Estradiol Hemihydrate + Progesterone Micronized

Approved Indications:

A. Menopausal Hormone Replacement Therapy (HRT):

• Treatment of moderate to severe vasomotor symptoms (e.g., hot flashes, night sweats) due to menopause.
• Treatment of moderate to severe vulvar and vaginal atrophy associated with estrogen deficiency.
• Prevention of postmenopausal osteoporosis in high-risk women who cannot use non-estrogen therapies.

B. Secondary Amenorrhea (Functional or Hypothalamic Origin):

• Restoration of menstrual cycles in women with hormone-related amenorrhea, by inducing withdrawal bleeding and regulating hormonal balance.

C. Assisted Reproductive Technology (ART):

• Support of luteal phase in women undergoing IVF, FET, or IUI, where natural progesterone production is insufficient.
• Endometrial preparation in frozen embryo transfer (FET) or donor oocyte cycles.

D. Hormonal Imbalance & Luteal Phase Deficiency:

• Regulation of menstrual irregularities due to insufficient endogenous progesterone.

Clinically Accepted Off-Label Uses:

• Management of premature ovarian insufficiency (POI).
• Perimenopausal hormone symptom relief.
• Gender-affirming hormone therapy (in transgender women), under specialist guidance.

Route of Administration: Oral (tablet or capsule), Vaginal (capsule or gel), or Transdermal (estradiol only, in combination regimens)

Postmenopausal Women (with Intact Uterus):

• Cyclic Regimen:
  Estradiol Hemihydrate 1–2 mg orally daily for 25 days of a 28-day cycle
• Micronized Progesterone 200 mg orally once daily at bedtime for the last 12–14 days
• Continuous Combined Regimen:
  Estradiol Hemihydrate 1 mg + Micronized Progesterone 100 mg orally once daily without interruption

Secondary Amenorrhea:

• Estradiol 2 mg orally once daily for 14–21 days, followed by Micronized Progesterone 200 mg orally once daily for 10–14 days to induce withdrawal bleeding.

Luteal Phase Support (IVF/FET):

• Estradiol Hemihydrate 2–6 mg orally or transdermally daily (dose titrated based on endometrial response)
• Micronized Progesterone 200–400 mg vaginally twice to three times daily, beginning post-ovulation or post-oocyte retrieval.

Elderly:

• Use lowest effective dose. Avoid long-term use unless benefits clearly outweigh risks.

Renal or Hepatic Impairment:

• Use with caution; contraindicated in severe hepatic dysfunction.

Duration of Treatment:

• Use the lowest effective dose for the shortest duration consistent with treatment goals and risk profile. Reassess periodically.

3. Mechanism of Action (MOA)

Estradiol Hemihydrate is a synthetic form of 17β-estradiol, the principal estrogen in premenopausal women. It binds to intracellular estrogen receptors (ERα and ERβ), forming receptor-hormone complexes that modulate gene transcription. These effects restore estrogen-dependent physiological processes such as thermoregulation, vaginal epithelial integrity, and bone homeostasis.
Micronized Progesterone, a bioidentical form of natural progesterone, binds to progesterone receptors in the uterus and reproductive tissues. It induces secretory transformation of the endometrium, counteracting estrogen-induced proliferation, thereby reducing the risk of endometrial hyperplasia in women with a uterus.

Estradiol Hemihydrate:

• Absorption: Rapid oral absorption; extensive first-pass hepatic metabolism.
• Bioavailability: ~5–10% (oral); higher when administered transdermally.
• Peak Plasma Time: 4–6 hours (oral).
• Distribution: Binds to SHBG and albumin.
• Metabolism: Primarily hepatic via CYP3A4 to estrone and estriol.
• Half-life: 13–20 hours.
• Excretion: Renal and fecal as conjugated metabolites.

Micronized Progesterone:

• Absorption: Enhanced oral and vaginal absorption via micronization.
• Bioavailability: ~10% (oral); 30–50% (vaginal).
• Peak Plasma Time: 1–3 hours (oral); 4–6 hours (vaginal).
• Distribution: >90% bound to plasma proteins (albumin, corticosteroid-binding globulin).
• Metabolism: Hepatic metabolism via hydroxylation and conjugation.
• Half-life: 13–18 hours.
• Excretion: Mostly renal, as glucuronide and sulfate conjugates.

