. Perform adequate diagnostic measures, including directed or random endometrial sampling when indicated, to rule out malignancy in postmenopausal women with undiagnosed persistent or recurring abnormal genital bleeding.
The Women's Health Initiative (WHI) estrogen-alone substudy reported increased risks of stroke and deep vein thrombosis (DVT) in postmenopausal women (50 to 79 years of age) during 7.1 years of treatment with daily oral conjugated estrogens (CE) (0.625 mg) alone, relative to placebo. Do not use estrogen-alone therapy for the prevention of cardiovascular disease.
The WHI estrogen plus progestin substudy reported increased risks of DVT, pulmonary embolism, stroke, and myocardial infarction in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral CE (0.625 mg) combined with medroxyprogesterone acetate (MPA) (2.5 mg), relative to placebo. Do not use estrogen plus progestogen therapy for the prevention of cardiovascular disease.
The WHI estrogen plus progestin substudy also demonstrated an increased risk of invasive breast cancer.
The WHI Memory Study (WHIMS) estrogen-alone ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women ≥65 years of age during 5.2 years of treatment with daily CE (0.625 mg) alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. Do not use estrogen-alone therapy for the prevention of dementia.
The WHIMS estrogen plus progestin ancillary study of the WHI reported an increased risk of developing probable dementia in postmenopausal women ≥65 years of age during 4 years of treatment with daily CE (0.625 mg) combined with MPA (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women. Do not use estrogen plus progestogen therapy for the prevention of dementia.
Only daily oral CEs (0.625 mg) and daily oral CE (0.625 mg) and MPA (2.5 mg) were studied in the estrogen-alone and estrogen plus progestin substudies of the WHI, respectively. Therefore, the relevance of the WHI findings regarding the adverse cardiovascular events and dementia to lower CE doses, other routes of administration, or other estrogen alone products is not known. Likewise, the relevance of the WHI findings regarding the adverse cardiovascular events, dementia, and breast cancer to lower CE plus other MPA doses, other routes of administration, or other estrogen plus progestogen products is not known. Without such data, it is not possible to definitively exclude these risks or determine the extent of the risks for other products. Discuss with your patient the benefits and risks of estrogen-alone or estrogen plus progestogen therapy, taking into account her individual risk profile. Prescribe estrogens with or without progestogens at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
Breast budding and breast masses in prepubertal females and gynecomastia and breast masses in prepubertal males have been reported following unintentional secondary exposure to Evamist by women using this product. In most cases, the condition resolved with removal of Evamist exposure. Women should ensure that children do not come into contact with the site(s) where Evamist is applied. Health care providers should advise patients to strictly adhere to recommended instructions for use.
Breast cancer, metastatic: Oral (Estrace): Males and postmenopausal females: 10 mg 3 times/day for at least 3 months or (off-label dosing) postmenopausal females: 2 mg 3 times/day (Ref).
Hormone therapy for transgender females (assigned male at birth), monotherapy or combination therapy (off-label use):
Note: Alternative routes of administration (eg, sublingual administration of the oral tablet) may be used by some centers (limited data; additional study needed) (Ref).
Usual dosage:
IM:
Estradiol cypionate: 2 to 10 mg every week (Ref).
Estradiol valerate: 5 to 30 mg every 2 weeks (Ref).
Oral: 2 to 6 mg/day administered once daily or divided twice daily (Ref).
SUBQ: Estradiol cypionate or estradiol valerate: 3 to 4 mg every week (Ref).
Transdermal: Apply 0.025 to 0.2 mg/day patch every 3 to 5 days. Note: Apply two 0.1 mg patches to create a 0.2 mg/day dose (Ref).
Dosage adjustment: Adjust dose with a goal of elevating serum estradiol levels and suppressing serum testosterone levels into the normal female range (Ref).
Osteoporosis, postmenopausal, prevention (alternative agent):
Note: For use as an alternative to first-line therapies to prevent bone loss in patients with moderate to severe vasomotor symptoms of menopause (Ref). In patients without menopausal vasomotor symptoms who require fracture risk reduction, other first-line therapies are preferred. Avoid initiating in patients >60 years of age or who are >10 years beyond menopause (Ref). Ensure adequate calcium and vitamin D intake during therapy.
Transdermal:
Note: Initial dose and dosage adjustments are individualized based on menopausal symptoms. Transdermal doses ≥0.025 mg/day have been associated with BMD benefits; separate therapy to reduce the risk of osteoporotic fractures is not required for patients who attain bone mineral density (BMD) targets (Ref).
Alora, Minivelle, Vivelle-Dot: Initial: Apply 0.025 mg/day patch twice weekly.
Climara: Initial: Apply 0.025 mg/day patch once weekly.
Estradot [Canadian product]: There are no specific initial dosage recommendations provided in the manufacturer's labeling; a minimum effective dose of one 0.025 mg/day patch applied twice weekly has been established off label (Ref).
Menostar: Apply 0.014 mg/day patch once weekly. In patients with a uterus, also administer a progestin for 14 days every 6 to 12 months. Note: Although this dosage resulted in modest BMD benefits, the effect may be greatest in patients with low baseline endogenous estrogen levels (Ref). Additional antiresorptive therapy (eg, with a bisphosphonate) may be needed based on BMD response (Ref).
Oral (Estrace): Initial dose and dosage adjustments are individualized based on menopausal symptoms. Oral doses ≥0.5 mg/day have been associated with BMD benefits; separate therapy to reduce the risk of osteoporotic fractures is not required for patients who attain BMD targets (Ref). The lowest effective dose has not been determined; estradiol increases BMD in a dose-dependent fashion, with higher doses (eg, 0.5 to 1 mg/day) associated with greater BMD increases (Ref).
Duration of therapy: The optimal duration of therapy has not been established. Estrogens should be used for the shortest duration possible consistent with treatment goals (Ref). Extended use may be considered in patients in whom alternative therapies are not appropriate and when benefits of therapy are expected to outweigh risks (Ref).
Discontinuation of therapy: If continued osteoporosis therapy is necessary, switch to antiresorptive therapy (eg, with a bisphosphonate) following discontinuation (Ref).
Prostate cancer, advanced:
IM: Valerate (Delestrogen): 30 mg or more every 1 to 2 weeks.
Oral (Estrace): 1 to 2 mg 3 times/day.
Secondary amenorrhea, hypoestrogenism:
Note: For functional hypothalamic amenorrhea (FHA), initiate only if menses have not returned after 6 to 12 months of nonpharmacologic (eg, behavioral, lifestyle) therapy (Ref). For hypoestrogenism due to other causes (eg, primary ovarian insufficiency), may initiate after diagnosis confirmed if no contraindications (eg, breast cancer). For patients with a uterus, give estrogen with either cyclical (preferred in FHA) or continuous progestogen (ie, a natural progesterone or synthetic progestin) (Ref).
Oral : 1 to 2 mg per day (Ref).
Transdermal: 0.1 mg per day patch applied once weekly (Climara) or twice weekly (Alora, Vivelle-Dot) (Ref). Note: For twice-weekly dosing, replace patch every 3 to 4 days. When switching from oral to transdermal therapy, start transdermal patch 1 week after discontinuing oral hormone (may begin sooner if symptoms reappear within 1 week).
IM: Note: IM route of administration is considered nonpreferred to oral or transdermal (Ref).
Cypionate (Depo-Estradiol): 1.5 to 2 mg every 4 weeks.
Valerate (Delestrogen): 10 to 20 mg every 4 weeks.
Duration of therapy: If amenorrhea is expected to be transient (eg, FHA), discontinue after ~18 months to assess for recovery (Ref). If amenorrhea is expected to be permanent (eg, primary ovarian insufficiency), continue at least until the average age of natural menopause (age ~50 years) (Ref).
Vasomotor symptoms associated with menopause: Note:For use in symptomatic patients who are <60 years of age or within 10 years of menopause who do not have contraindications to hormone therapy (eg, breast cancer) (Ref). Nonoral estrogen preparations are preferred in patients with hypertriglyceridemia, risk factors for venous thromboembolic disease, active gallbladder disease, and/or migraine headache with aura (Ref). Initiate at the lowest dose and increase approximately every 4 weeks as needed to relieve symptoms (Ref). Evaluate routinely to minimize drug exposure and optimize administration route. Younger patients (eg, bilateral oophorectomy) may require higher doses. In patients with a uterus, give estrogen with a progestogen (ie, a natural progesterone or synthetic progestin), dosed either cyclically (preferred in late menopausal transition or early postmenopause) or continuously (preferred if >2 to 3 years postmenopause) (Ref).
