Version July 2025
There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens. Adding a progestin 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 progestin therapy for the prevention of cardiovascular disease.
The WHI estrogen plus progestin substudy 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 progestin 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 progestin 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 progestin therapy, taking into account her individual risk profile. Prescribe estrogens with or without progestins at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
Dosage guidance:
Safety: While prescribing information includes the same boxed warnings as systemic estrogen therapy, vaginal preparations have not been associated with the adverse effects associated with systemic therapy, and most patients are candidates for treatment (Ref).
Clinical considerations: For use in patients whose symptoms did not respond to nonhormonal therapies (ie, vaginal moisturizer, lubricant) and have no contraindications to use (eg, selected patients with breast cancer). Unlike systemic therapy, a progestogen is generally not indicated. Consider patient preference, convenience, and cost with product choice (Ref).
Genitourinary syndrome of menopause (vulvovaginal atrophy), treatment:
Intravaginal:
Vaginal cream (Estrace): Note: May also be applied directly to vulvar and vestibular tissues (Ref). Dosing is provided in grams of cream; 1 g of cream contains 0.1 mg of estradiol. Initial: 0.5 to 1 g once daily for 2 weeks (Ref). Maintenance: 0.5 to 1 g one to three times per week (Ref).
Alternative regimen (manufacturer’s labeling): Initial: 2 to 4 g once daily for 1 to 2 weeks, then gradually reduce to one-half the initial dose for 1 to 2 weeks. Maintenance: 1 g one to three times per week. Note: Dosing in the prescribing information may not reflect current clinical practice.
Vaginal insert (Imvexxy): Initial: 4 mcg or 10 mcg insert: 1 insert once daily for 2 weeks, then gradually reduce to maintenance dose (Ref). Note: Select the initial dose (4 mcg or 10 mcg) based on clinical symptom severity and patient preference (Ref). Maintenance: 4 mcg or 10 mcg insert: 1 insert twice weekly; adjust dose based on patient response (Ref). In patients with insufficient symptom relief, some experts use 3 times per week or switch from the 4 mcg to 10 mcg insert (Ref).
Vaginal ring (Estring): 1 ring inserted vaginally. Ring should be removed and replaced every 90 days (Ref). Note: Ring delivers 7.5 mcg of estradiol per 24 hours.
Vaginal tablet (Vagifem, Yuvafem): Initial: 1 tablet (10 mcg) inserted vaginally once daily for 2 weeks (Ref). Maintenance: 1 tablet (10 mcg) inserted vaginally twice weekly (Ref). Some experts use 3 times per week (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied).
There are no dosage adjustments provided in the manufacturer's labeling (has not been studied); use is contraindicated with hepatic impairment or disease.
Cardiovascular events: Discontinue therapy immediately if adverse cardiovascular events (eg, deep vein thrombosis, myocardial infarction, pulmonary embolism, stroke) occur or are suspected.
Hepatotoxicity: Discontinue if jaundice develops or if acute or chronic hepatic disturbances occur.
Hypercalcemia: Estrogen use may lead to severe hypercalcemia in patients with breast cancer and bone metastases; discontinue therapy if hypercalcemia occurs.
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
>10%: Nervous system: Headache (4% to 13%)
1% to 10%:
Dermatologic: Urticaria
Endocrine & metabolic: Hot flash (2%)
Gastrointestinal: Diarrhea (5%), abdominal pain (4%), nausea (3%)
Genitourinary: Vulvovaginal pruritus (8%), genital candidiasis (6% to 8%), leukorrhea (7%), vaginitis (5%), vaginal discomfort (≤5%), vaginal pain (≤5%), bacterial vaginosis (4%; asymptomatic), vaginal hemorrhage (4%), urinary tract infection (2%), mastalgia (1%)
Hypersensitivity: Hypersensitivity reaction (1%)
Nervous system: Insomnia (4%), stress (2%), migraine
Neuromuscular & skeletal: Back pain (6% to 7%), arthritis (4%), arthralgia (3%), skeletal pain (2%)
Respiratory: Upper respiratory tract infection (5%), sinusitis (4%), flu-like symptoms (3%), pharyngitis (1%)
Frequency not defined:
Cardiovascular: Acute myocardial infarction, cerebrovascular accident, pulmonary embolism
Dermatologic: Allergic skin rash
Nervous system: Dementia
<1%, postmarketing and/or case reports: Abdominal distention, arthropathy, breast engorgement, breast hypertrophy, decreased libido, deep vein thrombosis, depression, dizziness, endometrial carcinoma, endometrial hyperplasia, erythematous rash, exacerbation of migraine headache, excoriation of skin (vaginal), fluid retention, genital edema, genital pruritus, increased plasma estrogen concentration, intermenstrual bleeding, intestinal obstruction (ring), malignant neoplasm of breast, mechanical complication of genitourinary device (ring adherence to vaginal wall), nervousness, pruritic rash, pruritus, pruritus ani, skin rash, thrombophlebitis, urethral disease, urinary frequency, vaginal discharge, vaginal disease (erosion), vaginal ulcer, vaginismus, visual disturbance, vomiting, vulvar disease, vulvar swelling, vulvovaginal burning, weight changes, weight gain
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); estrogen-dependent tumor (known or suspected); hepatic impairment or disease; known protein C, protein S, antithrombin deficiency, or other known thrombophilic disorders; pregnancy.
