Estradiol Valerate

Approved Indications:

A. Menopausal Hormone Replacement Therapy (HRT):

• Management of moderate to severe vasomotor symptoms due to estrogen deficiency (e.g., hot flashes, night sweats).
• Treatment of vulvovaginal atrophy, including vaginal dryness, burning, and dyspareunia.
• Prevention of postmenopausal osteoporosis in women at significant risk who cannot tolerate or do not respond to non-estrogen therapies.

B. Estrogen Deficiency Disorders:

• Hypoestrogenism due to hypogonadism, oophorectomy, or primary ovarian failure.

C. Hormone Therapy in Transgender Women:

• As part of feminizing hormone therapy, often combined with anti-androgens or progestins, under specialized supervision.

D. Menstrual Disorders:

• Dysfunctional uterine bleeding due to hormonal imbalance.
• Amenorrhea or oligomenorrhea due to estrogen deficiency.

E. Assisted Reproductive Technology (ART):

• Endometrial preparation in frozen embryo transfer (FET) or donor egg cycles.

Clinically Accepted Off-label Uses:

• Management of premature ovarian insufficiency (POI).
• Delayed puberty in females with gonadal dysgenesis or Turner syndrome.
• Palliative treatment of advanced androgen-dependent prostate cancer (in men).

Routes of Administration: Intramuscular injection (IM), oral tablet, or transdermal patch (if part of a combination regimen).

Adults (Postmenopausal Women):

• Oral: 1–2 mg daily (cyclic or continuous regimens), titrated to the lowest effective dose.
• IM Injection: 10–20 mg every 4 weeks, depending on indication and response.

Estrogen Deficiency (e.g., Primary Ovarian Failure):

• Oral: 2–4 mg daily in cyclic regimens (e.g., 21 days on, 7 days off).
• IM: 10–20 mg every 2–4 weeks.

Feminizing Hormone Therapy (Transgender Women):

• IM: 5–20 mg every 2 weeks, or 10–40 mg monthly, depending on individual needs and serum estradiol levels.

Endometrial Preparation in ART:

• Oral: 2 mg twice or three times daily (total 4–6 mg/day), started on cycle day 2 or 3 and continued until appropriate endometrial thickness is achieved.

Elderly:

• Use the lowest effective dose. Evaluate cardiovascular, thromboembolic, and cognitive risks regularly.

Renal/Hepatic Impairment:

• Use with caution. Contraindicated in severe hepatic impairment due to estrogen metabolism.

Duration:

• Shortest effective duration consistent with treatment goals and risk profile. Regular re-evaluation is required.

Estradiol Valerate is a synthetic estrogen ester that, upon administration, is hydrolyzed to 17β-estradiol, the primary endogenous estrogen in women. Estradiol diffuses into target cells and binds to intracellular estrogen receptors (ERα and ERβ), forming complexes that translocate to the nucleus. These complexes bind to estrogen response elements on DNA, modulating gene expression to produce estrogenic effects. This includes regulation of the menstrual cycle, maintenance of urogenital tissues, bone metabolism, and modulation of the hypothalamic-pituitary axis. The therapeutic effects alleviate menopausal symptoms, restore hormonal balance, and support reproductive function.

• Absorption: Estradiol valerate is rapidly absorbed after intramuscular injection; oral absorption is also efficient but subject to first-pass metabolism.
• Bioavailability:
• Oral: ~5–10% (after first-pass effect)
• IM: Complete systemic availability
• Onset:
• IM: Gradual onset, with peak serum estradiol levels in ~3–5 days
• Distribution: Binds extensively to sex hormone-binding globulin (SHBG) and albumin
• Metabolism: Hydrolyzed to 17β-estradiol and valeric acid in the liver and plasma; estradiol further metabolized by CYP3A4 and other hepatic enzymes
• Half-life:
• Oral: ~12–14 hours
• IM: ~3–7 days depending on dose and formulation
• Excretion: Primarily via the kidneys as glucuronide and sulfate conjugates; minor amounts via feces

Pregnancy:

• Category X: Contraindicated during pregnancy. Use during pregnancy is associated with risks of fetal abnormalities, particularly urogenital malformations in male fetuses.

