What is the recommended hormone replacement therapy regimen for a postmenopausal woman with an intact uterus?

Hormone Replacement Therapy for Postmenopausal Women with Intact Uterus

For postmenopausal women with an intact uterus, combined estrogen-progestogen therapy is mandatory to prevent endometrial hyperplasia and cancer. 1, 2, 3, 4

Rationale for Combined Therapy

• Unopposed estrogen significantly increases the risk of endometrial hyperplasia and adenocarcinoma 4
• The risk increases with duration of use (relative risk of 9.5 for 10 years of use) 1
• Adding progestogen to estrogen therapy provides essential endometrial protection 5

Recommended Regimen

Estrogen Component

• Oral options:
  • Estradiol: 1-2 mg daily 2
  • Conjugated equine estrogens: 0.3-0.625 mg daily 3

Progestogen Component

• Oral options:
  • Medroxyprogesterone acetate: 2.5 mg daily (continuous) or 5-10 mg for 12-14 days per month (cyclic) 6
  • Micronized progesterone: 200 mg daily for 12-14 days per month (cyclic) 6, 5
  • Norethisterone acetate: minimum 1 mg daily 4

Administration Patterns

1. Continuous combined regimen:

   • Daily estrogen + daily progestogen
   • Advantages: Minimizes breakthrough bleeding after initial months
   • Best for women >1 year post-menopause 5

2. Cyclic/sequential regimen:

   • Daily estrogen + progestogen for 12-14 days per month
   • Advantages: May have lower breast cancer risk compared to continuous regimens 7
   • Results in predictable withdrawal bleeding

Monitoring and Follow-up

• Initial follow-up at 3 months to assess symptom control and side effects 6
• Annual follow-up thereafter to monitor:
  • Blood pressure and weight
  • Bleeding patterns (any abnormal bleeding requires evaluation)
  • Breast examination and mammography
  • Endometrial assessment if abnormal bleeding occurs 2, 3

Important Considerations and Risks

Benefits

• Effective relief of vasomotor symptoms and urogenital atrophy 3
• Prevention of osteoporosis and reduced fracture risk 1
• Possible reduced risk of colorectal cancer 1

Risks

• Increased risk of:
  • Breast cancer (higher with combined therapy than estrogen alone) 7
  • Venous thromboembolism (risk highest in first year, RR 3.49) 1
  • Stroke (RR 1.20) 1
  • Coronary heart disease 1
  • Cholecystitis (RR 1.8-2.5) 1

Clinical Pearls

• Natural progesterone and dydrogesterone may be associated with lower breast cancer risk compared to synthetic progestins 7
• Transdermal estradiol is preferred for women with hypertension 1
• 17-β estradiol is preferred to ethinylestradiol or conjugated equine estrogens 1
• Use the lowest effective dose for the shortest duration needed for symptom control 2, 3
• Reevaluate need for therapy every 3-6 months 2
• Hormone therapy should not be used for primary prevention of chronic conditions 1

Special Situations

• For women with endometriosis who required oophorectomy, combined therapy can reduce risk of disease reactivation 1
• For women with migraine, consider changing dose, route of administration, or regimen if migraines worsen during HRT 1

By providing combined estrogen-progestogen therapy at appropriate doses, clinicians can effectively manage menopausal symptoms while protecting the endometrium from hyperplasia and cancer in women with an intact uterus.