Canadian labeling: Additional contraindications (not in US labeling):
Estring, Vagifem: Endometrial hyperplasia; partial or complete loss of vision due to ophthalmic vascular disease; breastfeeding; porphyria.
Imvexxy: Endometrial hyperplasia; partial or complete loss of vision due to ophthalmic vascular disease.
Concerns related to adverse effects:
• Anaphylaxis: Anaphylaxis requiring emergency medical management has been reported following oral estrogen administration and may develop at any time during therapy. Angioedema involving the face, feet, hands, larynx, and tongue has also been reported.
• Breast cancer: Estrogen with or without progestogen for the management of menopausal symptoms may be associated with an increased risk of breast cancer. 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. Patients with genitourinary syndrome of menopause (GSM) in whom nonhormone therapy has failed may be treated with local estrogen based on specific breast cancer diagnosis, evaluation of symptoms, and risk for recurrence. Products with the lowest systemic absorption are recommended (NAMS [Faubion 2018]).
• Endometrial cancer: The use of unopposed estrogen in patients with a uterus is associated with an increased risk of endometrial cancer. The risk of endometrial cancer appears to be dose and duration dependent, greatest with use ≥5 years, and may persist following discontinuation of therapy. Based on available data, the risk of endometrial cancer following low-dose vaginal estrogen is similar to rates observed in the general population. 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 2017; NAMS 2020). When nonhormonal treatments are not effective for GSM, low-dose vaginal therapy that has limited systemic absorption may be considered in appropriately selected patients with endometrial cancer (ES [Stuenkel 2015]; NAMS 2017). Patients with endometrial cancer should be closely monitored (NAMS 2020).
• Endometriosis: Estrogens may exacerbate endometriosis. Malignant transformation of residual endometrial implants has been reported posthysterectomy with unopposed estrogen therapy. Consider adding a progestin 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 use if pancreatitis occurs.
• 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 thrombosis: Estrogens may cause retinal 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.
• 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 oral conjugated estrogens (CE) and an increased risk of DVT, stroke, pulmonary emboli (PE), and myocardial infarction (MI) has been reported with oral CE with medroxyprogesterone acetate (MPA) in postmenopausal patients 50 to 79 years of age. Additional risk factors include diabetes mellitus, hypercholesterolemia, hypertension, systemic lupus erythematosus (SLE), obesity, tobacco use, and/or history of venous thromboembolism. Manage risk factors appropriately. The increased risks of cardiovascular outcomes associated with systemic estrogen or estrogen/progestin therapy may not be the same and are unlikely with low dose vaginal estrogen (Crandall 2018; NAMS 2020).
• Diabetes: 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]).
• Diseases exacerbated by fluid retention: Use with caution in patients with diseases which may be exacerbated by fluid retention, including cardiac or renal dysfunction; consider discontinuation of therapy if medically concerning fluid retention occurs.
• 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 impairment: 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 with caution in patients with hepatic hemangiomas; may exacerbate disease.
• Hereditary angioedema: Exogenous estrogens may exacerbate angioedema symptoms in patients with hereditary angioedema.
• Hypoparathyroidism: Use caution in patients with hypoparathyroidism; estrogen-induced hypocalcemia may occur.
• Migraine: Use caution with migraine; may exacerbate disease.
• Porphyria: Use with caution in patients with porphyria; may exacerbate disease.
