Prescribe a Progestogen with Estradiol to Prevent Endometrial Cancer
Women with an intact uterus who receive estradiol must also receive a progestogen to prevent endometrial cancer—this is non-negotiable. Unopposed estrogen increases endometrial cancer risk 10- to 30-fold if continued for 5 years or more, with the risk persisting for years after discontinuation 1. The FDA explicitly mandates that when estrogen is prescribed for a postmenopausal woman with a uterus, a progestogen should also be initiated to reduce the risk of endometrial cancer 2.
Why Progestogen is Mandatory
- Unopposed estrogen dramatically increases endometrial cancer risk with a relative risk of 2.3 (95% CI 2.1-2.5) compared to non-users, escalating to 9.5-fold after 10 years of use 1, 3.
- Adding a progestogen reduces endometrial cancer risk by approximately 90% compared to unopposed estrogen, effectively counteracting the proliferative effects of estrogen on the endometrium 4, 5.
- Combined estrogen-progestogen therapy shows either reduced or neutral endometrial cancer risk: continuous combined preparations have a relative risk of 0.71 (95% CI 0.56-0.90), while cyclic combined preparations show no significant increase (RR 1.05,95% CI 0.91-1.22) 6.
Recommended Progestogen Regimens
First-line choice: Micronized progesterone 200 mg orally at bedtime 4, 5. This is preferred because it has lower rates of venous thromboembolism and breast cancer risk compared to synthetic progestogens 4, 7.
Alternative options include:
- Medroxyprogesterone acetate (MPA) 10 mg daily for 12-14 days per month (cyclic) or 2.5 mg daily (continuous) 1, 2
- Dydrogesterone 10 mg daily for 12-14 days per month 4
- Levonorgestrel-releasing intrauterine system (52 mg), which provides local endometrial protection with minimal systemic absorption 1, 5
- Transdermal norethisterone acetate (NETA) in combination patches 4
Continuous vs. Cyclic Progestogen Administration
Continuous combined therapy (progestogen added daily) provides the most effective endometrial protection and eliminates withdrawal bleeding 8, 6. This is the preferred approach for most women.
Sequential/cyclic therapy (progestogen added 12-14 days per month) also provides adequate endometrial protection if the progestogen exposure lasts at least 12 days per month 8, 9. However, intervals longer than this are not safe 8.
The Progestogen Trade-Off
While progestogens are essential for endometrial protection, they come with important caveats:
- Breast cancer risk increases with combined estrogen-progestogen therapy (8 additional cases per 10,000 women-years) compared to estrogen alone, which paradoxically reduces breast cancer risk 1, 4, 2.
- Progestogens may diminish some beneficial effects of estrogen on cardiovascular health and colorectal cancer risk 8.
- Micronized progesterone, dydrogesterone, and levonorgestrel IUD appear safest regarding breast cancer risk compared to synthetic progestogens like MPA 8.
Critical Clinical Pitfalls to Avoid
- Never prescribe estrogen alone to a woman with an intact uterus—this is the single most important contraindication, as it dramatically increases endometrial cancer risk 4, 5, 2.
- Do not assume all progestogens are equivalent—micronized progesterone has a more favorable safety profile than synthetic progestogens, particularly regarding breast cancer and thrombotic risk 4, 8.
- Ensure adequate duration of progestogen exposure—if using cyclic therapy, the progestogen must be given for at least 12 days per month; shorter intervals do not provide adequate endometrial protection 8, 9.
Monitoring Requirements
- Investigate any undiagnosed persistent or recurring abnormal vaginal bleeding with endometrial sampling to rule out malignancy, regardless of progestogen use 2, 7.
- Annual clinical evaluation to assess adherence, adverse effects, and ongoing need for therapy 5.
- Use the lowest effective dose for the shortest duration consistent with treatment goals, with reassessment every 3-6 months 2.