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. Undertake 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.
Estrogen-alone therapy should not be used for the prevention of cardiovascular disease. 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 0.625 mg alone, relative to placebo.
Estrogen plus progestin therapy should not be used for the prevention of cardiovascular disease. The WHI estrogen plus progestin substudy reported increased risks of DVT, pulmonary embolism (PE), stroke, and myocardial infarction (MI) in postmenopausal women (50 to 79 years of age) during 5.6 years of treatment with daily oral conjugated estrogens (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg), relative to placebo.
The WHI estrogen-plus-progestin substudy demonstrated an increased risk of invasive breast cancer.
Estrogen-alone therapy should not be used for the prevention of dementia. 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 or older during 5.2 years of treatment with daily conjugated estrogens (0.625 mg) alone, relative to placebo. It is unknown whether this finding applies to younger postmenopausal women.
Estrogen plus progestin therapy should not be used 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 or older during 4 years of treatment with daily conjugated estrogens (0.625 mg) combined with medroxyprogesterone acetate (2.5 mg), relative to placebo. It is unknown whether this finding applies to younger postmenopausal women.
In the absence of comparable data, these risks should be assumed to be similar for other doses of conjugated estrogens (with or without medroxyprogesterone acetate) and other dosage forms of estrogens (with or without progestins). Estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman.
Labial adhesions: Limited data available: Infants ≥3 months and Children (pre-pubertal): Topical: Cream: Apply once or twice daily; usual duration: 2 to 6 weeks; for recurrence, treatment courses have been repeated with success (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 dysfunction or disease.
(For additional information see "Conjugated equine estrogens (topical): Drug information")
Dosage guidance:
Dosage form information: Dosing is provided in grams of cream; 1 g of cream contains 0.625 mg conjugated equine estrogen.
Genitourinary syndrome of menopause (vulvovaginal atrophy), treatment: Note: 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). 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. Unlike systemic therapy, a progestogen is generally not indicated. Consider patient preference, convenience, and cost with product choice. May also be applied directly to vulvar and vestibular tissues (Ref).
Intravaginal: 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); adjust dose based on patient response (range: 0.5 to 2 g/day).
Alternative regimen (manufacturer’s labeling): 0.5 g once daily administered in a cyclic regimen (21 days on, 7 days off); adjust dose based on patient response (range: 0.5 to 2 g/day). Note: Dosing in the prescribing information may not reflect current clinical practice.
Kraurosis vulvae, treatment: Intravaginal: 0.5 g once daily administered in a cyclic regimen (21 days on, 7 days off); adjust dose based on patient response (range: 0.5 to 2 g/day).
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 dysfunction or disease.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Due to systemic absorption, other adverse effects associated with systemic therapy may also occur. Frequency of adverse events reported with daily use.
1% to 10%:
Cardiovascular: Vasodilation (4%)
Central nervous system: Pain (7%)
Gastrointestinal: Abdominal pain (8%)
Genitourinary: Mastalgia (6%), vaginitis (6%)
Neuromuscular & skeletal: Weakness (6%), back pain (5%)
<1%, postmarketing, and/or case reports: Abdominal cramps, abnormal uterine bleeding, acne vulgaris, alopecia, anaphylaxis, application site reaction (application site burning, application site irritation, genital pruritus), arthralgia, bloating, breast hypertrophy, breast tenderness, cerebrovascular accident, change in cervical secretions, change in libido, chloasma, contact lens intolerance, cystitis-like syndrome, decreased glucose tolerance, deep vein thrombosis, dementia, depression, dizziness, dysmenorrhea, dysuria, edema, endometrial carcinoma, endometrial hyperplasia, exacerbation of asthma, fibrocystic breast changes, gallbladder disease, gynecomastia, headache, hirsutism, hypersensitivity reaction, hypertension, increased serum triglycerides, irritability, leg cramps, leukorrhea, malignant neoplasm of breast, migraine, mood disorder, muscle cramps, myocardial infarction, nausea, nervousness, nipple discharge, pelvic pain, polyuria, precocious puberty, pulmonary embolism, retinal thrombosis, skin rash, spotting, urinary tract infection, urinary urgency, urticaria, uterine fibroids (increase in size), vomiting, vulvovaginal disease, weight changes
Angioedema, anaphylactic reaction or hypersensitivity to conjugated estrogens 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 dysfunction or disease; known protein C, protein S, antithrombin deficiency or other known thrombophilic disorders; pregnancy
Canadian labeling: Additional contraindications (not in US labeling): Endometrial hyperplasia; partial or complete vision loss due to ophthalmic vascular disease; migraine with or without aura
Concerns related to adverse effects:
• Anaphylaxis: Anaphylaxis requiring emergency medical management has been reported and may develop at any time during therapy (reported to occur within minutes to hours with oral 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 patients who are postmenopausal receiving 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 (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 progestin therapy. Estrogen use may lead to severe hypercalcemia in patients with breast cancer and bone metastases. Due to increased risks, estrogens are contraindicated in patients with known or suspected breast cancer; however, 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; agents other than vaginal CEs may be preferred (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 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 2022).