Oral (Estrace): Initial: 0.5 to 1 mg once daily (Ref). Dosage range: 0.5 to 2 mg per day (Ref).
Topical gel:
Divigel: Initial: 0.25 g per day. Dosage range: 0.25 to 1.25 g per day (equivalent to estradiol 0.25 to 1.25 mg per day); maximum: 1.25 g per day.
Elestrin: Initial: Apply 1 pump (0.87 g) at the same time each day (equivalent to estradiol 0.52 mg per day).
EstroGel: Apply 1 pump (1.25 g) at the same time each day (equivalent to estradiol 0.75 mg per day).
Topical spray: Initial: 1 spray (estradiol 1.53 mg) per day. Dosing range: 1 to 3 sprays per day.
Transdermal: Note: For twice-weekly dosing, replace patch every 3 to 4 days. When switching from oral to transdermal therapy, start transdermal patch 1 week after discontinuing oral hormone (may begin sooner if symptoms reappear within 1 week). When switching from other topical therapy, no waiting period is necessary.
Alora, Estradot [Canadian product]: Initial: Apply 0.025 mg per day patch twice weekly (Ref). Dosage range: 0.025 to 0.1 mg per day patch twice weekly.
Climara: Initial: Apply 0.025 mg per day patch once weekly. Dosage range: 0.025 to 0.1 mg per day patch once weekly.
Minivelle, Vivelle-Dot: Initial: Apply 0.025 mg/day patch twice weekly (Ref). Dosage range: 0.025 to 0.1 mg per day patch twice weekly.
Oesclim [Canadian product]: Initial: Apply 0.025 to 0.05 mg per day patch twice weekly. Dosage range: 0.025 to 0.1 mg per day patch twice weekly.
Vaginal ring (Femring): Initial: 0.05 mg per day intravaginally every 3 months. Dosage range: 0.05 to 0.1 mg per day intravaginally every 3 months.
IM: Note: IM route of administration is considered nonpreferred to other routes (Ref).
Cypionate (Depo-Estradiol): 1 to 5 mg every 3 to 4 weeks.
Valerate (Delestrogen): 10 to 20 mg every 4 weeks.
Duration of therapy: Not clearly established; continued use may be appropriate in patients ≥60 years of age or >10 years after menopause with a low risk of cardiovascular disease and breast cancer and with persistent vasomotor symptoms after attempted taper/discontinuation of estrogen and trial of alternative therapies. Evaluate routinely for comorbidities and appropriateness of lower doses, nonoral routes of administration (preferred in patients ≥60 years of age), choice of progestogen, and discontinuation of therapy (Ref).
Vulvar and vaginal atrophy associated with menopause:
IM: Valerate (Delestrogen): 10 to 20 mg every 4 weeks.
Intravaginal: Vaginal ring (Femring): Initial: 0.05 mg intravaginally; following insertion, dose is released daily for 3 months. Usual dose: 0.05 mg to 0.1 mg intravaginally every 3 months.
Oral (Estrace): 0.5 to 1 mg/day (Ref).
Topical gel (EstroGel): 1.25 g/day applied at the same time each day.
Transdermal : No te: Indicated dose may be used continuously in patients without a uterus. Continuous or cyclic schedules (3 weeks on, 1 week off) may be used in patients with a uterus (indication and product specific; refer to manufacturer's labeling). When changing patients from oral to transdermal therapy, start transdermal patch 1 week after discontinuing oral hormone (may begin sooner if symptoms reappear within 1 week). Adjust dose as necessary.
Alora: Initial: Apply 0.05 mg/day patch twice weekly.
Climara: Initial: Apply 0.025 mg/day patch once weekly.
Vivelle-Dot: Initial: Apply 0.0375 mg/day patch twice weekly.
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
For most products, there are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
Use is contraindicated with hepatic dysfunction or disease
Note: The Beers Criteria recommends avoiding systemic estrogen therapy in postmenopausal patients ≥65 years of age (independent of diagnosis or condition). In older postmenopausal patients already taking systemic estrogens, consider deprescribing (Ref). Duration of use is not clearly established; continued use may be appropriate in patients ≥60 years of age or >10 years after menopause with a low risk of cardiovascular disease and breast cancer with persistent vasomotor symptoms after attempted taper/discontinuation of estrogen and trial of alternative therapies. Evaluate routinely for comorbidities and appropriateness of lower doses, non-oral routes of administration (preferred in patients ≥60 years of age), choice of progestogen, and discontinuation of therapy (Ref).
Refer to adult dosing.
(For additional information see "Estradiol (systemic): Pediatric drug information")
Note: Estrasorb has been discontinued in the US for more than 1 year. Use lowest effective dose for shortest duration possible that is consistent with an individual's treatment goals and risks; all dosage needs to be adjusted based upon the patient's response.
Constitutional delay of growth and puberty (CDGP) (females): Limited data available: Children ≥12 years and Adolescents: Note: Begin with the lowest available dose and gradually increase. Obtain bone age every 6 months to avoid premature epiphyseal closure. If treatment continues beyond 1 year or breast growth is significant and has plateaued or breakthrough bleeding occurs, add cyclic progesterone. Continue until menstruation has been established, or longer if clinically indicated (Ref).
Oral (micronized, Estrace): Initial dose: 5 mcg/kg once daily; after 6 to 12 months of therapy, may increase to 10 mcg/kg once daily (Ref). Using currently available dosage forms, some have recommended starting at a fixed dose of 0.25 mg once daily (1/2 of the 0.5 mg tablet) and increasing to 0.5 mg once daily after 6 to 12 months.
Transdermal: Initial dose: 3.1 to 6.2 mcg/day patch (eg, 1/8 to 1/4 of a 25 mcg/day patch), apply at night, remove in the morning. Increase by 3.1 to 6.2 mcg/day patch every 6 months (Ref). Note: The practice of cutting patches to achieve low doses is cited frequently in the literature (Ref); however, product specific data may not be available for all transdermal products due to product availability/manufacturing changes.
Hypogonadism (females): Limited data available: Children ≥12 years and Adolescents: Note: Begin with the lowest available dose and gradually increase. Obtain bone age every 6 months to avoid premature epiphyseal closure. Once breast growth is significant and has plateaued or breakthrough bleeding occurs, add cyclic progesterone. Continue until menstruation has been established, or longer if clinically indicated (Ref).
Oral (micronized): Initial dose: 5 mcg/kg once daily for 6 to 12 months; may then increase to 10 mcg/kg/day for 6 to 12 months; dose may be increased at every 6 to 12 month intervals by 5 mcg/kg/day, up to 20 mcg/kg/day. Do not exceed adult dose of 2 mg daily (Ref).
Transdermal: Initial dose: 3.1 to 6.2 mcg/day patch (eg, 1/8 to 1/4 of a 25 mcg/day patch), apply at night, remove in the morning. Increase by 3.1 to 6.2 mcg/day patch every 6 months; Do not exceed adult dose of 50 to 100 mcg/24 hours (Ref). Note: The practice of cutting patches to achieve low doses is cited frequently in the literature (Ref); however, product specific data may not be available for all transdermal products due to product availability/manufacturing changes.
Turner syndrome (females): Limited data available: Children ≥12 years and Adolescents: Begin at ~12 years of age using a low dose and gradually increase dose over 2 to 4 years to full adult dose. After 2 years of estrogen or when breakthrough bleeding occurs, add cyclic progesterone. Note: Full dose estrogen will be needed until at least age 30 years (Ref).
IM: Cypionate (Depot-Estradiol): Initial: 0.2 to 0.4 mg every 4 weeks, slowly increase dose over about 2 years to the goal adult dose: 3 mg/month; one trial started at 0.2 mg/dose, then increased dose at 6 month intervals in 0.2 mg/dose increments until dose of 1 mg reached and then increased in 0.5 mg/dose increments thereafter to a final dose of 3 mg (Ref).
Oral (micronized, Estrace): Initial dose: 5 mcg/kg once daily for the first 2 years, followed by 7.5 mcg/kg for the 3rd year, then 10 mcg/kg thereafter; once final height is attained, increase to adult dose of 1 to 2 mg/day (Ref). A fixed dose of 0.25 mg once daily; increasing to the adult dose of 2 to 4 mg/day over the course of 2 years has also been suggested (Ref). Note: Due to extensive first-pass metabolism, other routes of administration may be preferable.
