What is the best approach to hormone replacement therapy (HRT) for a woman with a uterus?

Optimal Hormone Replacement Therapy for Women with an Intact Uterus

For women with an intact uterus, combined estrogen-progestogen therapy is essential, with transdermal 17β-estradiol (50-100 μg/day) plus oral micronized progesterone (200 mg daily for 12-14 days every 28 days in sequential regimens) being the optimal regimen for hormone replacement therapy. 1

Estrogen Component Selection

First-Line Option:

• Transdermal 17β-estradiol (50-100 μg/day)
  • Provides more physiological serum estradiol concentrations
  • Reduces thromboembolism risk compared to oral formulations
  • Preferred method of delivery for women with hypertension 2, 1
  • Start with lowest effective dose (typically 50 μg/day)

Alternative Option:

• Oral estradiol (1-2 mg daily)
  • Adjust as necessary to control symptoms
  • Less preferred than transdermal due to increased thrombotic risk 1
  • 17-β estradiol is preferred over ethinylestradiol or conjugated equine estrogens 2

Progestogen Component (Mandatory with Intact Uterus)

Progestogen must be given with estrogen therapy to protect the endometrium from hyperplasia and cancer risk 2, 3, 4.

First-Line Option:

• Oral micronized progesterone (200 mg daily for 12-14 days per month)
  • Lower cardiovascular and thromboembolism risk 1
  • More favorable metabolic profile
  • Can be used in sequential regimens (12-14 days per month)

Alternative Option:

• Medroxyprogesterone acetate (10 mg daily for 10-14 days per month)
  • Strongest evidence for endometrial protection 2
  • Can be used in continuous combined regimens (2.5 mg daily) 1

Administration Regimens

Sequential/Cyclic Regimen (Preferred for Perimenopausal Women):

• Daily estrogen therapy
• Progestogen added for 12-14 days per month
• Results in monthly withdrawal bleeding
• Administration should be cyclic (e.g., 3 weeks on and 1 week off) 3

Continuous Combined Regimen (Better for Postmenopausal Women):

• Daily estrogen plus daily progestogen
• Aims to eliminate withdrawal bleeding after initial adjustment period
• May cause irregular bleeding in first 3-6 months

Monitoring and Follow-up

• Initial follow-up every 1-3 months to assess symptom control and bleeding patterns 1
• Annual clinical review with attention to compliance 2, 1
• No routine monitoring tests required, but specific symptoms may prompt testing 2
• For women with undiagnosed persistent or recurring abnormal vaginal bleeding, endometrial sampling should be performed 3, 4

Special Considerations

Duration of Therapy:

• Use lowest effective dose for shortest duration consistent with treatment goals 3, 4
• Reevaluate periodically (every 3-6 months) to determine if treatment is still necessary 3
• Attempt to discontinue or taper medication at 3-6 month intervals 3

Contraindications:

• History of breast cancer 1
• Women aged ≥60 years or >10 years post-menopause have increased vascular risk 1
• Combined therapy increases risk of venous thromboembolism and gallbladder disease 1

Risk Mitigation:

• Cardiovascular risk should be assessed and monitored annually 2
• For women with cardiovascular risk factors, transdermal estradiol with micronized progesterone offers the safest profile 1
• Smokers over 35 should be prescribed HRT with caution due to significantly increased cardiovascular risks 1

Common Pitfalls to Avoid

1. Prescribing estrogen alone to women with intact uterus - This significantly increases endometrial cancer risk
2. Using excessive doses - Start with lowest effective dose and titrate as needed
3. Continuing therapy indefinitely without reassessment - Evaluate need for continued therapy every 3-6 months
4. Ignoring breakthrough bleeding - This requires appropriate diagnostic evaluation to rule out endometrial pathology
5. Overlooking cardiovascular risk factors - These should be assessed before initiating therapy and monitored annually

By following this evidence-based approach to HRT in women with an intact uterus, clinicians can effectively manage menopausal symptoms while minimizing risks associated with hormone therapy.