What are the risks and considerations for estrogen replacement therapy (ERT) post menopause?

Risks of Estrogen Replacement Therapy Post Menopause

The harmful effects of estrogen replacement therapy are likely to exceed the chronic disease prevention benefits in most postmenopausal women, with increased risks of venous thromboembolism, stroke, breast cancer, and cardiovascular disease. 1

Major Risks of Estrogen Replacement Therapy

Cardiovascular Risks

• Venous thromboembolism (VTE):

  • Increased risk of DVT (23 vs 15 per 10,000 women-years) with estrogen-alone therapy 2
  • 2-fold greater rate of VTE with combined estrogen-progestin therapy (35 vs 17 per 10,000 women-years) 2
  • Risk appears within first 1-2 years of therapy and persists during treatment 2

• Stroke:

  • 33% increased risk with estrogen-alone therapy 2
  • 31% increased risk with estrogen-progestin therapy 2
  • Particularly increased risk of ischemic stroke 2

• Coronary Heart Disease (CHD):

  • Women's Health Initiative (WHI) showed increased CHD events in the first year of combined therapy 2
  • No cardiovascular benefit demonstrated in women with established coronary heart disease 2

Cancer Risks

• Breast Cancer:

  • 24% increased risk with estrogen-progestin therapy (41 vs 33 cases per 10,000 women-years) 2
  • Risk increases with longer duration of use 2
  • Estrogen-alone therapy showed no significant increased risk in women who had hysterectomy 2

• Endometrial Cancer:

  • 2-12 times greater risk with unopposed estrogen in women with intact uterus 2
  • Risk increases with duration of treatment (15-24 fold for 5-10 years of use) 2
  • Risk persists for 8-15 years after discontinuation 2
  • Adding progestin reduces this risk 2

• Ovarian Cancer:

  • Non-significant increased risk (relative risk 1.58) with combined therapy 2
  • Some epidemiologic studies show increased risk with 5+ years of use 2

Other Significant Risks

• Dementia:

  • 49% increased risk of probable dementia with estrogen-alone therapy in women 65-79 years 2
  • 105% increased risk with combined therapy in same age group 2
  • Absolute risk: 45 vs 22 cases per 10,000 women-years 2

• Gallbladder Disease:

  • 2-4 fold increased risk requiring surgery 2

• Hypercalcemia:

  • Risk in patients with breast cancer and bone metastases 2

• Visual Abnormalities:

  • Risk of retinal vascular thrombosis 2

• Allergic Reactions:

  • Rare anaphylactic reactions and angioedema 2

Absolute Risk Perspective

For 10,000 women taking estrogen-progestin for 1 year 1:

• 7 additional CHD events
• 8 more strokes
• 8 more pulmonary emboli
• 8 more invasive breast cancers
• 6 fewer cases of colorectal cancer
• 5 fewer hip fractures

Contraindications

Estrogen replacement therapy is absolutely contraindicated in women with 3:

• Active liver disease
• History of breast cancer
• History of coronary heart disease
• Previous venous thromboembolism or stroke
• Positive antiphospholipid antibodies

Clinical Decision Making

When considering ERT for menopausal symptoms:

1. First-line therapy should be non-hormonal options 3:

   • SSRIs/SNRIs (e.g., paroxetine, venlafaxine) at lower doses
   • Anticonvulsants (gabapentin, pregabalin)
   • Lifestyle modifications (weight loss, smoking cessation, limiting alcohol)
   • Cognitive behavioral therapy and physical activity

2. Consider ERT only for moderate to severe menopausal symptoms that significantly impact quality of life, after screening for contraindications 3

3. If ERT is used:

   • Use lowest effective dose for shortest duration necessary 3
   • Women with intact uterus must use combined estrogen-progestin therapy 3
   • Women with prior hysterectomy can use estrogen-only therapy (somewhat better risk profile) 3
   • Consider transdermal administration (may have lower thrombotic risk) 3

Monitoring and Follow-up

If ERT is initiated despite risks:

• Initial follow-up at 3 months 3
• Annual follow-up thereafter to monitor:
  • Blood pressure, weight, lipid profile
  • Emerging symptoms
  • Bleeding patterns (if uterus intact) 3
• Annual mammography 3
• Consider bone density testing 3

Key Pitfalls to Avoid

1. Using ERT solely for chronic disease prevention - USPSTF explicitly recommends against this practice 3
2. Failing to recognize contraindications - Especially history of breast cancer, VTE, stroke, or CHD
3. Not adding progestin for women with intact uterus - Critical for preventing endometrial cancer
4. Continuing therapy longer than necessary - Risks increase with duration of use
5. Overlooking drug interactions - Particularly between SSRIs and tamoxifen in breast cancer patients 3

Remember that the decision to use ERT should prioritize mortality, morbidity, and quality of life outcomes, with the evidence clearly showing that for most women, the risks outweigh the benefits for long-term use.