Topical gel (Divigel): Initial: 0.1 mg of estradiol once daily for the first year, 0.2 mg of estradiol once daily for the second year, 0.5 mg of estradiol once daily for the third year, 1 mg of estradiol once daily for the fourth year, and 1.5 mg of estradiol once daily for the fifth year. Dosing based on a trial of 23 girls that followed development for 5 years; long-term dose is unknown. Due to lack of commercially available product for lower doses, individual sachets of 0.1 mg estradiol were prepared (Ref).
Transdermal patch: Initial: 6.25 mcg/day patch; slowly increase over about 2 years to the goal adult dose: 100 to 200 mcg/day patch (Ref).
Note: The lowest-dose commercially available patches deliver 14 and 25 μg daily; preferred dose fractionation method has not been established (eg, administering a partial patch, limiting to overnight use, or administering whole patches for 7 to 10 days per month). Product specific data may not be available for splitting/cutting some transdermal patches; one center has used the following titration method using Vivelle-Dot product (Ref):
Treatment month:
0 to <6 months of treatment: 3.125 mcg to 4.17 mcg/dose (equals 1/8 to 1/6 of a 25 mcg/day patch), apply at night, remove in the morning (not continuous)
6 to <12 months of treatment: 3.125 mcg to 4.17 mcg/dose (equals 1/8 to 1/6 of a 25 mcg/day patch) apply twice weekly (continuous)
12 to <18 months of treatment: 6.25 mcg to 8.33 mcg/dose (equals 1/4 to 1/3 of a 25 mcg/day patch), apply twice weekly (continuous)
18 to <24 months of treatment: 12.5 mcg/dose (equals 1/2 of a 25 mcg/day patch), apply twice weekly (continuous)
≥24 months of treatment: 25 mcg/day patch, apply twice weekly (continuous); then increase by one patch strength every 6 months to a final goal of 100 mcg/day continuously
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
For most products, there are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
For most products, there are no dosage adjustments provided in the manufacturer's labeling (has not been studied); use is contraindicated with hepatic dysfunction or disease.
There is an increased risk of breast cancer (ie, malignant neoplasm of breast) with menopausal hormone therapy (MHT) (Ref). The use of estrogen-only therapy (ET) for <1 year is considered low risk (Ref). Multiple studies, including the Women’s Health Initiative (WHI), show a higher risk of breast cancer with combined estrogen-progesterone therapy (EPT) versus ET regimens (continuous exposure > intermittent) (Ref). Data indicate risk with EPT may be doubled versus ET; a trend continued at 20 years follow-up in WHI participants (Ref). Cessation of MHT rapidly decreases risk, but increased risk of breast cancer may persist for up to 5 years (Ref). MHT did not increase risk in women with genetic risk factors; however, systemic MHT is not recommended in breast cancer survivors (especially those with hormone-receptor positive disease) (Ref). Breast cancer in patients receiving MHT is more likely to be estrogen-receptor positive (ER+) (Ref). In transgender people receiving gender affirming hormone therapy, there does not appear to be an increased risk of breast cancer (Ref).
Mechanism: Time-related; not clearly established; research continues to identify specific genetic mutations and pathways stimulated by increased estrogen levels, leading to accelerated proliferation causing mutagenesis (Ref).
Onset: Varied; increased risk of breast cancer observed with therapy beyond 1 year (Ref).
Risk factors:
• Longer duration of use; highest risk with >5 years of MHT (Ref)
• Systemic dosage forms; nonoral routes may confer less risk, but no clinical trials have been designed to examine this outcome (NAMS 2022). Topical vaginal estrogen is associated with little risk (Ref).
• Use of combination MHT regimens (Ref)
The use of hormone replacement therapy (HRT) as prevention or treatment for decline in cognitive function, dementia, and/or Alzheimer disease is not recommended (Ref). Data are mixed for combination menopausal hormone therapy regimens as well as estrogen-only therapy (ET) (Ref). The Women’s Health Initiative memory study showed that users of conjugated equine estrogens (CEEs) plus medroxyprogesterone acetate had twice the risk (23/10,000) of all-cause dementia when therapy was initiated at >65 years of age, while users of CEE alone had no increased signs of dementia (Ref). Estrogen therapy may have protective cognitive benefits in patients who have had a bilateral oophorectomy before the natural age of menopause and do not have any contraindications (Ref).
Mechanism: Not clearly established; hypotheses include estrogen protection from glutamate toxicity, prevention of β-amyloid–induced cellular changes, and increased/preserved cholinergic activity in the forebrain (Ref).
Risk factors:
• Decline of cognition at baseline; potential positive outcomes in patients with normal cognition at therapy initiation (Ref)
• Late menopause; protective exogenous estrogen benefits may be limited to perimenopause and/or early menopause (Ref)
Unopposed estrogen-only therapy (ET) in a postmenopausal patient with an intact uterus is contraindicated due to an increased risk of endometrial cancer (ie, endometrial carcinoma) (Ref). Systemic ET should be used with an adequate dose of progesterone (Ref). A conjugated equine estrogen (CEE) plus medroxyprogesterone acetate in the Women’s Health Initiative showed equivalent endometrial cancer risk to placebo with a potential reduction in risk at 13 years follow-up (Ref). It is also acceptable to use a CEE plus bazedoxifene to mitigate endometrial cancer risk (Ref). There is no increased risk of endometrial cancer with low-dose vaginal estrogen therapy; however, trial data are limited to 1 year duration of therapy (Ref). After discontinuation of ET, increased risk of endometrial cancer persists for several years (Ref).
Mechanism: Dose- and time-related; unopposed estrogen precipitates increased mitotic activity/proliferation of endometrial cells (Ref).
Onset: Delayed; increased risk of endometrial cancer appears after 2 to 3 years of unopposed ET (Ref). Endometrial hyperplasia occurs within 1 year in 20% of patients receiving unopposed ET (Ref).
Risk factors:
• Higher doses (Ref)
• Longer duration (highest risk >10 years) (Ref)
• Unopposed ET with intact uterus (Ref)
Malignant transformation of endometriosis postsurgical intervention has been rarely reported in patients receiving unopposed estrogen-only therapy (ET) (Ref). Endometrioid adenocarcinoma is the most common diagnosis among these patients; however, the quality of evidence is low and mostly observational (Ref). While most patients responded to oncologic intervention, the carcinoma was fatal in some cases (Ref).
Mechanism: Dose- and time-related; exogenous estrogen stimulation of remaining endometrial tissue postsurgical intervention, leading to reactivation of tissue proliferation (Ref).
Onset: Delayed; most patients were currently taking unopposed ET when diagnosed; however, several of the malignancies were diagnosed years after menopausal hormone therapy (MHT) discontinuation (Ref). Range of onset was 4 months to 20 years with a mean MHT duration of 7.8 years (Ref).
Risk factors:
• Unopposed exogenous estrogen (Ref)
• Previous endometriosis (Ref)
• Incomplete definitive gynecologic surgery (Ref)
Estrogen is associated with an increased risk of cholelithiasis, cholecystitis, and cholecystectomy; however, no increased risk of biliary cancer has been observed (Ref). Despite discontinuation of estrogen-only therapy, the risk of gallbladder disease may persist 10 years later (Ref). Cisgender men and transgender women may be at increased risk of a biliary event, including acute gallstone pancreatitis (Ref). Any disease of the liver is a contraindication to estrogen use, as endogenous and exogenous sources of estrogen have been associated with liver growth (Ref). No increase in liver function tests among transgender adults on hormone therapy has been observed (Ref).
Mechanism: Dose-related; first-pass hepatic effects on lipid metabolism in addition to relaxation effects of the gallbladder via G protein–coupled estrogen receptors (Ref)
Risk factors:
• Higher dose (Ref)
• Oral products pose increased risk, while transdermal products have minimal risk due to bypass of the first-pass hepatic effects (Ref)
• Hysterectomy (Ref)
• Elevated triglycerides (Ref)
• Obesity (Ref)
Data related to the risk of ovarian cancer (ie, ovarian carcinoma) with menopausal hormone therapy (MHT) are conflicting (Ref). The Women’s Health Initiative showed that conjugated equine estrogen plus medroxyprogesterone acetate use after 5.6 years conferred no increased risk, and this trend was continued after 13 years of hormone use. An association has been reported in observational data; however, the risk is small (<1/1000) (Ref). Additionally, there is no increased risk of recurrence or death after treatment for ovarian cancer in patients receiving MHT (Ref). Increased ovarian cancer risk may be limited to serous and endometrioid tumors (Ref). Discontinuation of MHT diminishes risk within 5 years (Ref).
