Protective Dose of Progesterone for Endometrial Cancer Prevention in Menopausal Women on HRT
For menopausal women with an intact uterus receiving estrogen therapy, progestogen must be added at specific minimum doses to prevent endometrial cancer: 200 mg oral micronized progesterone for 12-14 days every 28 days for sequential regimens, or 2.5 mg medroxyprogesterone acetate (MPA) daily for continuous combined regimens. 1, 2
Critical Evidence on Endometrial Protection
The evidence unequivocally demonstrates that unopposed estrogen dramatically increases endometrial cancer risk with a relative risk of 2.3 (95% CI 2.1-2.5), escalating to RR 9.5 after 10 years of use 1. This risk remains elevated for at least 5 years after discontinuation 3. In stark contrast, combined estrogen-progestin therapy does not increase endometrial cancer risk (RR 0.83 in the WHI trial) 1.
Specific Protective Doses by Regimen Type
Sequential (Cyclic) Regimens
For sequential administration (progestogen given 12-14 days per month):
- Micronized progesterone (first choice): 200 mg orally or vaginally for 12-14 days every 28 days 1, 2
- Medroxyprogesterone acetate: 10 mg daily for 12-14 days per month 1, 2
- Dydrogesterone: 10 mg daily for 12-14 days per month 1
The duration of progestogen exposure is critical—10 days minimum is required for adequate endometrial protection 4, 5. Studies demonstrate that 7 days of progestogen per month provides inadequate protection and still increases endometrial cancer risk, while 10 days provides complete protection 5. This sharp threshold effect suggests that adequate endometrial sloughing or terminal differentiation requires at least 10 days of progestogen exposure 5.
Continuous Combined Regimens
For continuous daily administration (both estrogen and progestogen taken every day):
- Medroxyprogesterone acetate: minimum 2.5 mg daily 1, 2
- Norethisterone acetate: minimum 1 mg daily 1, 2
- Dydrogesterone: minimum 5 mg daily 1, 2
Continuous combined regimens provide superior endometrial protection compared to sequential regimens 6, 4. The Cochrane review confirms that low-dose estrogen continuously combined with at least 1 mg norethisterone acetate or 1.5 mg medroxyprogesterone acetate carries no increased risk of endometrial hyperplasia compared to placebo 4.
Choosing the Optimal Progestogen
Micronized progesterone is the preferred first-line choice because it provides equivalent endometrial protection while demonstrating lower risks of cardiovascular disease, venous thromboembolism, and breast cancer compared to synthetic progestogens 1, 6. Experimental evidence shows that micronized progesterone does not increase breast cell proliferation, unlike medroxyprogesterone acetate, due to differences in glucocorticoid activity and gene expression regulation 6.
Second-line options include MPA, dydrogesterone, or norethisterone 1. Avoid progestogens with anti-androgenic effects in women with low testosterone or sexual dysfunction 1.
Critical Dosing Pitfalls
The most dangerous error is using inadequate progestogen doses or durations. Several case reports document endometrial carcinoma developing in women receiving continuous combined HRT with 2.5 mg MPA, attributed to inadequate progestogen dose, prior unopposed estrogen use, poor compliance, or less efficient reversal of hyperplasia 7.
Sequential regimens with less than 10 days of progestogen per month fail to provide adequate protection 5. The sharp contrast between 7-day and 10-day regimens demonstrates that partial endometrial protection is insufficient 5.
Alternative Dosing Strategies
For women who cannot tolerate monthly progestogen, 10 mg MPA for 14 days every 3-4 months with standard-dose conjugated estrogen (0.625 mg/day) may provide satisfactory endometrial protection with less breast impact 5. However, this approach requires more long-term safety data 5.
Route of Administration Considerations
Transdermal estradiol combined with oral or vaginal progestogen is preferred over oral formulations because transdermal routes show lower thrombotic risk (odds ratio 0.9 vs 4.2 for oral) 3. Vaginal or direct endometrial progestogen delivery provides adequate endometrial protection with minimal systemic absorption and reduced breast effects 5.
Monitoring Requirements
Women on combined HRT require annual clinical reviews with mammography 3. Any undiagnosed, persistent, or recurrent abnormal vaginal bleeding mandates investigation to rule out malignancy 8. Endometrial assessment should be performed if breakthrough bleeding occurs on continuous combined regimens 8.
Duration of Therapy
HRT should be continued until the average age of spontaneous menopause (45-55 years) in women with premature ovarian insufficiency 1. For standard menopausal HRT, use the lowest effective dose for the shortest duration needed for symptom control 3, 2.