• Systemic lupus erythematosus: Use with caution in patients with SLE; may exacerbate disease.
Special populations:
• Surgical patients: 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:
• Vaginal ring: Use may not be appropriate in patients with narrow or short vagina, vaginal stenosis, vaginal infections, prolapse, or other conditions that may increase the risk of vaginal irritation, or ulceration. Remove ring in case of infection, ulceration, erosion, or adherence to vaginal wall; do not reinsert until healing is complete.
• Vaginal tablet: Local applicator-induced abrasion may occur in patients with severely atrophic vaginal mucosa.
Other warnings/precautions:
• Genitourinary syndrome of menopause (GSM): Low-dose vaginal estrogen is preferred over systemic therapy for GSM in the absence of vasomotor symptoms due to increased efficacy and decreased systemic effects (eg, cardiovascular effects, cancer risk) (Crandall 2018; NAMS 2017; NAMS 2020).
• Risks vs benefits: Systemic absorption occurs following vaginal use; however, the risk of adverse events associated with low-dose vaginal estrogens (defined as ≤0.5 g/day) may be lower than with systemic estrogens. Consider warnings, precautions, and adverse events observed with oral therapy and weigh risk versus benefit before and during therapy (NAMS [Pinkerton 2020]). 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. Consider risk factors for cardiovascular disease when evaluating therapy and route of administration (AACE/ACE [Cobin 2017]; NAMS 2017). Use the shortest duration possible at the lowest effective dose consistent with treatment goals and risks for the individual patient. Reevaluate 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 postmenopausal women. Other combinations and dosage forms of estrogens and progestins were not studied; consider similar until comparable data are available.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product
Cream, Vaginal:
Estrace: 0.1 mg/g (42.5 g) [contains edetate (edta) disodium, methylparaben, propylene glycol]
Generic: 0.1 mg/g (42.5 g)
Insert, Vaginal:
Imvexxy Maintenance Pack: 4 mcg (8 ea); 10 mcg (8 ea) [contains alcohol, usp, fd&c red #40 (allura red ac dye)]
Imvexxy Starter Pack: 4 mcg (18 ea); 10 mcg (18 ea) [contains alcohol, usp, fd&c red #40 (allura red ac dye)]
Ring, Vaginal, as base:
Estring: 7.5 mcg/24 hr (1 ea); 2 mg (1 ea [DSC])
Tablet, Vaginal, as base:
Vagifem: 10 mcg [contains corn starch]
Yuvafem: 10 mcg [contains corn starch]
Generic: 10 mcg
May be product dependent
Cream (Estrace Vaginal)
0.1 mg/g (per gram): $9.74
Cream (Estradiol Vaginal)
0.1 mg/g (per gram): $2.82 - $8.45
INST (Imvexxy Maintenance Pack Vaginal)
4 mcg (per each): $32.35
10 mcg (per each): $32.35
INST (Imvexxy Starter Pack Vaginal)
4 mcg (per each): $32.35
10 mcg (per each): $32.35
Ring (Estring Vaginal)
7.5 mcg/24 hrs (per each): $674.41
Tablets (Estradiol Vaginal)
10 mcg (per each): $24.25
Tablets (Vagifem Vaginal)
10 mcg (per each): $25.52
Tablets (Yuvafem Vaginal)
10 mcg (per each): $24.25
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.
Insert, Vaginal:
Imvexxy: 4 mcg (2 ea, 18 ea); 10 mcg (2 ea, 18 ea) [contains fd&c red #40 (allura red ac dye)]
Ring, Vaginal, as base:
Estring: 2 mg (1 ea)
Tablet, Vaginal, as base:
Vagifem: 10 mcg
Vaginal cream: Gently insert applicator filled with vaginal cream deeply into vagina. Cleanse applicator after use with warm water and mild soap (do not boil or use hot water).
Vaginal insert: Insert with smaller end up approximately 2 inches into the vaginal canal at the same time each day.
Vaginal ring: Insert as deeply as possible into the upper one-third of the vagina; exact positioning is not critical for efficacy; however, patient should not feel anything once inserted. In case of discomfort, push ring further into vagina. Straining at defecation may make the ring move down in the lower part of the vagina; if this occurs, push up ring with finger. If ring is expelled prior to 90 days, it may be rinsed in lukewarm water and reinserted. If vaginal infection, ulceration, erosion, or adherence to vaginal wall develops, remove ring and reinsert only after healing is complete.
