Bi-Est

Estriol (E3) is an endogenous estrogen formed mainly from estradiol and estrone and produced in large amounts by the placenta during pregnancy. It is a weaker estrogen than estradiol. Estriol is not a component of any FDA-approved drug product in the United States; it is approved in some other countries, mainly as vaginal cream or pessaries. In the United States it is a bulk drug substance used in compounded preparations. Lake Hills Pharmacy compounds it, pursuant to patient-specific prescriptions, in estriol/estradiol (Bi-Est) cream and rapid dissolve tablets.

Drug class: estrogen. Non-controlled.

No FDA-labeled indication or dose exists. Prescribers use compounded estriol, usually combined with estradiol, for menopausal vasomotor and genitourinary symptoms. A 2020 National Academies report found the clinical evidence for compounded bioidentical hormone preparations limited and noted variable dosing and absorption.

Estriol binds estrogen receptors ER-alpha and ER-beta, with lower affinity and shorter receptor occupancy than estradiol. It produces estrogenic effects in the urogenital tract, endometrium, breast and other tissues; with sufficient dose or frequency it can stimulate endometrial proliferation.

Orally administered estriol is extensively conjugated (glucuronide and sulfate) in the gut wall and liver, so little unconjugated estriol reaches the circulation; it has a short elimination half-life. Vaginal and transdermal administration avoid first-pass conjugation, and absorption from compounded preparations varies with vehicle, site and patient. Estriol is not appreciably converted to estradiol or estrone and is excreted in urine, mainly as conjugates.

• Undiagnosed abnormal genital bleeding.
• Known, suspected or past breast cancer, or known or suspected estrogen-dependent neoplasia.
• Active or past deep vein thrombosis or pulmonary embolism, or active or past arterial thromboembolic disease (stroke, myocardial infarction).
• Known liver impairment or disease.
• Known protein C, protein S or antithrombin deficiency, or another known thrombophilic disorder.
• Known anaphylactic reaction or angioedema with the drug or its ingredients.
• Known or suspected pregnancy.

• Estriol has no US prescribing information; estrogen class labeling is applied by analogy. Boxed warning (estrogen-alone products): endometrial cancer. An estrogen used without a progestogen in a woman with a uterus increases the risk of endometrial cancer; adding a progestogen reduces the risk. FDA's 2026 menopausal hormone therapy labeling revision removed cardiovascular disease, breast cancer and probable dementia from the boxed warning; stroke, venous thromboembolism and breast cancer remain under Warnings & Precautions.
• Starting hormone therapy for moderate to severe vasomotor symptoms can be considered for women under 60 or within 10 years of menopause.
• Women with a uterus who receive estriol should also receive a progestogen; evaluate persistent or recurring abnormal genital bleeding.
• Thromboembolic events, gallbladder disease, elevated blood pressure, hypertriglyceridemia and hepatic effects are class warnings for estrogens.
• Exposure from compounded estriol preparations varies; estriol is often combined with estradiol, and the combined estrogen exposure is what matters for safety.
• Secondary exposure: topical estrogen can transfer to children and pets through contact with the application site.

• Other estrogen- or hormone-containing products add to estrogen exposure.
• Enzyme inducers (rifampin, carbamazepine, phenobarbital, phenytoin, St. John's wort) may increase estrogen clearance; this is a class interaction and is not well characterized for estriol.
• Thyroid hormone: oral estrogen can raise thyroxine-binding globulin; review thyroid replacement dose.

Reported effects are those of estrogens: breast tenderness, vaginal bleeding or spotting, vaginal discharge, nausea, headache and fluid retention, plus local irritation, burning or itching with topical or vaginal use. Serious class effects include endometrial hyperplasia and cancer, thromboembolism and breast cancer.

Estriol has no indication in pregnancy and should not be used in known or suspected pregnancy. Estrogens pass into breast milk and may reduce milk supply; use during breastfeeding is generally avoided.

Reassess the need for therapy periodically. Monitor blood pressure, breast examination and mammography, and abnormal genital bleeding, with endometrial evaluation when indicated in women with a uterus. Serum and salivary estriol measurements are not validated for dose adjustment.

• National Academies of Sciences, Engineering, and Medicine. Report on the clinical utility of compounded bioidentical hormone therapy. 2020.
• The 2022 Hormone Therapy Position Statement of The North American Menopause Society. Menopause. 2022.
• Estrace (estradiol tablets, USP) Prescribing Information (estrogen class labeling).
• USP General Chapter <795> Pharmaceutical Compounding: Nonsterile Preparations.

Estradiol (17-beta-estradiol) is the principal endogenous human estrogen. FDA-approved estradiol products include oral tablets (Estrace), transdermal patches, gels (EstroGel, Divigel), spray, vaginal products and injectable esters. Lake Hills Pharmacy compounds estradiol, pursuant to patient-specific prescriptions, in creams, capsules, estriol/estradiol (Bi-Est) preparations and a topical scalp solution.

Drug class: estrogen. Non-controlled.

