Estrogen is Required When Taking Progesterone for Endometrial Protection
Women with an intact uterus should always receive estrogen when taking progesterone to prevent endometrial hyperplasia and cancer. 1 Unopposed progesterone without estrogen is not recommended for postmenopausal women with an intact uterus.
Why Estrogen and Progesterone Must Be Combined
Endometrial Protection Mechanism
- Progesterone is primarily added to estrogen therapy to protect the endometrium from hyperplasia and cancer risk
- Taking estrogen alone (unopposed) in women with an intact uterus dramatically increases endometrial cancer risk 1
- Progesterone provides this protection by:
- Counteracting estrogen's proliferative effects on the endometrium
- Inducing secretory changes in the endometrial lining
- Reducing the risk of endometrial hyperplasia that may lead to cancer 2
Clinical Evidence
- The FDA-approved indication for progesterone in postmenopausal women specifically states it is "used in combination with estrogen-containing medications in a postmenopausal woman with a uterus" 2
- Studies from the Women's Health Initiative (WHI) evaluated combined estrogen plus progestin therapy, not progesterone alone, for postmenopausal women 3
- Progestogens are mandatory for menopausal women requiring hormone therapy who have an intact uterus 4
Appropriate Progesterone Regimens
For Postmenopausal Women
- For endometrial protection: 200 mg progesterone capsules at bedtime for 12 continuous days per 28-day cycle when combined with estrogen 2
- Sequential regimen: Progestogen for at least 12 days/month with estrogen (shorter intervals are not safe) 5
- Continuous regimen: Daily progestogen with daily estrogen (most effective endometrial protection) 5
Progesterone Options
- Micronized progesterone (100-200 mg daily): Preferred due to more favorable cardiovascular profile and potentially lower breast cancer risk 1
- Medroxyprogesterone acetate (MPA): Historically common but may have less favorable cardiovascular and metabolic effects 6
- Dydrogesterone: May have a safer profile regarding breast cancer risk 5
Risks of Incorrect Hormone Therapy
Risks of Unopposed Estrogen
- Significantly increased risk of endometrial hyperplasia and cancer 1, 2
- 2.6-fold increased risk for endometrial cancer in postmenopausal women 7
Risks of Unopposed Progesterone
- Not indicated for postmenopausal women with an intact uterus 2
- May not provide symptom relief for menopausal symptoms
- No evidence supporting use of progesterone alone for prevention of chronic conditions 7
Benefits of Combined Therapy vs. Risks
Benefits
- Reduction in fracture risk: 27% reduction in nonvertebral fractures with combined therapy 7
- Possible reduction in colorectal cancer risk (though evidence is mixed) 7
Risks
- Combined therapy increases risk of:
Special Considerations
Route of Administration
- Transdermal estrogen is preferred over oral due to:
- Lower thrombotic risk profile
- Avoidance of first-pass hepatic metabolism
- More physiological hormone levels 1
Monitoring
- Annual clinical reviews to assess:
- Symptom control
- Side effects
- Compliance with therapy 1
- No routine laboratory monitoring required unless specific concerns arise 1
Duration of Therapy
- Use lowest effective dose for shortest duration consistent with treatment goals 1
- For women with premature ovarian insufficiency: Continue until at least the average age of natural menopause (around 51 years) 1
Conclusion
Progesterone should not be prescribed without estrogen for women with an intact uterus. The primary purpose of progesterone in hormone therapy is to protect the endometrium from the cancer-promoting effects of estrogen. Using the appropriate combination of hormones, at the correct dosages and administration schedules, is essential for maximizing benefits while minimizing risks.