Problems with Unopposed Estrogen Treatment
Unopposed estrogen therapy should not be started or should be discontinued in women with an intact uterus due to dramatically increased endometrial cancer risk. 1
Primary Risk: Endometrial Cancer
The most critical problem with unopposed estrogen is endometrial cancer, which represents a severe mortality risk:
- Unopposed estrogen increases endometrial cancer risk with a relative risk of 2.3 (95% CI 2.1-2.5) compared to nonusers 1, 2, 3
- Risk escalates dramatically with duration: relative risk reaches 9.5 after 10 years of unopposed estrogen use 1, 2
- The elevated risk persists for at least 5 years after discontinuation of therapy 1, 2
- This is precisely why estrogen without progestin has been restricted to women who have had a hysterectomy 1, 3
Mechanism and Clinical Context
- Chronic unopposed endometrial exposure to estrogen increases the risk of endometrial hyperplasia, which can progress to cancer 4
- At 36 months of moderate-dose unopposed estrogen, 62% of women developed some form of endometrial hyperplasia compared to 2% with placebo 5
- Even low-dose unopposed estrogen shows a 3% incidence of hyperplasia versus no incidence in placebo groups 5
Additional Significant Harms
Cardiovascular Risks
- Increased stroke risk with relative risk of 1.12 (95% CI 1.01-1.23), primarily thromboembolic stroke 1, 6
- Small but significant increase in deep venous thrombosis risk 1, 3
- No beneficial effect on coronary heart disease, contrary to earlier beliefs 1
Other Serious Complications
- Increased gallbladder disease and cholecystitis risk (RR 1.8,95% CI 1.6-2.0 for current users) 1
- Urinary incontinence is more likely with unopposed estrogen therapy 1
Clinical Management Pitfalls
Critical Error to Avoid
Never prescribe unopposed estrogen to women with an intact uterus. 1 This represents a Level III evidence, Grade A recommendation with 100% consensus from the ESMO-ESGO-ESTRO consensus conference 1
Proper Approach
- Women with an intact uterus must receive progestogen in combination with estrogen to protect against endometrial hyperplasia and cancer 2, 3, 6
- The addition of progestogens (either continuous combined or sequential regimens) reduces the risk of endometrial hyperplasia and improves adherence 7, 5
- Continuous combined therapy with minimum doses of 1 mg norethisterone acetate or 1.5 mg medroxyprogesterone acetate shows no significant difference from placebo in endometrial hyperplasia risk at two years 7
When Unopposed Estrogen Is Acceptable
- Only in women who have undergone hysterectomy can unopposed estrogen be considered, as endometrial cancer risk is eliminated 1
- Even in these women, other risks (stroke, DVT, gallbladder disease) remain present 1
Patient Education Requirements
Women at increased risk for endometrial cancer due to unopposed estrogen therapy should be: