Estradiol

Approved Indications:

• Moderate to severe vasomotor symptoms due to menopause (e.g., hot flashes, night sweats)
• Vulvovaginal atrophy associated with menopause (dryness, itching, burning)
• Prevention of postmenopausal osteoporosis
• Hypoestrogenism due to:
• Hypogonadism
• Primary ovarian failure
• Surgical menopause (bilateral oophorectomy)
• Female castration or ovarian failure
• Palliative treatment of advanced androgen-dependent cancers in men (e.g., prostate cancer)
• Palliative treatment of advanced breast cancer in postmenopausal women

Clinically Accepted Off-label Uses:

• Gender-affirming hormone therapy in transgender women (male-to-female transition)
• Amenorrhea or oligomenorrhea associated with PCOS or hypothalamic suppression
• In vitro fertilization protocols for endometrial preparation
• Delayed puberty in girls
• Premature ovarian insufficiency (POI)

Adults:

Oral Tablets (e.g., Estradiol 1 mg, 2 mg):

• Vasomotor symptoms, atrophic vaginitis, osteoporosis prevention:
  Initial: 0.5–2 mg/day
  Adjust based on response; lowest effective dose for shortest duration
• Breast cancer (palliative): 10 mg TID
• Prostate cancer (palliative): 1–2 mg TID

Transdermal Patch (e.g., 25–100 mcg/day):

• Apply to dry, hairless area (e.g., lower abdomen); change twice weekly or weekly depending on product

Topical Gel/Cream (e.g., 0.06% to 0.1%):

• Apply to skin once daily (upper thigh or arm); allow to dry before dressing

Vaginal Ring/Tablets:

• Vaginal tablet: 10 mcg daily for 2 weeks, then twice weekly
• Vaginal ring: Replace every 3 months

IM Injection (e.g., Estradiol valerate or cypionate):

• Estradiol valerate: 10–20 mg every 4 weeks (HRT); up to 30 mg every 1–2 weeks (oncology use)
• Estradiol cypionate: 1–5 mg every 3–4 weeks

Pediatrics:

• For delayed puberty in females:
  Start with 0.2–0.5 mg/day orally; gradually increase over 6–12 months

Elderly:

• Use lowest effective dose
• Evaluate cardiovascular, thrombotic, and cognitive risks

Renal/Hepatic Impairment:

• Use with caution
• Estradiol undergoes hepatic metabolism; avoid in severe liver disease

Estradiol is the most potent naturally occurring human estrogen. It binds to estrogen receptors (ERα and ERβ) located in various tissues such as the reproductive tract, breast, bone, liver, and brain. Upon binding, the complex translocates into the cell nucleus, where it regulates gene transcription and modulates the synthesis of proteins responsible for estrogenic effects. These include maintenance of vaginal and endometrial tissue, regulation of menstrual cycles, preservation of bone density, and modulation of lipids. Estradiol also exerts feedback control over the hypothalamic-pituitary axis to regulate gonadotropin secretion.

Absorption:

• Oral bioavailability: ~5%–10% (due to extensive first-pass metabolism)
• Transdermal and vaginal: Bypasses first-pass; higher systemic availability

Distribution:

• Widely distributed; binds to sex hormone-binding globulin (SHBG) and albumin

Metabolism:

• Hepatic metabolism to estrone and estriol via CYP3A4 and conjugation (sulfation/glucuronidation)

Elimination:

• Half-life: 13–27 hours (oral); longer with depot IM formulations
• Excretion via urine (as glucuronide/sulfate conjugates) and bile

Onset:

• Symptom relief may begin within a few days to weeks

Pregnancy:

• Category X (contraindicated)
  Estradiol is teratogenic and poses significant risk to the fetus

Lactation:

• Not recommended
  Excreted into breast milk in small amounts
  May suppress lactation and alter milk composition
  Use alternative therapies if breastfeeding

• Primary Class: Estrogen
• Subclass: Natural estrogen (17β-estradiol), sex hormone
• Pharmacologic Category: Hormonal Replacement Therapy (HRT), antineoplastic agent (in oncology uses)

• Known hypersensitivity to estradiol or formulation excipients
• Undiagnosed abnormal genital bleeding
• Active or past thromboembolic disorders (e.g., DVT, PE, stroke)
• Active or history of estrogen-dependent neoplasia (e.g., breast cancer)
• Liver dysfunction or disease
• Pregnancy or suspected pregnancy
• Porphyria

• Boxed Warning (HRT use):
• Increased risk of endometrial cancer (if used without progestin in women with uterus)
• Increased risk of cardiovascular events (MI, stroke)
• Increased risk of breast cancer, especially with long-term use
• Use lowest effective dose for shortest duration
• High-risk groups: Smokers, obese patients, those with family history of cancer or thrombosis
• Monitor: Blood pressure, liver enzymes, lipid profile, mammography, pelvic exams, thyroid function
• Discontinue immediately if:
• Sudden vision changes, chest pain, severe headache, or signs of thromboembolism occur

Common (≥1%):

• Breast tenderness, nipple discharge
• Nausea, bloating, abdominal cramps
• Headache, mood swings
• Weight gain, fluid retention
• Spotting or breakthrough bleeding

Serious:

• Thromboembolic events (DVT, PE, stroke, MI)
• Endometrial hyperplasia/carcinoma
• Breast cancer
• Gallbladder disease
• Hepatic dysfunction (rare)

Onset & Severity:

• Most mild symptoms start within days to weeks
• Serious adverse events are dose- and duration-dependent

• CYP3A4 inducers (e.g., rifampin, phenytoin, carbamazepine): Decrease estradiol levels
• CYP3A4 inhibitors (e.g., ketoconazole, erythromycin): Increase estradiol exposure
• Thyroid hormones: Estradiol may increase thyroxine-binding globulin, affecting free T4 levels
• Anticoagulants (e.g., warfarin): Estrogens may reduce anticoagulant effect
• Tamoxifen/clomiphene: May antagonize estradiol activity
• Alcohol: May enhance hepatic estrogen metabolism and increase side effects

• NAMS (North American Menopause Society) 2022:
  HRT (including estradiol) remains first-line for vasomotor symptoms in healthy women <60 or within 10 years of menopause
• FDA update: Emphasis on lowest effective dose, particularly with systemic estradiol formulations
• Gender-affirming hormone therapy protocols (WPATH 8th edition) include estradiol as a core agent, often combined with anti-androgens
• New vaginal estradiol micro-dose tablets approved to minimize systemic exposure

Oral Tablets:

• Store at 20°C to 25°C (68°F to 77°F)
• Protect from moisture and heat

Transdermal Patches:

• Store at room temperature
• Do not refrigerate or freeze
• Apply immediately upon removal from pouch

Vaginal Tablets/Rings:

• Store at 15°C to 30°C
• Protect from light and humidity

Injectables:

• Store at 20°C to 25°C
• Protect from light
• Use aseptic technique; discard unused vial contents after drawing