Lactation:

• Excreted in breast milk. Estrogens may decrease the quantity and quality of breast milk. Use is not recommended in breastfeeding mothers unless deemed essential.

• Primary Class: Estrogen (Systemic Hormone Therapy)
• Subclass: Synthetic Estrogen Ester (Estradiol Ester)

• Known hypersensitivity to estradiol valerate or excipients
• Undiagnosed abnormal genital bleeding
• Active or history of estrogen-dependent malignancies (e.g., breast, endometrial cancer)
• Known or suspected pregnancy
• Active or past history of venous thromboembolism (e.g., DVT, PE)
• Arterial thromboembolic disease (e.g., stroke, myocardial infarction)
• Severe hepatic impairment or active liver disease
• Porphyria

• Cardiovascular Risk: Increased risk of stroke, deep vein thrombosis, pulmonary embolism, and myocardial infarction—especially in women over 60 or with other risk factors.
• Breast and Endometrial Cancer: Risk increases with prolonged use, particularly when not opposed by a progestin in women with a uterus.
• Dementia Risk: Women over 65 using estrogen alone may have an increased risk of dementia.
• Gallbladder Disease: Estrogens can increase the risk of gallbladder problems, especially in older women.
• Thyroid Effects: May increase thyroxine-binding globulin (TBG), altering free thyroid hormone levels.
• Hypertriglyceridemia: May increase serum triglycerides, especially in women with familial hyperlipidemia.
• Epilepsy or Migraine: May exacerbate symptoms.

Monitoring Required:

• Blood pressure, breast exams, mammograms, endometrial surveillance (if uterus present), and periodic liver function tests.

Common Adverse Effects (by body system):

• Endocrine/Reproductive:
• Breast tenderness
• Breakthrough bleeding or spotting
• Increased vaginal discharge
• Central Nervous System:
• Headache
• Dizziness
• Mood swings
• Gastrointestinal:
• Nausea
• Bloating
• Abdominal cramps

Serious Adverse Effects:

• Thromboembolic events (DVT, PE, stroke)
• Myocardial infarction
• Endometrial hyperplasia or carcinoma (if unopposed by progestin)
• Gallstones or cholecystitis
• Visual disturbances or retinal vascular thrombosis

Onset & Severity:

• Many side effects are dose- and duration-dependent. Serious effects typically occur with prolonged or high-dose use.

• CYP450 Interactions:
• Estradiol is metabolized via CYP3A4.
• CYP3A4 inhibitors (e.g., ketoconazole, ritonavir) may increase serum estradiol levels.
• CYP3A4 inducers (e.g., phenytoin, rifampin, carbamazepine) may reduce efficacy.
• Anticoagulants (e.g., warfarin): Estrogens may antagonize anticoagulant effects. Monitor INR.
• Thyroid Medications: May increase TBG, necessitating adjustment of levothyroxine doses.
• Herbal Products: St. John’s Wort may reduce efficacy due to enzyme induction.
• Alcohol: May increase estradiol side effects such as nausea and flushing.

• NAMS (2024): Estradiol valerate remains recommended for systemic estrogen therapy in symptomatic menopausal women. Micronized progesterone is preferred over synthetic progestins for endometrial protection.
• Endocrine Society (2023): Continues to include estradiol valerate as an option in feminizing hormone therapy, with dosing individualized based on target estradiol levels.
• FDA Safety Notices: Emphasis on thromboembolic risks and long-term cancer surveillance.

• Oral Tablets:
• Store at 20°C to 25°C (68°F to 77°F)
• Protect from light and moisture
• Keep in original container
• IM Injection:
• Store between 15°C and 30°C (59°F to 86°F)
• Do not freeze
• Protect from light
• Shake well before use if suspension
• Shelf Life: As indicated on the product packaging; do not use after expiration date.