Mechanism: Time-related, unknown; unopposed estrogen may elicit proliferation and/or abnormal transformation of ovarian cells (Ref).
Onset: Delayed; in studies showing increased risk, duration of ≥5 years of unopposed estrogen therapy was consistently observed (Ref).
Risk factors:
• Duration of therapy ≥5 years (including past use of ≥5 years) (Ref)
• Unopposed estrogen therapy (Ref)
• Age >50 years (Ref)
Estrogen is associated with an increased risk of thromboembolic complications among users (Ref). Venous thromboembolism events (VTEs) of the legs or pulmonary vessels are most common (Ref). However, the absolute risk in healthy patients is considered low (Ref). Risk returns to baseline after discontinuation (Ref). Retrospective data estimate equivalency in risk between transgender women (TGW) and cisgender women at 2 years of estrogen therapy (Ref). At 8 years of therapy, TGW had a higher risk of thromboembolic events (Ref). Estradiol confers less risk of thromboembolic events than conjugated equine estrogens (CEEs) (Ref).
Mechanism: Dose-related; estrogens are known to be prothrombotic, but the specific hemostatic pathway affected has not been identified (Ref). Increase in factors VII, VIII, X, prothrombin, and fibrinogen, as well as decrease in antithrombin and protein S, are potential etiologies (Ref).
Onset: Delayed; usually develops within the first few months of initiation (Ref).
Risk factors:
• Higher dose (Ref)
• Longer duration of therapy; data suggest increased risk of VTE after 1 to 2 years and increased stroke risk after 7 years (Ref)
• Estrogen product; estradiol confers less risk than CEE (Ref)
• Current smoker (Ref)
• Hypercholesteremia (Ref)
• Hypertension (Ref)
• Ischemic heart disease/prior myocardial infarction (Ref)
• Stroke (Ref)
• Migraine with aura (Ref)
• Surgery/immobilization (Ref)
• Thrombophilia (Ref)
• Strong family history of VTE without identifiable cause (Ref)
• Prior thromboembolic event (Ref)
• Less than 21 days postpartum (Ref)
• Route of administration; oral products may confer more risk than transdermal products; however, trials have not been designed to detect differences in routes of administration (Ref)
• Use as feminizing therapy in TGW may increase risk when compared to use as menopausal hormone therapy in cisgender women (Ref)
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%:
Cardiovascular: Edema (transdermal: 10% to 13%)
Gastrointestinal: Abdominal pain (oral: 2%; transdermal: 6% to 16%)
Genitourinary: Breakthrough bleeding (transdermal: 6% to 11%), breast tenderness (3% to 17%), endometrium disease (15%), leukorrhea (transdermal: 2% to 11%), mastalgia (including discomfort; transdermal: 5% to 35%), vulvovaginal candidiasis (intravaginal: 6% to 11%)
Local: Application-site erythema (transdermal: ≤17%), application-site irritation (transdermal: ≤17%)
Nervous system: Depression (transdermal: 1% to 11%), headache (intravaginal, oral, topical: 3% to 12%; transdermal: 13% to 50%), pain (transdermal: 6% to 13%)
Neuromuscular & skeletal: Arthralgia (topical, transdermal: 4% to 12%), back pain (intravaginal, transdermal: 6% to 11%; topical: 3% to 5%)
Respiratory: Nasopharyngitis (topical, transdermal: 4% to 20%), sinus headache (transdermal: 9% to 11%), sinusitis (intravaginal, transdermal: 4% to 13%), upper respiratory tract infection (topical: 6%; transdermal: 9% to 17%)
Miscellaneous: Accidental injury (transdermal: 14%)
1% to 10%:
Cardiovascular: Hypertension (transdermal: 3% to 7%)
Dermatologic: Acne vulgaris (oral: 2%), pruritus (transdermal: 7%), skin rash (transdermal: 7% to 9%)
Endocrine & metabolic: Hirsutism (transdermal: 2% to 5%), hot flash (transdermal: 6%), intermenstrual bleeding (intravaginal, oral: 2% to 10%), weight gain (transdermal: 4% to 9%)
Gastrointestinal: Abdominal distention (intravaginal: 7%), constipation (transdermal: 4% to 7%), dyspepsia (transdermal: 3% to 9%), flatulence (transdermal: 3% to 7%), gastroenteritis (transdermal: 3% to 4%), nausea (transdermal: 4% to 7%)
Genitourinary: Abnormal uterine bleeding (topical: 4% to 10%), breast hypertrophy (transdermal: 7%), cervical polyp (transdermal: 6%), dysmenorrhea (transdermal: 7%), genital pruritus (oral: 1% to 2%), nipple pain (topical: 1% to 7%), urinary tract infection (intravaginal: 4%), uterine pain (intravaginal: 2% to 5%), vaginal discharge (oral: ≤4%), vaginal hemorrhage (oral: 3% to 7%), vaginal mycosis (topical: 6%)
Infection: Fungal infection (transdermal: 3% to 10%)
Local: Application-site reaction (topical: ≤1%)
Nervous system: Anxiety (transdermal: 4% to 6%), asthenia (transdermal: 8%), dizziness (transdermal: 5% to 8%), fatigue (oral: 2%), migraine (transdermal: 7%)
Neuromuscular & skeletal: Limb pain (transdermal: 7% to 8%), myalgia (transdermal: 5%), neck pain (transdermal: 3% to 6%)
Respiratory: Bronchitis (transdermal: 6%), flu-like symptoms (transdermal: 8%), paranasal sinus congestion (transdermal: 7%), pharyngitis (transdermal: 7%), rhinitis (transdermal: 2% to 6%)
Miscellaneous: Cyst (transdermal: 7%)
Postmarketing:
Cardiovascular: Acute myocardial infarction, altered blood pressure, chest discomfort, chest pain, deep vein thrombosis (Laliberte 2018), irregular pulse, palpitations, peripheral edema, portal vein thrombosis, premature ventricular contractions, pulmonary embolism (Laliberte 2018), tachycardia, thrombophlebitis, thrombosis (including thromboembolic complications) (Vinogradova 2019), unstable angina pectoris, varicose veins, venous thromboembolism (Vinogradova 2019)
Dermatologic: Alopecia, chloasma, contact dermatitis, dyschromia, erythema multiforme (can be application site), erythema nodosum (can be application site), erythema of skin, hemorrhagic eruption of the skin, hyperhidrosis, night sweats, pruritic rash, skin discoloration (including nipple and areola discoloration), swelling of skin, urticaria, xeroderma
Endocrine & metabolic: Amenorrhea, change in libido, change in menstrual flow (alterations in frequency and flow of bleeding patterns), exacerbation of porphyria, fibrocystic breast changes, galactorrhea not associated with childbirth, gynecomastia, heavy menstrual bleeding, hypercholesterolemia, hypocalcemia, impaired glucose tolerance, increased serum triglycerides, loss of libido, menopausal symptoms, spotting, weight loss
Gastrointestinal: Abdominal cramps, bloating, cholecystitis, cholelithiasis, decreased appetite, diarrhea, dysgeusia, gallbladder disease, oral paresthesia, pancreatitis, vomiting, xerostomia
Genitourinary: Breast secretion, breast swelling, change in cervical ectropion, change in cervical secretions, endometrial carcinoma (Altaras 1990), endometrial hyperplasia, malignant neoplasm of breast, nipple discharge, ovarian carcinoma, ovarian cyst, pelvic pain, uterine carcinoma, uterine fibroids, uterine hypertrophy, vaginal dryness, vaginitis, vulvar dryness, vulvovaginal pruritus
Hematologic & oncologic: Hemorrhage, purpuric disease
Hepatic: Abnormal hepatic function tests, cholestatic jaundice, exacerbation of hepatic hemangioma
Hypersensitivity: Anaphylaxis, angioedema, hypersensitivity reaction, nonimmune anaphylaxis, swelling of lips, swollen tongue
Local: Application-site burning, application-site pain, application-site rash, application-site vesicles, local inflammation (application site), localized edema (application site)
Nervous system: Cerebrovascular accident, chorea, dementia, drowsiness, emotional disturbance, emotional lability, exacerbation of epilepsy, hemiparesis, hypoesthesia, insomnia, irritability, lethargy, malaise, mood disorder, nervousness, paresthesia, transient ischemic attacks, tremor, vertigo
Neuromuscular & skeletal: Arthritis, lower leg cramp, muscle spasm
Ophthalmic: Blindness, blurred vision, contact lens intolerance, eye irritation, ocular hyperemia, retinal vein occlusion, visual impairment
Respiratory: Cough, dry throat, dyspnea, exacerbation of asthma, pharyngeal edema
Miscellaneous: Mass (breast)
Angioedema, anaphylactic reaction, or hypersensitivity to estradiol or any component of the formulation; undiagnosed abnormal genital bleeding; DVT or PE (current or history of); active or history of arterial thromboembolic disease (eg, stroke, MI); breast cancer (known, suspected or history of), except in appropriately selected patients being treated for metastatic disease; estrogen-dependent tumor (known or suspected); hepatic impairment or disease; known protein C, protein S, antithrombin deficiency or other known thrombophilic disorders; pregnancy (Note: Products approved for use only in patients who are postmenopausal are not appropriate for use in pregnancy; use of some products is specifically contraindicated in the manufacturer's labeling).
