What is the recommended combined medication for hormone replacement therapy (HRT)?

Recommended Combined Medication for Hormone Replacement Therapy (HRT)

The recommended first-choice combined medication for hormone replacement therapy is transdermal 17β-estradiol with micronized progesterone, as this combination provides the optimal safety profile with effective symptom management and reduced cardiovascular and thrombotic risks. 1

Optimal HRT Regimens Based on Patient Needs

For Women Not Requiring Contraception:

First Choice: Transdermal 17β-Estradiol + Progestin

• Transdermal 17β-estradiol patches (50-100 μg/24h) combined with either: 1
  • Transdermal progestin patches (sequential or continuous combined) 1
  • Oral micronized progesterone (200 mg daily for 12-14 days every 28 days in sequential regimens) 1, 2

Specific Regimen Options:

• Sequential Combined Regimen (if withdrawal bleeding is acceptable):

  • Patches releasing 50 μg of 17β-estradiol daily for 2 weeks, followed by patches releasing 50 μg of 17β-estradiol and 10 μg of levonorgestrel daily for 2 additional weeks 1
  • Alternative: Transdermal 17β-estradiol (50 μg daily) continuously with oral micronized progesterone (200 mg daily for 12-14 days every 28 days) 1

• Continuous Combined Regimen (to avoid withdrawal bleeding):

  • Patches releasing 50 μg of 17β-estradiol and 7 μg of levonorgestrel daily administered continuously 1
  • Alternative: Transdermal 17β-estradiol with vaginal progesterone gel (45 mg/day) 3

For Women Requiring Contraception:

• First Choice: 17β-estradiol-based combined oral contraceptives: 1

  • 17β-estradiol + nomegestrol acetate 1
  • 17β-estradiol + dienogest 1

• Second Choice: Ethinylestradiol-based combined oral contraceptives 1

Benefits of Transdermal 17β-Estradiol + Micronized Progesterone

Cardiovascular Benefits:

• Transdermal 17β-estradiol does not increase risk of venous thromboembolism, unlike oral estrogens 2
• Provides cardioprotection by reducing incidence of myocardial infarction compared to non-users 2
• Significantly reduces incidence of new-onset diabetes, a risk factor for cardiovascular disease 2

Safety Profile:

• Micronized progesterone has a neutral effect on vasculature and blood pressure 2
• Lower risk of cardiovascular disease and venous thromboembolism compared to synthetic progestogens 1
• Avoids first-pass hepatic metabolism, minimizing impact on coagulation cascade 1, 2

Efficacy:

• Effectively manages vasomotor symptoms and genitourinary symptoms of menopause 4, 5
• Provides endometrial protection when combined with appropriate progestin dosing 6
• Demonstrated to prevent depressive symptoms in perimenopausal and early postmenopausal women 7

Dosing Considerations

• Initial dosage: Transdermal 17β-estradiol 50 μg/day, adjusted based on symptom control 1, 6
• Progestin dosing depends on regimen type: 1
  • Sequential regimens: Micronized progesterone 200 mg for 12-14 days per month
  • Continuous regimens: Lower doses may be used (e.g., 1 mg norethisterone, 2.5 mg MPA, or 5 mg dydrogesterone daily)

Important Clinical Considerations and Pitfalls

• Progestin selection is crucial: Micronized progesterone is preferred due to lower cardiovascular and thrombotic risks 1
• Avoid progestins with anti-androgenic effects in women with iatrogenic POI who may already have low testosterone levels 1
• Route of administration matters: Transdermal delivery avoids first-pass hepatic metabolism, reducing thrombotic risk 1, 2
• Duration of therapy: For women with premature ovarian insufficiency, HRT should be continued until the average age of natural menopause (45-55 years) 1
• Monitoring: Annual clinical review focusing on compliance; no routine laboratory monitoring is required unless specific symptoms arise 1
• Contraindications to transdermal delivery: Consider oral 17β-estradiol (1-2 mg daily) when transdermal administration is contraindicated (e.g., diffuse cutaneous disorders) or refused 1

By following these evidence-based recommendations, clinicians can provide optimal HRT that effectively manages menopausal symptoms while minimizing cardiovascular and thrombotic risks.