Vaginal tablet: Insert tablet with supplied applicator at the same time each day. Once inserted, press plunger until fully depressed, then remove applicator and discard. If tablet comes out of applicator prior to insertion, do not replace; use a new tablet filled applicator instead (if the tablet has fallen out of applicator but still remains in the package, it can be reinserted in the applicator for use). Local abrasion caused by the vaginal applicator has been reported in patients with severely atrophic vaginal mucosa.
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.
Genitourinary syndrome of menopause (vulvovaginal atrophy), treatment: Treatment of genitourinary syndrome of menopause (vulvovaginal atrophy).
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).
The Institute for Safe Medication Practices (ISMP) includes this medication among its list of drugs (contraindicated in pregnancy) which have a heightened risk of causing significant patient harm when used in error (High-Alert Medications in Community/Ambulatory Care Settings).
Estring [US, Canada, and multiple international markets] may be confused with Estrena [Finland]
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 drug interactions program by clicking on the “Launch drug interactions program” link above.
Ajmaline: Estrogen Derivatives may increase adverse/toxic effects of Ajmaline. Specifically, the risk for cholestasis may be increased. Risk C: Monitor
Anastrozole: Estrogen Derivatives may decrease therapeutic effects of Anastrozole. Risk X: Avoid
Anthrax Immune Globulin (Human): Estrogen Derivatives may increase thrombogenic effects of Anthrax Immune Globulin (Human). Risk C: Monitor
Antidiabetic Agents: Hyperglycemia-Associated Agents may decrease therapeutic effects of Antidiabetic Agents. Risk C: Monitor
C1 Inhibitors: Estrogen Derivatives may increase thrombogenic effects of C1 Inhibitors. Risk C: Monitor
Chenodiol: Estrogen Derivatives may decrease therapeutic effects of Chenodiol. Risk C: Monitor
Chlorprothixene: Estrogen Derivatives may increase adverse/toxic effects of Chlorprothixene. Estrogen Derivatives may increase therapeutic effects of Chlorprothixene. Risk C: Monitor
Clofazimine: May increase serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Risk C: Monitor
CloZAPine: CYP1A2 Inhibitors (Weak) may increase serum concentration of CloZAPine. Risk C: Monitor
Corticosteroids (Systemic): Estrogen Derivatives may increase serum concentration of Corticosteroids (Systemic). Risk C: Monitor
Cosyntropin: Coadministration of Estrogen Derivatives and Cosyntropin may alter diagnostic results. Management: Discontinue estrogen containing drugs 4 to 6 weeks prior to cosyntropin (ACTH) testing. Risk D: Consider Therapy Modification
CYP3A4 Inducers (Moderate): May decrease serum concentration of Estrogen Derivatives. Risk C: Monitor
CYP3A4 Inducers (Strong): May decrease serum concentration of Estrogen Derivatives. Risk C: Monitor
CYP3A4 Inhibitors (Strong): May increase serum concentration of Estrogen Derivatives. Risk C: Monitor
Dantrolene: Estrogen Derivatives may increase hepatotoxic effects of Dantrolene. Risk C: Monitor
Exemestane: Estrogen Derivatives may decrease therapeutic effects of Exemestane. Risk X: Avoid
Fezolinetant: CYP1A2 Inhibitors (Weak) may increase serum concentration of Fezolinetant. Risk X: Avoid
Fusidic Acid (Systemic): May increase serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Consider avoiding this combination if possible. If required, monitor patients closely for increased adverse effects of the CYP3A4 substrate. Risk D: Consider Therapy Modification
Growth Hormone Analogs: Estrogen Derivatives may decrease therapeutic effects 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 decrease therapeutic effects of Hemin. Risk X: Avoid
Hyaluronidase: Estrogen Derivatives may decrease therapeutic effects of Hyaluronidase. Risk C: Monitor
Hydrocortisone (Systemic): Estrogen Derivatives may increase serum concentration of Hydrocortisone (Systemic). Estrogen Derivatives may decrease serum concentration of Hydrocortisone (Systemic). Risk C: Monitor
Immune Globulin: Estrogen Derivatives may increase thrombogenic effects of Immune Globulin. Management: Use the lowest dose of immune globulin and minimum infusion rate practicable during coadministration with estrogen derivatives. Risk D: Consider Therapy Modification