Canadian labeling: Additional contraindications (not in US labeling): Note: May be dosage form dependent (consult product labeling): Breastfeeding; endometrial hyperplasia; active thrombophlebitis; partial or complete loss of vision or diplopia due to ophthalmic vascular disease; presence or history of hepatic tumors (benign or malignant); porphyria; classical migraine.
Concerns related to adverse effects:
• Anaphylaxis: Anaphylaxis requiring emergency medical management has been reported and may develop at any time during therapy. Angioedema involving the face, feet, hands, larynx, and tongue has also been reported.
• Breast cancer: Based on data from the Women’s Health Initiative (WHI) studies, an increased risk of invasive breast cancer was observed in patients who are postmenopausal 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 patients with a hysterectomy using CE alone. The risk of breast cancer in patients who are postmenopausal receiving hormone therapy may depend upon type of estrogen and/or progestogen, dose, timing of therapy initiation, duration of therapy, route of administration, and individual patient characteristics (AACE/ACE [Cobin 2017]; NAMS 2022). Hormone therapy may be associated with increased breast density (NAMS 2022); an increase in abnormal mammogram findings requiring further evaluation has been reported with estrogen alone or in combination with progestogen therapy. Estrogen use may lead to severe hypercalcemia in patients with breast cancer and bone metastases; discontinue estrogen if hypercalcemia occurs.
• Dementia: Do not use estrogens with or without progestogen to prevent dementia. In the Women’s Health Initiative Memory Study (WHIMS), an increased incidence of probable dementia was observed in patients ≥65 years of age taking CE alone or in combination with MPA. Because the WHIMS was conducted in patients ≥65 years of age, it is unknown if these findings apply to younger patients who are postmenopausal. However, hormone therapy is not recommended at any age to prevent or treat cognitive decline or dementia (NAMS 2022).
• Endometrial cancer: The use of unopposed estrogen in patients with a uterus is associated with an increased risk of endometrial cancer. The addition of a progestogen to estrogen therapy may decrease the risk of endometrial hyperplasia, a precursor to endometrial cancer. Perform adequate diagnostic measures, including endometrial sampling if indicated, to rule out malignancy in patients who are postmenopausal 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 progestogen 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 2022).
• Endometriosis: Estrogens may exacerbate endometriosis. Malignant transformation of residual endometrial implants has been reported posthysterectomy with unopposed estrogen therapy. Consider adding a progestogen in patients with residual endometriosis posthysterectomy.
• Lipid effects: Estrogen compounds are generally associated with lipid effects such as increased HDL-cholesterol and decreased LDL-cholesterol. Triglycerides may also be increased in patients with preexisting hypertriglyceridemia; discontinue if pancreatitis occurs.
• Ovarian cancer: Available information related to the use of menopausal estrogen or estrogen/progestogen 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 (ES [Stuenkel 2015]; NAMS 2022).
• 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 with asthma; may exacerbate disease.
• Cardiovascular disease: Do not use estrogens with or without progestogen to prevent cardiovascular disease. The WHI studies reported an increased risk of deep vein thrombosis (DVT) and stroke with CE and an increased risk of DVT, stroke, pulmonary emboli (PE) and myocardial infarction (MI) with CE with MPA in patients who are postmenopausal and 50 to 79 years of age. Additional risk factors include diabetes mellitus, hypercholesterolemia, hypertension, systemic lupus erythematosus, obesity, tobacco use, and/or history of venous thromboembolism. Adverse cardiovascular events have also been reported in patients taking estrogens for prostate cancer. Manage risk factors 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]).
• Diabetes mellitus: May impair glucose tolerance; use caution in patients with diabetes mellitus. Prior to therapy, consider age, cardiovascular and metabolic risk factors in patients previously diagnosed with diabetes (AACE/ACE [Cobin 2017]).
• Diseases exacerbated by fluid retention: Use caution 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.
• Hepatic hemangiomas: Use caution with hepatic hemangiomas; may exacerbate disease.
• Hereditary angioedema: Exogenous estrogens may exacerbate angioedema symptoms in patients with hereditary angioedema.
• Hypoparathyroidism: Use caution with hypoparathyroidism; estrogen-induced hypocalcemia may occur.
• Migraine: Use caution with migraine; may exacerbate disease.
• Porphyria: Use caution with porphyria; may exacerbate disease.
• SLE: Use caution with SLE; may exacerbate disease.
Special populations:
• Pediatric: Prior to puberty, estrogens may cause premature closure of the epiphyses. Premature breast development, vaginal bleeding, and vaginal cornification may be induced in girls. Modification of the normal puberty process may occur in boys.
• Surgery: Whenever possible, discontinue estrogens at least 4 to 6 weeks prior to elective surgery associated with an increased risk of thromboembolism or during periods of prolonged immobilization.
Dosage form specific issues:
• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer's labeling.
• Chlorobutanol: Some products may contain chlorobutanol (a chloral derivative) as a preservative, which may be habit forming.
• Tartrazine: Some products may contain tartrazine.
• Topical gel: Absorption of the topical gel (Elestrin) is increased by application of sunscreen; do not apply sunscreen within close proximity of estradiol. Application of sunscreen after EstroGel decreases absorption of estradiol, while application of moisturizer lotion after EstroGel increases the absorption of estradiol; the effect of applying sunscreen or lotion prior to Estrogel has not been studied. Application of Divigel with sunscreen has not been evaluated.
• Topical spray: When sunscreen is applied ~1 hour prior to the topical spray (Evamist), no change in absorption was observed (estradiol absorption was decreased when sunscreen is applied 1 hour after Evamist).
• Transdermal patch: May contain conducting metal (eg, aluminum); remove patch prior to MRI.
• Vaginal ring: Use may not be appropriate in patients with narrow vagina, vaginal stenosis, vaginal infections, cervical prolapse, rectoceles, cystoceles, or other conditions that may increase the risk of vaginal irritation, ulceration, or increase the risk of expulsion. Remove ring in case of ulceration, erosion, or adherence to vaginal wall; do not reinsert until healing is complete. Ensure proper vaginal placement of the ring to avoid inadvertent urinary bladder insertion.
Other warnings/precautions:
• Duration of use: Not clearly established; continued use may be appropriate in patients ≥60 years of age or >10 years after menopause with a low risk of cardiovascular disease and breast cancer with persistent vasomotor symptoms after attempted taper/discontinuation of estrogen and trial of alternative therapies. Evaluate routinely for comorbidities and appropriateness of lower doses, nonoral routes of administration (preferred in patients ≥60 years of age), choice of progestogen, and discontinuation of therapy (NAMS 2022).
• 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 2020; NAMS 2022).
• Osteoporosis use: In patients with premature menopause, hormone therapy to prevent bone loss may be used unless otherwise contraindicated; reassess therapy when the average age of menopause is reached. It is also an appropriate bone-active therapy for patients with vasomotor symptoms who are <60 years of age or within 10 years of menopause onset. Consider for patients at high risk of fractures who are not candidates for other osteoporosis therapies (ES [Eastell 2019]; NAMS 2021; NAMS 2022).
• Risks vs benefits: When used for the relief of menopausal symptoms or increased risk of bone fracture/loss, 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. Consider cardiovascular disease risk factors when evaluating therapy and route of administration (AACE/ACE [Cobin 2017]; NAMS 2022). Use for the shortest duration possible at the lowest effective dose consistent with treatment goals and risks for the individual patient. Reevaluate patients as clinically appropriate to determine if treatment is still necessary. Available data related to treatment risks are from WHI studies, which evaluated oral CE 0.625 mg with or without MPA 2.5 mg relative to placebo in patients who were postmenopausal. Other combinations and dosage forms of estrogens and progestogens were not studied. Assume outcomes reported from clinical trials using CE with or without MPA to be similar for other doses and other dosage forms of estrogens and progestogens until comparable data becomes available.