FDA-labeled indications vary by product and route. Oral estradiol tablets (Estrace) are labeled for moderate to severe vasomotor symptoms and moderate to severe vulvar and vaginal atrophy due to menopause, hypoestrogenism due to hypogonadism, castration or primary ovarian failure, prevention of postmenopausal osteoporosis, and palliative treatment of selected breast and advanced androgen-dependent prostate cancer. Transdermal gels are labeled for moderate to severe vasomotor symptoms due to menopause; vaginal products are labeled for vulvar and vaginal atrophy and dyspareunia.

Prescribers use compounded estradiol preparations for menopausal hormone therapy and, in combination topical products, for other uses such as hair loss, which have no FDA-labeled indication.

Estradiol binds nuclear estrogen receptors (ER-alpha and ER-beta) in the reproductive tract, breast, bone, liver, brain and blood vessels, regulating gene transcription. In postmenopausal women it reduces vasomotor symptoms, maintains urogenital epithelium and reduces bone resorption. Oral estrogen also increases hepatic production of binding globulins and clotting factors.

Oral estradiol undergoes extensive first-pass metabolism to estrone and conjugates, giving low bioavailability and a high estrone-to-estradiol ratio. Transdermal and vaginal routes avoid first-pass metabolism; absorption depends on dose, vehicle and site, and varies between patients with compounded creams. Circulating estradiol is bound to sex hormone-binding globulin and albumin. It is metabolized in the liver, largely by CYP3A4, to estrone and estriol, undergoes sulfate and glucuronide conjugation and enterohepatic recirculation, and is excreted in urine.

• Undiagnosed abnormal genital bleeding.
• Known, suspected or past breast cancer, or known or suspected estrogen-dependent neoplasia.
• Active or past deep vein thrombosis or pulmonary embolism, or active or past arterial thromboembolic disease (stroke, myocardial infarction).
• Known liver impairment or disease.
• Known protein C, protein S or antithrombin deficiency, or another known thrombophilic disorder.
• Known anaphylactic reaction or angioedema with the drug or its ingredients.
• Known or suspected pregnancy.

• Starting hormone therapy for moderate to severe vasomotor symptoms can be considered for women under 60 or within 10 years of menopause.
• Cardiovascular disorders: stroke and venous thromboembolism have been reported with estrogen therapy; the WHI estrogen-alone substudy reported increased stroke and DVT, and the estrogen-plus-progestin substudy reported increased PE, DVT, stroke and MI.
• Thromboembolic disorders: discontinue immediately if stroke, DVT, PE or MI occurs or is suspected. If feasible, stop estrogen at least 4 to 6 weeks before surgery associated with increased thromboembolic risk or prolonged immobilization.
• Malignancy: breast cancer (estrogen plus progestin; invasive breast cancer was reported in the WHI estrogen-plus-progestin substudy), endometrial cancer (unopposed estrogen) and ovarian cancer have been reported. Women should have regular breast examinations and mammography based on age and risk.
• Other: gallbladder disease; hypercalcemia in patients with breast cancer and bone metastases; retinal vascular thrombosis; elevated blood pressure; hypertriglyceridemia and pancreatitis; cholestatic jaundice; fluid retention; hypocalcemia; and exacerbation of endometriosis, hereditary angioedema, asthma, diabetes, epilepsy, migraine, porphyria, lupus and hepatic hemangiomas.
• Secondary exposure with topical forms: estradiol on the skin can transfer to children and pets through contact with the application site. Reported effects in children include early breast development and genital changes.
• Older women: the 2022 NAMS position statement does not support routine discontinuation at age 65; continuing therapy is individualized with periodic reassessment of risks and benefits.

• CYP3A4 inducers (rifampin, carbamazepine, phenobarbital, phenytoin, St. John's wort) may reduce estradiol concentrations and effect.
• CYP3A4 inhibitors (ketoconazole, itraconazole, clarithromycin, erythromycin, ritonavir, grapefruit juice) may increase estradiol concentrations and adverse effects.
• Thyroid hormone: oral estrogen raises thyroxine-binding globulin, and patients on thyroid replacement may need a higher dose.
• Other estrogen- or hormone-containing products add to estrogen exposure.

Common adverse effects in labeling include headache, breast pain or tenderness, irregular vaginal bleeding or spotting, abdominal cramping or bloating, nausea, fluid retention, mood changes and, with topical forms, application-site reactions.

Estradiol has no indication in pregnancy and is contraindicated in known or suspected pregnancy. Estrogens are present in human milk and can reduce the quantity and quality of milk; use during breastfeeding is generally avoided.

Reassess the need for therapy periodically. Monitor blood pressure, breast examination and mammography, and abnormal genital bleeding (with endometrial evaluation when indicated in women with a uterus); check lipids in patients with hypertriglyceridemia and thyroid function in patients on thyroid replacement. Salivary hormone testing is not validated for dose adjustment.

• Estrace (estradiol tablets, USP) Prescribing Information.
• EstroGel (estradiol gel) 0.06% Prescribing Information.
• Divigel (estradiol gel) 0.1% Prescribing Information.
• The 2022 Hormone Therapy Position Statement of The North American Menopause Society. Menopause. 2022.
• National Academies of Sciences, Engineering, and Medicine. Report on the clinical utility of compounded bioidentical hormone therapy. 2020.