Hormone Replacement Therapy Dosing: With Uterus vs Without Uterus
Women WITHOUT a Uterus (Post-Hysterectomy)
Women who have had a hysterectomy should receive estrogen-alone therapy without progestin, as there is no endometrium requiring protection. 1, 2, 3
Recommended Estrogen-Only Regimens:
Transdermal estradiol 50 μg patch applied twice weekly is the preferred first-line option due to lower cardiovascular and thromboembolic risks compared to oral formulations 1, 2
Oral conjugated equine estrogen (CEE) 0.625 mg daily is an acceptable alternative 1, 2
- Lower dose option: 0.3 mg daily for minimal symptoms 4
Oral estradiol 1-2 mg daily can be used, adjusted to control symptoms 3
- Administer cyclically (3 weeks on, 1 week off) 3
Key Safety Advantage:
- Estrogen-alone therapy shows no increased breast cancer risk and may even be protective (hazard ratio 0.80) 1, 2
- Per 10,000 women taking estrogen-alone for 1 year: 5 fewer hip fractures, 75% reduction in vasomotor symptoms, but 8 additional strokes and 8 additional venous thromboembolic events 1
Women WITH an Intact Uterus
Women with a uterus MUST receive combined estrogen-progestin therapy to prevent endometrial cancer—unopposed estrogen increases endometrial cancer risk 2.3-fold, escalating to 9.5-fold after 10 years. 5, 1, 3
Recommended Combined Regimens:
First-Line: Transdermal Estradiol + Oral Progestin
Alternative: Combined Estradiol/Progestin Patches
- Estradiol 50 μg + levonorgestrel 10 μg daily patch 1
Alternative: Oral Combined Therapy
- Conjugated equine estrogen 0.625 mg + MPA 2.5 mg daily (the WHI-studied regimen) 1, 7
- This is the most extensively studied combination but carries higher breast cancer risk than micronized progesterone 1
Critical Progestin Requirements:
Minimum effective progestin doses for endometrial protection: 8, 7
- MPA: 2.5 mg daily (continuous) or 10 mg for 12-14 days/month (sequential)
- Micronized progesterone: 200 mg daily (continuous) or for 12-14 days/month (sequential)
- Norethisterone acetate: minimum 1 mg daily
Without adequate progestin, endometrial hyperplasia occurs in 27.7% of women on unopposed estrogen within 3 years 7
Combined therapy reduces endometrial cancer risk by approximately 90% compared to unopposed estrogen 5, 1
Risk Profile for Combined Therapy:
- Per 10,000 women taking combined estrogen-progestin for 1 year: 1, 2
- Harms: 8 additional invasive breast cancers, 8 additional strokes, 8 additional pulmonary emboli, 7 additional coronary events
- Benefits: 6 fewer colorectal cancers, 5 fewer hip fractures, 75% reduction in vasomotor symptoms
Universal Principles for All Women:
- Use the lowest effective dose for the shortest duration necessary 1, 2, 3
- Reassess necessity every 3-6 months 3
- Most favorable risk-benefit profile: women under 60 years OR within 10 years of menopause onset 1, 2
- Transdermal routes preferred over oral due to reduced cardiovascular and thromboembolic risks 1
- Never initiate HRT solely for chronic disease prevention (Grade D recommendation from USPSTF) 1, 2
Common Pitfalls to Avoid:
- Never prescribe estrogen-alone to women with an intact uterus—this dramatically increases endometrial cancer risk 1, 3
- Do not assume all progestins are equivalent—micronized progesterone has superior breast safety compared to synthetic progestins like MPA 1
- Do not use inadequate progestin doses—minimum MPA 1.5 mg or NETA 1 mg daily required for endometrial protection 8
- Do not continue HRT beyond symptom management needs—breast cancer risk increases significantly after 4-5 years 1
- Avoid initiating HRT in women over 60 or more than 10 years past menopause due to unfavorable risk-benefit profile 1