• Secondary exposure: Following application of the topical gel or mist, estradiol may be transferred to another person following skin-to-skin contact with the application site. Breast budding and breast masses in prepubertal females and gynecomastia and breast masses in prepubertal males have been reported following unintentional contact with application sites of patients using topical estradiol (Evamist). Instruct patients to strictly adhere to instructions for use in order to prevent secondary exposure. In most cases, conditions resolved with removal of estradiol exposure. If unexpected changes in sexual development occur in prepubertal children, evaluate the possibility of unintentional estradiol exposure. Discontinue if conditions for safe use cannot be met.
Some dosage forms may contain propylene glycol; in neonates large amounts of propylene glycol delivered orally, intravenously (eg, >3,000 mg/day), or topically have been associated with potentially fatal toxicities which can include metabolic acidosis, seizures, renal failure, and CNS depression; toxicities have also been reported in children and adults including hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP, 1997; Shehab, 2009).
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Gel, Transdermal:
Divigel: 0.25 mg/0.25 g (30 ea); 0.5 mg/0.5 g (30 ea); 0.75 mg/0.75 g (30 ea); 1 mg/g (1 g); 1.25 mg/1.25 g (1.25 g) [contains propylene glycol, trolamine (triethanolamine)]
Elestrin: 0.06% (26 g) [contains edetate (edta) disodium, propylene glycol, trolamine (triethanolamine)]
Estrogel: 0.06% (50 g) [contains alcohol, usp, trolamine (triethanolamine)]
Generic: 0.25 mg/0.25 g (1 ea, 30 ea); 0.5 mg/0.5 g (1 ea, 30 ea); 0.75 mg/0.75 g (1 ea, 30 ea); 1 mg/g (1 g); 1.25 mg/1.25 g (1.25 g)
Oil, Intramuscular, as cypionate:
Depo-Estradiol: 5 mg/mL (5 mL) [contains chlorobutanol (chlorobutol)]
Oil, Intramuscular, as valerate:
Delestrogen: 10 mg/mL (5 mL) [contains chlorobutanol (chlorobutol), sesame oil]
Delestrogen: 20 mg/mL (5 mL); 40 mg/mL (5 mL) [contains benzyl alcohol, benzyl benzoate, castor oil (ricine oil)]
Generic: 10 mg/mL (5 mL); 20 mg/mL (5 mL); 40 mg/mL (5 mL)
Patch Twice Weekly, Transdermal:
Alora: 0.025 mg/24 hr (1 ea, 8 ea [DSC]); 0.05 mg/24 hr (1 ea [DSC], 8 ea [DSC]); 0.075 mg/24 hr (1 ea, 8 ea [DSC]); 0.1 mg/24 hr (1 ea, 8 ea [DSC])
Dotti: 0.025 mg/24 hr (1 ea, 8 ea); 0.0375 mg/24 hr (1 ea, 8 ea); 0.05 mg/24 hr (1 ea, 8 ea); 0.075 mg/24 hr (1 ea, 8 ea); 0.1 mg/24 hr (1 ea, 8 ea)
Lyllana: 0.025 mg/24 hr (1 ea, 8 ea); 0.0375 mg/24 hr (1 ea, 8 ea); 0.05 mg/24 hr (1 ea, 8 ea); 0.075 mg/24 hr (1 ea, 8 ea); 0.1 mg/24 hr (1 ea, 8 ea)
Minivelle: 0.025 mg/24 hr (1 ea, 8 ea); 0.0375 mg/24 hr (1 ea, 8 ea); 0.05 mg/24 hr (1 ea, 8 ea); 0.075 mg/24 hr (1 ea, 8 ea); 0.1 mg/24 hr (1 ea, 8 ea)
Vivelle-Dot: 0.025 mg/24 hr (1 ea, 8 ea); 0.0375 mg/24 hr (1 ea, 8 ea); 0.05 mg/24 hr (1 ea, 8 ea); 0.075 mg/24 hr (1 ea, 8 ea); 0.1 mg/24 hr (1 ea, 8 ea)
Generic: 0.025 mg/24 hr (1 ea, 8 ea); 0.0375 mg/24 hr (1 ea, 8 ea); 0.05 mg/24 hr (1 ea, 8 ea); 0.075 mg/24 hr (1 ea, 8 ea); 0.1 mg/24 hr (1 ea, 8 ea)
Patch Weekly, Transdermal:
Climara: 0.025 mg/24 hr (1 ea, 4 ea); 0.0375 mg/24 hr (1 ea, 4 ea); 0.05 mg/24 hr (1 ea, 4 ea); 0.06 mg/24 hr (1 ea, 4 ea); 0.075 mg/24 hr (1 ea, 4 ea); 0.1 mg/24 hr (1 ea, 4 ea)
Menostar: 14 mcg/24 hr (4 ea)
Generic: 0.025 mg/24 hr (1 ea, 4 ea); 0.0375 mg/24 hr (1 ea, 4 ea); 0.05 mg/24 hr (1 ea, 4 ea); 0.06 mg/24 hr (1 ea, 4 ea); 0.075 mg/24 hr (1 ea, 4 ea); 0.1 mg/24 hr (1 ea, 4 ea)
Ring, Vaginal, as acetate:
Femring: 0.05 mg/24 hr (1 ea); 0.1 mg/24 hr (1 ea)
Solution, Transdermal:
Evamist: 1.53 mg/spray (8.1 mL)
Tablet, Oral:
Estrace: 0.5 mg, 1 mg, 2 mg [scored]
Generic: 0.5 mg, 1 mg, 2 mg
May be product dependent
Gel (Divigel Transdermal)
0.25 mg/0.25gm (per each): $6.74
0.5 mg/0.5 g (per each): $6.74
0.75MG/0.75GM (per each): $6.74
1 mg/g (per gram): $6.74
1.25 mg/1.25 g (per gram): $5.40
Gel (Elestrin Transdermal)
0.52 MG/0.87 GM (0.06%) (per gram): $5.77
Gel (Estradiol Transdermal)
0.25 mg/0.25gm (per each): $6.32
0.5 mg/0.5 g (per each): $6.32
0.75MG/0.75GM (per each): $6.32
1 mg/g (per gram): $6.32
1.25 mg/1.25 g (per gram): $5.06
Gel (Estrogel Transdermal)
0.75 MG/1.25 GM (0.06%) (per gram): $3.67
Oil (Delestrogen Intramuscular)
10 mg/mL (per mL): $31.86
20 mg/mL (per mL): $44.90
40 mg/mL (per mL): $74.47
Oil (Depo-Estradiol Intramuscular)
5 mg/mL (per mL): $44.52
Oil (Estradiol Valerate Intramuscular)
10 mg/mL (per mL): $28.64 - $29.87
20 mg/mL (per mL): $33.38 - $40.36
40 mg/mL (per mL): $55.37 - $66.95
Patch weekly (Climara Transdermal)
0.025 mg/24 hrs (per each): $22.90
0.0375 mg/24 hrs (per each): $22.90
0.05 mg/24 hrs (per each): $22.90
0.06 mg/24 hrs (per each): $22.90
0.075 mg/24 hrs (per each): $22.90
0.1 mg/24 hrs (per each): $22.90
Patch weekly (Estradiol Transdermal)
0.025 mg/24 hrs (per each): $23.21
0.0375 mg/24 hrs (per each): $23.21
0.05 mg/24 hrs (per each): $23.21
0.06 mg/24 hrs (per each): $23.21
0.075 mg/24 hrs (per each): $23.21
0.1 mg/24 hrs (per each): $23.21
Patch weekly (Menostar Transdermal)
14 mcg/24 hrs (per each): $48.68
Patch, twice-weekly (Alora Transdermal)
0.025 mg/24 hrs (per each): $15.48
0.075 mg/24 hrs (per each): $17.29
0.1 mg/24 hrs (per each): $17.69
Patch, twice-weekly (Dotti Transdermal)
0.025 mg/24 hrs (per each): $17.99
0.0375 mg/24 hrs (per each): $17.99
0.05 mg/24 hrs (per each): $18.00
0.075 mg/24 hrs (per each): $18.02
0.1 mg/24 hrs (per each): $18.03
Patch, twice-weekly (Estradiol Transdermal)
0.025 mg/24 hrs (per each): $11.33 - $24.46
0.0375 mg/24 hrs (per each): $11.34 - $24.46
0.05 mg/24 hrs (per each): $11.34 - $24.46
0.075 mg/24 hrs (per each): $11.35 - $24.46
0.1 mg/24 hrs (per each): $11.35 - $24.46
Patch, twice-weekly (Lyllana Transdermal)
0.025 mg/24 hrs (per each): $24.46
0.0375 mg/24 hrs (per each): $24.46
0.05 mg/24 hrs (per each): $24.46
0.075 mg/24 hrs (per each): $24.46
0.1 mg/24 hrs (per each): $24.46
Patch, twice-weekly (Minivelle Transdermal)
0.025 mg/24 hrs (per each): $34.87
0.0375 mg/24 hrs (per each): $34.87
0.05 mg/24 hrs (per each): $34.87
0.075 mg/24 hrs (per each): $34.87
0.1 mg/24 hrs (per each): $34.87
Patch, twice-weekly (Vivelle-Dot Transdermal)
0.025 mg/24 hrs (per each): $21.97
0.0375 mg/24 hrs (per each): $21.95
0.05 mg/24 hrs (per each): $21.95
0.075 mg/24 hrs (per each): $22.07
0.1 mg/24 hrs (per each): $22.00
Ring (Femring Vaginal)
0.05 mg/24 hrs (per each): $913.58
0.1 mg/24 hrs (per each): $973.54
Solution (Evamist Transdermal)
1.53 mg/spray (per mL): $20.96
Tablets (Estrace Oral)
0.5 mg (per each): $6.54
1 mg (per each): $6.54
2 mg (per each): $8.40
Tablets (Estradiol Oral)
0.5 mg (per each): $0.55 - $1.29
1 mg (per each): $0.68 - $2.06
2 mg (per each): $0.94 - $3.25
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Gel, Transdermal:
Divigel: 0.25 mg/0.25 g (1 ea); 0.5 mg/0.5 g (1 ea); 1 mg/g (1 ea, 1 g) [contains propylene glycol, trolamine (triethanolamine)]
Estrogel: 0.06% (80 g) [contains alcohol, usp, trolamine (triethanolamine)]
Patch Twice Weekly, Transdermal:
Estradot 25: 0.025 mg/24 hr (8 ea)
Estradot 37.5: 0.0375 mg/24 hr (8 ea)
Estradot 50: 0.05 mg/24 hr (8 ea)
Estradot 75: 0.075 mg/24 hr (8 ea)
