Estradiol + Dydrogesterone

Estradiol + Dydrogesterone is indicated for the following approved and clinically accepted uses:

Hormone Replacement Therapy (HRT):

• Relief of Menopausal Symptoms:
  Treatment of moderate to severe vasomotor symptoms (hot flashes, night sweats), sleep disturbances, mood swings, and vaginal atrophy in postmenopausal women with an intact uterus.
• Prevention of Postmenopausal Osteoporosis:
  As second-line therapy in women at high risk of fractures who are intolerant of, or contraindicated for, non-estrogen alternatives.

Hormonal Regulation:

• Endometrial Protection in HRT:
  Dydrogesterone component opposes unopposed estrogen-induced endometrial hyperplasia in women undergoing estrogen therapy.

Other Accepted Uses (Off-label/Clinically Accepted):

• Premature Ovarian Insufficiency (POI):
  Used in HRT regimens to restore hormonal balance and manage symptoms in women with POI.
• Menstrual Irregularities (Short-term therapy):
  Occasionally used to manage anovulatory cycles in perimenopausal women.

General Guidelines:

• Route of administration: Oral
• Treatment should be individualized based on indication, age, and patient response.

Postmenopausal Women (Intact Uterus):

• Estradiol 1 mg + Dydrogesterone 10 mg daily, continuously without interruption.
• Alternatively, Estradiol 2 mg + Dydrogesterone 10 mg daily may be used in women with more severe symptoms or higher estrogen requirement.

Cycle-based Regimen (Sequential):

• Estradiol taken continuously (1–2 mg daily).
• Dydrogesterone added for 12–14 days per 28-day cycle (10–20 mg/day).
• A withdrawal bleed may occur.

Elderly:

• Same as adult dose. Use lowest effective dose, regularly reviewed.

Renal Impairment:

• No specific dose adjustment; however, caution is advised.

Hepatic Impairment:

• Contraindicated in active or past liver disease. Use is not recommended.

Pediatrics:

• Not indicated for children or adolescents.

Estradiol, a synthetic form of endogenous 17β-estradiol, binds to estrogen receptors (ERα and ERβ), primarily in reproductive tissues, bone, breast, liver, and cardiovascular system. It modulates gene transcription and protein synthesis, leading to the restoration of estrogenic activity in postmenopausal women.
Dydrogesterone, a retroprogesterone, selectively binds to progesterone receptors without androgenic or estrogenic activity. It counteracts estrogen-induced endometrial proliferation, promoting secretory transformation and reducing the risk of endometrial hyperplasia and carcinoma. Together, the combination provides symptomatic relief while maintaining endometrial safety in women with an intact uterus.

• Absorption:
  Both components are well absorbed orally. Estradiol undergoes first-pass metabolism; dydrogesterone is rapidly absorbed with a Tmax of ~0.5–2.5 hours.
• Bioavailability:
• Estradiol: ~5% (due to first-pass effect).
• Dydrogesterone: ~28%.
• Distribution:
  Estradiol binds strongly to sex hormone-binding globulin (SHBG); dydrogesterone binds to albumin.
• Metabolism:
• Estradiol is metabolized in the liver to estrone and estriol via CYP3A4.
• Dydrogesterone is extensively converted to 20α-dihydrodydrogesterone (DHD), its major active metabolite.
• Elimination Half-life:
• Estradiol: 13–20 hours (varies by formulation).
• Dydrogesterone: 5–7 hours; DHD: 14–17 hours.
• Excretion:
  Primarily renal for both drugs, mainly as inactive metabolites.

• Pregnancy:
  Contraindicated.
  Estradiol and dydrogesterone are not indicated during pregnancy. Exposure may increase the risk of fetal harm, including urogenital malformations.
• Lactation:
  Not recommended during breastfeeding.
  Both components may be excreted in breast milk and can affect milk production or pose risks to the infant.

• Primary Class:
  Hormone Replacement Therapy (HRT)
• Subclasses:
• Estradiol: Natural Estrogen (Estrogen Receptor Agonist)
• Dydrogesterone: Selective Progestogen (Retroprogesterone derivative)

• Known hypersensitivity to estradiol, dydrogesterone, or excipients
• Known or suspected breast cancer or estrogen-dependent tumors
• Undiagnosed vaginal bleeding
• Active or history of venous thromboembolism (VTE), DVT, or pulmonary embolism
• Arterial thromboembolic disease (e.g., myocardial infarction, stroke)
• Active liver disease or hepatic dysfunction
• Known or suspected pregnancy
• Porphyria

• Increased Risk of Thromboembolism:
  Use with caution in women with cardiovascular risk factors.
• Hormone-sensitive Malignancies:
  Close monitoring in patients with a history of estrogen-dependent cancers.
• Hepatic Impairment:
  Avoid use in patients with impaired liver function or liver tumors.
• Gallbladder Disease:
  May increase risk of gallstone formation.
• Dementia Risk in Elderly:
  Use with caution in women over 65 years.
• Monitoring:
  Regular physical exams, mammography, liver function tests, and blood pressure monitoring are advised.
• Endometrial Surveillance:
  Any abnormal uterine bleeding should be investigated promptly.

Common Adverse Effects:

• Endocrine/Reproductive: Breast tenderness, vaginal bleeding, dysmenorrhea, leukorrhea
• CNS: Headache, migraine, mood changes, dizziness
• GI: Nausea, abdominal pain, bloating
• Skin: Rash, pruritus
• General: Weight changes, fatigue, fluid retention

Serious/Rare Side Effects:

• Deep vein thrombosis, pulmonary embolism
• Myocardial infarction, stroke
• Gallbladder disease
• Endometrial hyperplasia or cancer
• Visual disturbances, retinal thrombosis
• Hepatic dysfunction

Timing & Severity:

Most adverse effects are dose-dependent and occur within the first 3–6 months of therapy.

• CYP3A4 Inducers:
  (e.g., rifampin, carbamazepine, phenytoin, St. John's wort) may reduce estrogen and progestogen effectiveness.
• CYP3A4 Inhibitors:
  (e.g., ketoconazole, erythromycin) may increase plasma levels of estradiol and dydrogesterone.
• Anticoagulants:
  Estrogens may alter the efficacy of warfarin or similar drugs.
• Thyroid Hormones:
  Estrogen may increase thyroxine-binding globulin (TBG), requiring dose adjustment.
• Alcohol:
  May increase circulating estradiol levels through hepatic enzyme inhibition.

• EMA (European Medicines Agency):
  Emphasizes the use of the lowest effective dose for the shortest duration consistent with treatment goals.
• NICE (UK):
  Recommends combined HRT (e.g., Estradiol + Dydrogesterone) for symptomatic postmenopausal women with a uterus to prevent endometrial hyperplasia.
• Labeling Updates:
  Enhanced warnings for cardiovascular and breast cancer risks. Label includes detailed patient education on signs of thrombosis.

• Temperature: Store below 30°C
• Humidity: Store in a dry place; avoid high humidity
• Light Protection: Keep in the original packaging to protect from light
• Handling Precautions: Do not freeze. Keep away from children.
• Shelf Life: Refer to manufacturer packaging for expiry; typically 24–36 months