What are the risks of unopposed estrogen therapy in a perimenopausal female who has not had a hysterectomy?

Risks of Unopposed Estrogen Therapy in Perimenopausal Women with Intact Uterus

Unopposed estrogen therapy is strongly contraindicated in perimenopausal women with an intact uterus due to a substantial increased risk of endometrial cancer. 1, 2

Primary Risks

Endometrial Cancer

• Unopposed estrogen therapy in women with a uterus increases endometrial cancer risk by 2-12 times compared to non-users 2
• Risk increases with duration of use:
  • 15-24 fold increased risk with 5-10 years of use
  • Risk persists for 8-15 years after discontinuation 2
• The Million Women Study showed a 45% increased risk (RR 1.45) with estrogen-only HRT in women with intact uteri 3

Other Significant Risks

• Venous thromboembolism (VTE): Increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE)

  • 30 versus 22 events per 10,000 women-years compared to placebo 2
  • Risk is highest during the first 2 years of therapy 2

• Stroke: Increased risk, particularly in women over 60 years 1

• Gallbladder disease: Higher risk of cholecystitis 1

Risk Mitigation

The addition of progestin is mandatory for endometrial protection in women with an intact uterus:

• Continuous combined regimen (progestin added daily to estrogen) reduces endometrial cancer risk (RR 0.71) compared to never users 3
• Sequential/cyclic regimen (progestin added 10-14 days per month) still carries some risk (RR 1.05) 3
• Continuous progestin use for ≥5 years significantly reduces risk (OR 0.2) compared to never users 4

Clinical Implications

1. Absolute contraindication: Unopposed estrogen should never be prescribed to women with an intact uterus 1

2. Required protection: Combined estrogen-progestin therapy must be used in women with an intact uterus to protect the endometrium 1

3. Monitoring: Any woman with an intact uterus on hormone therapy requires:

   • Surveillance for abnormal uterine bleeding
   • Appropriate diagnostic measures including endometrial sampling when indicated 2

4. Regimen selection: Continuous combined therapy provides better endometrial protection than cyclic regimens 3, 4

Important Considerations

• The protective effect of progestins varies by:

  • Duration of progestin use per cycle (continuous > cyclic) 4
  • Body mass index (protective effects of combined HRT are greater in obese women) 3

• Even with progestin protection, hormone therapy should be prescribed at the lowest effective dose for the shortest duration necessary to manage symptoms 1

• For women with contraindications to HRT, alternative non-hormonal therapies should be considered for symptom management 1

The evidence is clear that unopposed estrogen therapy poses an unacceptable risk of endometrial cancer in perimenopausal women with an intact uterus, and combined estrogen-progestin therapy is mandatory if hormone therapy is indicated.