Estradot 100: 0.1 mg/24 hr (8 ea)
Oesclim: 0.025 mg/24 hr (8 ea); 0.05 mg/24 hr (8 ea)
Generic: 0.05 mg/24 hr (1 ea); 0.075 mg/24 hr (1 ea); 0.1 mg/24 hr (1 ea)
Patch Weekly, Transdermal:
Climara 25: 0.025 mg/24 hr (4 ea)
Climara 50: 0.05 mg/24 hr (4 ea)
Climara 75: 0.075 mg/24 hr (4 ea)
Tablet, Oral:
Generic: 0.5 mg, 1 mg, 2 mg
Consider the use of a progestogen when administering estrogens to patients who are postmenopausal with a uterus.
Injection formulation:
IM:
Estradiol cypionate: Shake or gently warm vial to redissolve crystals that may have formed during storage.
Estradiol valerate: Inject into the upper outer quadrant of the gluteal muscle; administer with a dry needle (solution may become cloudy with wet needle).
SUBQ (off-label route): Estradiol cypionate or estradiol valerate: When used for gender-affirming hormone therapy, administer into the thigh or abdomen; pause for 5 seconds with plunger depressed prior to removing needle (Ref).
Gel: Apply to clean, dry, unbroken skin at the same time each day. Wash hands after application. Gel is flammable; avoid fire or flame until skin is dry. Avoid secondary exposure (eg, to children) by preventing unintentional contact with the application site.
Divigel: Apply the entire contents of packet to right or left upper thigh each day (alternate sites) over a ~5 x 7-inch area. Do not apply to face, breasts, vaginal area, or irritated skin. Do not wash application site for 1 hour. Allow gel to dry before dressing.
Elestrin: Apply the entire dose to upper arm and shoulder area using 2 fingers to spread gel. Do not apply to breasts or vaginal area. Allow skin to dry for ≥5 minutes prior to dressing. Prior to first use, pump must be primed. After priming, the pump contains 30 metered doses; discard pump after 30 doses even though container may not be empty. If >1 dose is needed, wait 5 seconds before pumping next dose. To avoid secondary exposure, do not allow others to contact the application site for 2 hours after gel is applied. Allow at least 2 hours between applying gel and going swimming. Wait at least 25 minutes before applying sunscreen to application area. When sunscreen and gel are applied to the same site for >7 consecutive days, the absorption of estradiol is increased; do not apply sunscreen to an area where the gel was applied for ≥7 consecutive days.
EstroGel: Apply dose into the palm of hand and then apply gel to the other arm, from the wrist to the shoulder. Do not apply to breasts or vaginal area. Spread gel as thinly as possible over one arm but do not massage or rub in gel. Allow skin to dry for 5 minutes before dressing. Prior to first use, pump must be primed. After priming, the pump contains 32 daily doses (50 g canister) or 14 daily doses (25 g canister). Discard pump after allotted doses even though container may not be empty. To avoid secondary exposure, do not allow others to contact the application site for ≥1 hour after gel is applied. Wait as long as possible between applying gel and going swimming. When sunscreen was applied 1 hour after the gel to the same site for >7 consecutive days, the absorption of estradiol was decreased; when moisturizing lotion was applied 1 hour after the gel to the same site for >7 consecutive days, the absorption of estradiol was increased. The effect of applying sunscreen or lotion prior to the gel has not been studied.
Spray: Evamist: Prior to first use, prime pump by spraying 3 sprays with the cover on. To administer dose, hold container upright and vertical and rest the plastic cone flat against the skin while spraying. Spray to the inner surface of the forearm, starting near the elbow. If more than one spray is needed, apply to adjacent but not overlapping areas. Apply at the same time each day. Allow spray to dry for ~2 minutes; do not rub into skin; do not cover with clothing until dry. Do not wash application site for at least 60 minutes. Apply to clean, dry, unbroken skin. Do not apply to skin other than that of the forearm. Make sure that children do not come in contact with any skin area where the drug was applied. If contact with children is unavoidable, wear a garment with long sleeves that covers the site of application. If direct exposure occurs, wash the child in the area of exposure with soap and water as soon as possible. Solution contained in the spray is flammable; avoid fire, flame, or smoking until spray has dried. If needed, apply sunscreen ~1 hour prior to application of Evamist.
Transdermal patch: General administration instructions (also refer to product labeling): Apply patch immediately after removing from protective pouch to lower abdomen or buttocks. Apply to clean, dry, healthy skin that is free of oil, powder, or lotion. Avoid waistline or other areas where tight clothing may rub the patch off; do not apply to breasts. After application, hold patch in place using palm of hand for 10 seconds. Rotate application sites allowing a 1-week interval between applications at a particular site. In general, if patch falls off, the same patch may be reapplied or a new system may be used for the remainder of the dosing interval. When replacing patch, reapply to a new site. Remove patch slowly after use to avoid skin irritation. If any adhesive remains on the skin after removal, first allow skin to dry for 15 minutes, then gently rub area with an oil-based cream or lotion. Dispose of any used or unused patches by folding adhesive ends together, replace in pouch or sealed container, and discard properly in trash away from children and pets.
Climara, Menostar: Swimming, bathing, or wearing patch while in a sauna have not been studied.
Vaginal ring: Exact positioning is not critical for efficacy; however, patient should not feel anything once inserted. In case of discomfort, push ring further into vagina. If ring is expelled prior to 90 days, it may be rinsed off with warm water and reinserted. Ensure proper vaginal placement of the ring to avoid inadvertent urinary bladder insertion. Femring may remain in place during local treatment of a vaginal infection. Femring may remain in place during sexual intercourse; however, if it is removed or expelled, it may be rinsed off with warm water and reinserted.
Oral: May administer with food or after a meal to reduce GI upset
Parenteral: Injection for IM use only
Cypionate: Inspect for any particulate (particularly crystals); warming and shaking the vial should redissolve any crystals
Transdermal: Note: See package insert for administration related to postmenopausal symptoms, prevention of osteoporosis in postmenopausal women, and palliative treatment of breast cancer or androgen-dependent prostate cancer in adults.
Gel (Divigel): Apply to clean, dry, unbroken skin at the same time each day. Apply entire contents of packet to right or left upper thigh each day (alternate sites). Do not apply to face, breasts, vaginal area, or irritated skin. Apply over an area ~5x7 inches. Do not wash application site for 1 hour. Allow to dry for 5 minutes prior to dressing. Gel is flammable; avoid fire or flame until dry. After application, wash hands with soap and water. Prior to the first use, pump must be primed.