Indium 111 Capromab Pendetide: Coadministration of Estrogen Derivatives and Indium 111 Capromab Pendetide may alter diagnostic results. Risk X: Avoid
LamoTRIgine: Estrogen Derivatives may decrease serum concentration of LamoTRIgine. Risk C: Monitor
Lenalidomide: Estrogen Derivatives may increase thrombogenic effects of Lenalidomide. Risk C: Monitor
Melatonin: Estrogen Derivatives may increase serum concentration of Melatonin. Risk C: Monitor
MetyraPONE: Coadministration of Estrogen Derivatives and MetyraPONE may alter diagnostic results. 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 serum concentration of Mivacurium. Risk C: Monitor
Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective): May increase thrombogenic effects of Estrogen Derivatives. Nonsteroidal Anti-Inflammatory Agents (COX-2 Selective) may increase serum concentration of Estrogen Derivatives. Risk C: Monitor
Ospemifene: Estrogen Derivatives may increase adverse/toxic effects of Ospemifene. Risk X: Avoid
Pomalidomide: Estrogen Derivatives may increase thrombogenic effects of Pomalidomide. Risk C: Monitor
Protease Inhibitors: May decrease serum concentration of Estrogen Derivatives. Protease Inhibitors may increase serum concentration of Estrogen Derivatives. Risk C: Monitor
Raloxifene: Estrogen Derivatives may increase adverse/toxic effects of Raloxifene. Risk X: Avoid
ROPINIRole: Estrogen Derivatives may increase serum concentration of ROPINIRole. Risk C: Monitor
Succinylcholine: Estrogen Derivatives may increase serum concentration of Succinylcholine. Risk C: Monitor
Tacrolimus (Systemic): Estrogen Derivatives may increase serum concentration of Tacrolimus (Systemic). Risk C: Monitor
Thalidomide: Estrogen Derivatives may increase thrombogenic effects of Thalidomide. Risk C: Monitor
Theophylline Derivatives: CYP1A2 Inhibitors (Weak) may increase serum concentration of Theophylline Derivatives. Risk C: Monitor
Thyroid Products: Estrogen Derivatives may decrease therapeutic effects of Thyroid Products. Risk C: Monitor
TiZANidine: CYP1A2 Inhibitors (Weak) may increase serum concentration of TiZANidine. Management: Avoid the use of tizanidine with weak CYP1A2 inhibitors when possible. If combined, monitor closely for increased tizanidine toxicities (eg, hypotension, bradycardia, drowsiness). Tizanidine dose reduction or discontinuation may be necessary. Risk D: Consider Therapy Modification
Tranexamic Acid: Estrogen Derivatives may increase thrombogenic effects of Tranexamic Acid. Risk X: Avoid
Ursodiol: Estrogen Derivatives may decrease therapeutic effects of Ursodiol. Risk C: Monitor
Patients on gender affirming testosterone therapy may experience vaginal atrophy and require use of vaginal estrogen for 2 weeks prior to pelvic exam or placement of an intrauterine device (Bonnington 2020).
Use is contraindicated during pregnancy.
In general, the use of estrogen and progestin 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 may 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.
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 with obesity, diabetes, or a history of endometrial cancer); serum triglycerides (2 weeks after starting therapy in patients with baseline level >200 mg/dL); TSH. 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 symptoms associated with GSM.
In studies for vulvar and vaginal atrophy in postmenopausal patients, local estrogens have been shown to reduce vaginal pH levels and mature the vaginal and urethral mucosa after 12 weeks of therapy, thereby improving vaginal dryness and mucosal atrophy.
Absorption: Average serum estradiol concentrations (Cavg) vary by product
Vaginal: Vaginal absorption is typically low; any contribution to circulating estradiol concentrations via systemic absorption does not exceed normal postmenopausal ranges (Ulrich 2010; Weisberg 2005).
Estring: Average steady state serum concentrations decrease from 11.2 pg/mL at 48 hours to 8 pg/mL at 12 weeks
Imvexxy: Cavg: 3.6 pg/mL (4 mcg dose); 4.6 pg/mL (10 mcg dose) following once daily dose for 14 days
Vagifem: Cavg: 10.9 pg/mL on day 1, 5.5 pg/mL on day 83
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. Sulfate conjugates are the primary form found in postmenopausal patients.
Time to peak, serum: Estring: 0.5 to 1 hour
Excretion: Primarily urine (as estradiol, estrone, estriol and their glucuronide and sulfate conjugates)
