Estriol

Approved Indications:

• Menopausal Hormone Therapy (MHT):
• Management of moderate to severe vasomotor symptoms (e.g., hot flashes, night sweats) associated with menopause.
• Treatment of vulvovaginal atrophy and atrophic vaginitis due to estrogen deficiency.
• Prevention of postmenopausal osteoporosis when other treatments are inappropriate.
• Genitourinary Syndrome of Menopause (GSM):
• Vaginal dryness, irritation, and dyspareunia caused by estrogen deficiency.
• Hypoestrogenism due to:
• Hypogonadism
• Oophorectomy
• Primary ovarian failure

Off-Label/Clinically Accepted Uses:

• Adjunctive Treatment in Assisted Reproductive Technology (ART):
• Used for endometrial preparation in women undergoing embryo transfer.
• Menstrual Disorders:
• Occasionally used in cases of irregular menstruation associated with low estrogen levels.

Adults (Postmenopausal Women):

• Vaginal Cream:
• 0.5 mg to 1 mg intravaginally once daily for 1 to 2 weeks, then reduced to 1–2 times per week as maintenance.
• Oral Tablets:
• 0.5 mg to 4 mg once daily, adjusted according to response and indication.
• Vaginal Tablets/Pessary:
• 0.03 mg to 0.5 mg intravaginally once daily for 2–3 weeks, then maintenance dose twice weekly.

Elderly:

• Same as adult dosage; monitor for increased risk of thromboembolic events, dementia, or cardiovascular disorders.

Pediatrics:

• Not recommended unless clearly indicated and supervised by a pediatric endocrinologist.

Renal Impairment:

• Use with caution. No specific adjustment, but monitor estrogen effects closely.

Hepatic Impairment:

• Contraindicated in severe liver dysfunction. Use caution in mild impairment.

Route of Administration:

• Oral
• Intravaginal (cream, tablet, pessary)
• Transdermal or injectable forms are not typically available for Estriol.

Estriol is a naturally occurring weak estrogen and one of the three primary endogenous estrogens in women. It binds to estrogen receptors (ER-α and ER-β) in target tissues such as the vaginal epithelium, endometrium, and hypothalamus. Its activation of these receptors promotes transcription of estrogen-responsive genes, leading to epithelial maturation, increased vaginal lubrication, and improved blood flow. Unlike estradiol, estriol has predominantly local and short-acting systemic effects, resulting in reduced endometrial stimulation and a more favorable safety profile. It exerts a proliferative effect on the urogenital tract but has minimal systemic activity on the breast or liver when administered vaginally.

• Absorption:
• Rapidly absorbed via oral and intravaginal routes. Vaginal administration leads to localized high concentrations.
• Bioavailability:
• Oral: ~2–10% (subject to high first-pass metabolism)
• Vaginal: Higher bioavailability with less systemic exposure.
• Distribution:
• Extensively bound to albumin; does not bind significantly to sex hormone-binding globulin (SHBG).
• Metabolism:
• Primarily hepatic via conjugation (glucuronidation and sulfation). No active metabolites.
• Elimination:
• Excreted mainly in urine as conjugates.
• Elimination half-life: 1–2 hours after oral administration; prolonged with vaginal application due to depot effect.

• Pregnancy:
• Category X (Contraindicated):
  Estriol should not be used during pregnancy due to potential teratogenic and feminizing effects on the fetus.
• Lactation:
• Not recommended during breastfeeding as estriol is excreted in breast milk and may affect milk production or harm the nursing infant.
• Caution:
• Should only be used in non-pregnant, non-lactating women unless clearly indicated under specialized supervision.

• Primary Class: Estrogen Hormone
• Subclass: Natural Estrogen (Weak estrogen)
• Hormonal Category: Menopausal Hormone Replacement Therapy (HRT)

• Known hypersensitivity to estriol or any component of the formulation
• Active or history of estrogen-dependent malignancy (e.g., breast cancer)
• Undiagnosed abnormal genital bleeding
• Active or recent thromboembolic disorders (e.g., DVT, PE, stroke)
• Severe hepatic impairment or liver disease
• Pregnancy or breastfeeding
• Untreated endometrial hyperplasia

• Use lowest effective dose for the shortest duration compatible with treatment goals
• Increased risk of:
• Venous thromboembolism (VTE)
• Breast and endometrial cancer (especially with systemic use)
• Stroke and myocardial infarction in older women
• Regular monitoring of:
• Endometrial thickness (if oral used long-term)
• Liver function in hepatic patients
• Cardiovascular health in elderly users
• Not for use as cardiovascular protection or dementia prevention
• Caution in women with:
• Controlled epilepsy
• Diabetes mellitus
• Gallbladder disease
• Migraine headaches

Common (≥1%):

• Genitourinary: Vaginal discharge, irritation, itching, vaginal candidiasis
• Gastrointestinal: Nausea, bloating, abdominal cramps
• CNS: Headache, dizziness, mood changes
• Breast: Breast tenderness or pain

Less Common / Serious:

• Thromboembolic events (e.g., DVT, pulmonary embolism, stroke)
• Endometrial hyperplasia or carcinoma (with prolonged systemic use)
• Gallbladder disease
• Elevated liver enzymes
• Hypertension

Timing:

• Most adverse effects occur within weeks of initiation.
• Serious effects typically arise with long-term or systemic use.

• CYP450 Interactions:
• Estriol is a weak substrate of hepatic metabolism; not extensively affected by CYP450.
• Drug-Drug Interactions:
• Rifampicin, phenytoin, carbamazepine: May reduce estrogen efficacy by inducing metabolism
• Corticosteroids or cyclosporine: May increase systemic exposure/toxicity
• Warfarin: Estrogens may alter anticoagulant effect (monitor INR)
• Drug-Food Interaction:
• No significant interaction, but food may delay oral absorption slightly
• Drug-Alcohol Interaction:
• Excessive alcohol intake may increase hepatic metabolism and reduce hormone effect

• EMA & FDA Guidance (Recent Years):
• Emphasis on individualized risk-benefit assessment before initiating estrogen therapy.
• Vaginal estriol preferred for local GSM symptoms to minimize systemic exposure.
• Long-term use discouraged unless benefits outweigh risks.
• Endometrial safety measures advised if unopposed estrogen is used orally.

• Oral Tablets & Vaginal Tablets:
• Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C–30°C
• Protect from light and moisture
• Keep in original packaging until use
• Vaginal Cream:
• Store between 2°C and 25°C (36°F to 77°F)
• Do not freeze
• Shake gently before use if separation occurs
• Handling Precautions:
• Keep out of reach of children
• Discard any unused medication after expiration date
• Use applicator as directed and clean it after each use