Transdermal patch: Do not apply transdermal system to breasts, but place on trunk of body (preferably abdomen). Rotate application sites allowing a 1-week interval between applications at a particular site. Do not apply to oily, damaged or irritated skin; avoid waistline or other areas where tight clothing may rub the patch off. Apply patch immediately after removing from protective pouch. In general, if patch falls off, the same patch may be reapplied or a new system may be used for the remainder of the dosing interval (not recommended with all products) When replacing patch, reapply to a new site. Swimming, bathing, or showering are not expected to affect use of the patch. Note the following exceptions:
Climara, Menostar, Minivelle: Swimming, bathing, or wearing patch while in a sauna have not been studied; adhesion of patch may be decreased or delivery of estradiol may be affected. Showering is not expected to cause the Minivelle patch to fall off. Remove patch slowly after use to avoid skin irritation. If any adhesive remains on the skin after removal, first allow skin to dry for 15 minutes, then gently rub area with an oil-based cream or lotion. If patch falls off, a new patch should be applied for the remainder of the dosing interval.
Hazardous agent (NIOSH 2016 [group 2]).
Use appropriate precautions for receiving, handling, storage, preparation, dispensing, transporting, administration, and disposal. Follow NIOSH and USP 800 recommendations and institution-specific policies/procedures for appropriate containment strategy (NIOSH 2016; USP-NF 2020).
Note: Facilities may perform risk assessment of some hazardous drugs to determine if appropriate for alternative handling and containment strategies (USP-NF 2020). Refer to institution-specific handling policies/procedures.
Breast cancer, metastatic: Treatment of metastatic breast cancer (palliation) in appropriately selected males and postmenopausal females.
Osteoporosis, postmenopausal, prevention: Prevention of postmenopausal osteoporosis.
Limitations of use: For use only in patients at significant risk of postmenopausal osteoporosis; consider use of nonestrogen medications.
Prostate cancer, advanced: Treatment of androgen-dependent advanced prostatic cancer (palliation).
Secondary amenorrhea, hypoestrogenism: Treatment of hypoestrogenism due to hypogonadism, castration, or primary ovarian failure.
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 vulvar and vaginal atrophy associated with menopause.
Limitations of use: When used solely for the treatment of vulvar and vaginal atrophy, consider topical vaginal products.
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 (Ref).
Hormone therapy for transgender females (assigned male at birth)
Alora may be confused with Aldara
Elestrin may be confused with alosetron
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 potentially inappropriate medications to be avoided in postmenopausal patients ≥65 years of age (independent of diagnosis or condition) due to their carcinogenic potential (breast and endometrium) and lack of cardioprotection or cognitive protection. Starting therapy in postmenopausal patients ≥60 years of age has greater risks (eg, heart disease, stroke, blood clots, dementia) than benefits. In postmenopausal patients already taking systemic estrogens, consider deprescribing (Beers Criteria [AGS 2023]).
Transdermal patch may contain conducting metal (eg, aluminum); remove patch prior to MRI.
Vivelle: Brand name for estradiol [US and multiple international markets, but also the brand name for ethinyl estradiol and norgestimate [Austria]
Substrate of CYP1A2 (minor), CYP2A6 (minor), CYP2B6 (minor), CYP2C19 (minor), CYP2C9 (minor), CYP2D6 (minor), CYP2E1 (minor), CYP3A4 (major); Note: Assignment of Major/Minor substrate status based on clinically relevant drug interaction potential; Inhibits CYP1A2 (weak)
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
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. Risk C: Monitor therapy
Chlorprothixene: Estrogen Derivatives may enhance the adverse/toxic effect of Chlorprothixene. Estrogen Derivatives may enhance the therapeutic effect of Chlorprothixene. Risk C: Monitor therapy
Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
CloZAPine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of CloZAPine. 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
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
Fezolinetant: CYP1A2 Inhibitors (Weak) may increase the serum concentration of Fezolinetant. 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
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
MetyraPONE: Estrogen Derivatives may diminish the diagnostic effect of MetyraPONE. Management: Consider alternatives to the use of the metyrapone test in patients taking estrogen derivatives. Risk D: Consider therapy modification
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. 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
Raloxifene: Estrogen Derivatives may enhance the adverse/toxic effect of Raloxifene. Risk X: Avoid combination
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
Theophylline Derivatives: CYP1A2 Inhibitors (Weak) may increase the serum concentration of Theophylline Derivatives. Risk C: Monitor therapy
Thyroid Products: Estrogen Derivatives may diminish the therapeutic effect of Thyroid Products. Risk C: Monitor therapy
TiZANidine: CYP1A2 Inhibitors (Weak) may increase the serum concentration of TiZANidine. Management: Avoid these combinations when possible. If combined use is necessary, initiate tizanidine at an adult dose of 2 mg and increase in 2 to 4 mg increments based on patient response. Monitor for increased effects of tizanidine, including adverse reactions. Risk D: Consider therapy modification
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.
Estradiol is a component of therapy for transgender females (assigned male at birth). Gender-affirming hormone therapy may cause subfertility or infertility. Consider options for preserving fertility prior to therapy (ACOG 2021; Ellis 2019; ES [Hembree 2017]; WPATH [Coleman 2022]); however, gender-affirming hormone therapy should not be considered effective contraception; sexually active patients should consider the possibility of pregnancy and use contraception if pregnancy is not desired (ACOG 2021; WPATH [Coleman 2022]).
When treating patients with secondary amenorrhea (hypoestrogenism) due to primary ovarian failure, consider barrier methods of contraception or use of an IUD in patients not wishing to become pregnant (ACOG 2017).
Products approved for use only in patients who are postmenopausal are not appropriate for use during pregnancy; use of some products is specifically contraindicated in the manufacturer's labeling.
In general, the use of estrogen and progestogen as in combination hormonal contraceptives has not been associated with teratogenic effects when inadvertently taken early in pregnancy.
Estrogens are present in breast milk.
Estrogens have been shown to decrease the quantity and quality of human milk. According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. Monitor the growth of the infant closely.
Ensure adequate calcium and vitamin D intake when used for the prevention of osteoporosis.
Prior to therapy, baseline risk for breast cancer and CVD. During therapy, age-appropriate breast and pelvic exams; BP; 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. Evaluate duration of treatment at least annually (ES [Stuenkel 2015]).
Note: Monitoring of FSH and serum estradiol is not useful when managing vasomotor symptoms or genitourinary syndrome of menopause.
Prevention of osteoporosis: Bone density measurement
Menostar: When used in a patient with a uterus, endometrial sampling is recommended at yearly intervals or when clinically indicated.
Transgender hormone therapy: Serum estradiol levels (goal: ≤100 to 200 pg/mL) and serum testosterone levels (goal: <50 ng/dL) every 3 months during the first year and then annually or biannually; prolactin levels (as appropriate); routine cancer and laboratory screening as in cisgender individuals for all tissues present (ES [Hembree 2017]).
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. Following menopause, 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 in patients who are postmenopausal.
Absorption: Well absorbed from the gastrointestinal tract, mucous membranes, and the skin. Average serum estradiol concentrations (Cavg) vary by product
Injection: Estradiol valerate and estradiol cypionate are absorbed over several weeks following IM injection
Topical:
Alora: Cavg: 41 to 98 pg/mL
Climara: Cavg: 22 to 106 pg/mL
Divigel: Cavg: 9.8 to 30.5 pg/mL
Elestrin: Cavg: 15.4 to 39.2 pg/mL; Exposure increased by 55% with application of sunscreen 10 minutes prior to dose
Estrogel: Cavg on day 14 of therapy: 28.3 pg/mL. Cmax of estradiol is altered by repeated daily application (for 7 days) of sunscreen (decreased by 16%) or lotion (increased by 73%) when applied 1 hour after the dose.
Evamist: Cavg: 19.6 to 30.9 pg/mL
Menostar: Cavg: 13.7 pg/mL
Vivelle-Dot: Cavg: 34 to 104 pg/mL
Vaginal: Femring: Rapid during the first hour following application, then declines to a steady rate over 3 months; Cavg: 40.6 to 76 pg/mL
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 patients who are postmenopausal. With transdermal application, less estradiol is metabolized leading to higher circulating concentrations of estradiol and lower concentrations of estrone and conjugates.
Excretion: Primarily urine (as estradiol, estrone, estriol and their glucuronide and sulfate conjugates)
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