• 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 high-density lipoprotein-cholesterol and decreased low -density lipoprotein-cholesterol. Triglycerides may also be increased in patients with preexisting hypertriglyceridemia; discontinue if pancreatitis occurs.
• Ovarian cancer: Available data related to the use of menopausal estrogen or estrogen/progestin therapy and risk of ovarian cancer are 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 in patients 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 CEs and an increased risk of DVT, stroke, pulmonary emboli (PE) and myocardial infarction (MI) has been reported with CEs with MPA in patients who are postmenopausal 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. 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 mellitus.
• Diseases exacerbated by fluid retention: Use with caution in patients with diseases which may be exacerbated by fluid retention, including cardiac or renal dysfunction.
• Epilepsy: Use caution with epilepsy; may exacerbate disease.
• Gallbladder disease: Use of postmenopausal estrogen may be associated with an increased risk of gallbladder disease requiring surgery.
• Hepatic dysfunction: Estrogens are poorly metabolized in patients with hepatic dysfunction. Use caution with a history of cholestatic jaundice associated with prior estrogen use or pregnancy.
• Hepatic hemangiomas: Use with caution in patients with hepatic hemangiomas.
• 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.
• SLE: Use with caution in patients with systemic lupus erythematosus; may exacerbate disease.
Special populations:
• Surgical patients: Whenever possible, estrogens should be discontinued at least 4 to 6 weeks prior to elective surgery associated with an increased risk of thromboembolism or during periods of prolonged immobilization.
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.
Other warnings/precautions:
• Genitourinary syndrome of menopause: 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 2020; NAMS 2022).
• Risks versus 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 (NAMS 2022). Use estrogens with or without progestogen for 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.
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.
Cream, Vaginal:
Premarin: 0.625 mg/g (30 g) [contains benzyl alcohol, cetyl alcohol, propylene glycol monostearate]
No
Cream (Premarin Vaginal)
0.625 mg/g (per gram): $18.43
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.
Cream, Vaginal:
Premarin: 0.625 mg/g (14 g) [contains cetyl alcohol]
Topical: Labial adhesions: Wash hands prior to application. Apply with fingertip; gently retract skin in area (vulva) and apply to fusion site from anterior to posterior; cover area with diaper/undergarment; wash hands after application (Ref).
Intravaginal: Using applicator provided by the manufacturer, insert cream deeply into vagina. Insert as far as possible into the vagina without causing discomfort. The applicator is calibrated in 0.5 g increments up to 2 g. To clean applicator, remove plunger from barrel. Wash with mild soap and warm water; do not boil or use hot water. Allow to dry thoroughly before putting back together. The vaginal cream may also be applied to the external vulvar tissue (Ref).
Hazardous agent (NIOSH 2024 [table 1]).
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 2023; NIOSH 2024; 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.
Vaginal cream: Store at room temperature of 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).
Treatment of atrophic vaginitis and kraurosis vulvae and moderate to severe dyspareunia (pain during intercourse) due to vaginal/vulvar atrophy of menopause (FDA approved in adult females); has also been used to treat labial adhesion in prepubertal females
Premarin may be confused with Primaxin, Provera, Remeron
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).
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.
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
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
Use of the vaginal cream may weaken latex found in condoms, diaphragms, or cervical caps and may contribute to contraceptive failure.
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 have not been associated with teratogenic effects when inadvertently taken early in pregnancy.
Pediatric: Assess application site, monitor for excessive estrogen (eg, premature breast bud formation, hyperpigmentation of vulva, vaginal bleeding) (Bacon 2015).
Adult: Routine physical examination that includes blood pressure and Papanicolaou smear, breast exam, mammogram. Monitor for signs of endometrial cancer in female patients with a uterus. Adequate diagnostic measures, including endometrial sampling, if indicated, should be performed to rule out malignancy in all cases of undiagnosed abnormal genital bleeding. Monitor for loss of vision, sudden onset of proptosis, diplopia, migraine; signs and symptoms of thromboembolic disorders; glycemic control in patients with diabetes; lipid profiles in patients being treated for hyperlipidemias; thyroid function in patients on thyroid hormone replacement therapy.
Note: Monitoring of FSH and serum estradiol is not useful when managing symptoms associated with vulvar and vaginal atrophy.
Conjugated estrogens contain a mixture of estrone sulfate, equilin sulfate, 17 alpha-dihydroequilin, 17 alpha-estradiol and 17 beta-dihydroequilin. 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 postmenopausal patients.
Absorption: Systemic absorption occurs.
Protein binding: Binds to sex-hormone-binding globulin and albumin.
Metabolism: Hepatic via CYP3A4; estradiol is converted to estrone and estriol; also undergoes enterohepatic recirculation (avoided with vaginal administration); estrone sulfate is the main metabolite in postmenopausal patients.
Time to peak, plasma: Total estrone: 6 hours.
Excretion: Urine (primarily estriol, also as estradiol, estrone, and conjugates).