Pregnancy:

• Category X (Estradiol): Contraindicated. Estrogens may disrupt fetal development and increase the risk of congenital abnormalities.
• Progesterone: Generally not recommended during pregnancy unless prescribed for luteal phase support or prevention of recurrent miscarriage under supervision.

Lactation:

• Estradiol: Excreted into breast milk; may reduce milk supply and affect infant. Avoid during lactation.
• Micronized Progesterone: Small amounts pass into breast milk; considered relatively safe for short-term use, but long-term safety data are limited.

• Primary Class: Hormone Replacement Therapy (HRT)
• Components:
• Estradiol Hemihydrate: Natural Estrogen (Synthetic 17β-Estradiol derivative)
• Progesterone Micronized: Natural Progestogen (Micronized bioidentical form)

• Known hypersensitivity to estradiol, progesterone, or formulation excipients
• Undiagnosed abnormal genital bleeding
• Known, suspected, or history of estrogen-dependent cancers (e.g., breast, endometrial)
• Active or past venous thromboembolism (e.g., DVT, PE)
• Recent arterial thromboembolic disorders (e.g., stroke, MI)
• Active liver disease or severe hepatic impairment
• Known thrombophilic disorders (e.g., protein C or S deficiency)
• Pregnancy or suspected pregnancy

• Cardiovascular Events: Risk of stroke, VTE, and coronary heart disease increases with age and prolonged use.
• Malignancy Risk:
• Prolonged estrogen use without progestogen increases endometrial cancer risk.
• Combined HRT may slightly increase breast cancer risk with long-term use.
• Gallbladder Disease: Estrogens increase risk of gallstones.
• Thyroid Function: May alter TBG levels; monitor thyroid function in patients on thyroid replacement.
• Fluid Retention: May worsen conditions like hypertension, asthma, epilepsy, and migraines.
• Mood Disorders: May cause mood swings or depression. Discontinue if severe psychiatric symptoms occur.
• Monitoring Required:
• Baseline and periodic breast exams and mammography
• Endometrial assessment for abnormal bleeding
• Liver function tests if symptoms arise

Common Side Effects:

• Endocrine/Metabolic: Breast tenderness, weight changes
• CNS: Headache, mood changes, dizziness
• GI: Nausea, bloating, abdominal pain
• Reproductive: Vaginal discharge, breakthrough bleeding, spotting

Serious/Rare Adverse Effects:

• Venous thromboembolism (DVT, PE)
• Stroke, myocardial infarction
• Breast or endometrial cancer
• Gallbladder disease
• Visual disturbances, severe allergic reactions

Onset & Dose Dependence:

• Many side effects are dose-related and may resolve with dose adjustment or continued use.
• Serious events typically occur after prolonged exposure or in high-risk populations.

• CYP3A4 Substrates:
• Estradiol and progesterone are metabolized by CYP3A4.
• CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin) may increase plasma concentrations.
• CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin) may decrease effectiveness.
• Anticoagulants (e.g., warfarin): Estrogens may reduce anticoagulant effects; INR monitoring advised.
• Thyroid Hormone Therapy: Estrogens increase TBG, requiring potential dose adjustment of levothyroxine.
• Herbal Interactions: St. John's Wort may reduce efficacy via CYP induction.
• Alcohol: May exacerbate estrogen-related side effects.

• NAMS (2024): Supports individualized HRT in symptomatic women under 60 or within 10 years of menopause. Prefer micronized progesterone due to lower breast cancer risk vs. synthetic progestins.
• FDA Advisory (2023): Reinforces risk of thromboembolic events and advises regular evaluation of treatment necessity.
• Endocrine Society Guidelines: Endorses estradiol + progesterone combinations for optimal symptom control and endometrial protection.

• Temperature: Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C and 30°C.
• Humidity: Protect from excess moisture.
• Light: Store in original packaging; protect from direct light.
• Handling:
• Do not freeze.
• Shake well if suspension.
• Vaginal capsules should be stored in a dry place and inserted cleanly with or without applicator.
• Reconstitution: Not applicable.