What is the recommended hormone therapy regimen for a woman without a hysterectomy, considering her symptoms, medical history, and risk factors?

Hormone Therapy for Women Without Hysterectomy

Women with an intact uterus who require hormone therapy must receive combined estrogen-progestin therapy to prevent endometrial cancer—estrogen-alone therapy is contraindicated in this population due to the risk of endometrial hyperplasia and malignancy. 1, 2, 3

Mandatory Progestin Requirement

• Unopposed estrogen increases endometrial cancer risk by approximately 90% in women with an intact uterus, making progestin co-administration essential for endometrial protection. 4, 2
• The FDA explicitly mandates that when estrogen is prescribed for a postmenopausal woman with a uterus, progestin must also be initiated to reduce endometrial cancer risk. 3
• Combined estrogen-progestin therapy reduces endometrial cancer risk by approximately 90% compared to estrogen-alone. 4

Recommended Regimen

First-Line Therapy

Transdermal estradiol 50 μg daily (0.05 mg patches changed twice weekly) plus micronized progesterone 200 mg orally at bedtime is the preferred regimen. 4, 5, 2

Why Transdermal Estradiol?

• Transdermal delivery avoids first-pass hepatic metabolism, resulting in lower rates of venous thromboembolism, stroke, and cardiovascular events compared to oral formulations. 4, 5, 6
• Transdermal estradiol has a more favorable profile on coagulation factors and demonstrates better effects on bone mass accrual. 4

Why Micronized Progesterone?

• Micronized progesterone is the first-choice progestin due to lower rates of venous thromboembolism and breast cancer risk compared to synthetic progestins like medroxyprogesterone acetate. 4, 2
• The standard protective regimen is 200 mg micronized progesterone taken orally at bedtime for 12-14 consecutive days per 28-day cycle (cyclic regimen) or continuously. 2, 6
• Cyclic progesterone must be given for at least 12-14 days per month to adequately protect the endometrium—regimens with fewer than 16 days per cycle are associated with increased endometrial cancer risk. 2

Risk-Benefit Profile

Benefits

• Approximately 75% reduction in vasomotor symptom frequency (hot flashes, night sweats). 4, 7
• Reduces risk of all clinical fractures (RR 0.78,95% CI 0.71 to 0.86). 1, 8
• Prevents approximately 5 hip fractures per 10,000 women-years. 4

Harms

For every 10,000 women taking combined estrogen-progestin for 1 year: 1, 4

• 8 additional invasive breast cancers (RR 1.27,95% CI 1.03 to 1.56)
• 8 additional strokes (RR 1.39,95% CI 1.09 to 2.09)
• 8 additional pulmonary emboli (RR 2.03,95% CI 1.55 to 6.64)
• 7 additional coronary heart disease events
• Increased gallbladder disease requiring surgery (RR 1.64,95% CI 1.30 to 2.06)

Critical Timing Consideration

• The risk-benefit profile is most favorable for women under 60 years of age or within 10 years of menopause onset. 4
• Women over 60 or more than 10 years past menopause have a less favorable risk-benefit profile, with increased stroke risk. 4

Absolute Contraindications to Screen For

Before initiating hormone therapy, screen for: 4, 5

• History of breast cancer or hormone-sensitive malignancy
• Active or history of venous thromboembolism or pulmonary embolism
• Active or history of stroke
• History of myocardial infarction or coronary heart disease
• Active liver disease
• Antiphospholipid syndrome or positive antiphospholipid antibodies
• Thrombophilic disorders

Duration and Monitoring

Use Lowest Dose for Shortest Duration

• Prescribe at the lowest effective dose for the shortest duration consistent with treatment goals. 1, 3
• The FDA mandates periodic reevaluation (every 3-6 months) to determine if treatment is still necessary. 4, 3
• Breast cancer risk does not appear until after 4-5 years of combined therapy use, but other risks (stroke, VTE) emerge within the first 1-2 years. 7

Annual Reassessment Protocol

• Reassess symptom control and necessity of therapy every 3-6 months initially, then annually. 4, 5
• Attempt dose reduction to lowest effective level at 1 year. 4
• Continue standard mammography screening per guidelines. 4, 5

Common Pitfalls to Avoid

• Never prescribe estrogen-alone therapy to women with an intact uterus—this dramatically increases endometrial cancer risk. 1, 2
• Do not initiate hormone therapy solely for chronic disease prevention (osteoporosis, cardiovascular disease) in asymptomatic women—the USPSTF gives this a Grade D recommendation (recommends against). 1, 9
• Do not use custom-compounded "bioidentical" hormones—these lack standardization, safety data, and FDA approval. 4, 2
• Do not assume all progestins are equivalent—synthetic progestins like medroxyprogesterone acetate carry higher breast cancer and VTE risks than micronized progesterone. 4, 2
• Do not continue therapy beyond symptom management needs—breast cancer risk increases significantly with duration beyond 5 years. 4, 7

Clinical Decision Algorithm

1. Confirm menopausal status and assess symptom severity (vasomotor symptoms, genitourinary symptoms). 4

2. Screen for absolute contraindications (breast cancer history, VTE history, stroke history, active liver disease, thrombophilic disorders). 4, 5

3. If age <60 or within 10 years of menopause AND moderate-to-severe symptoms AND no contraindications:

   • Start transdermal estradiol 50 μg daily (patches changed twice weekly) 4, 5
   • Add micronized progesterone 200 mg orally at bedtime (cyclic or continuous) 4, 2

4. If age ≥60 or >10 years past menopause:

   • Use extreme caution—risks likely outweigh benefits 4
   • If symptoms are severe and patient insists, use absolute lowest dose for shortest time 4

5. Reassess at 3-6 months, then annually:

   • Evaluate symptom control 4, 3
   • Attempt dose reduction 4
   • Consider discontinuation trial 4

6. Monitor for:

   • Abnormal vaginal bleeding (requires endometrial evaluation) 3
   • Signs of VTE (leg swelling, chest pain, shortness of breath) 1, 8
   • Breast changes (continue routine mammography) 4, 5