What is the cancer risk associated with taking 8mg estriol (estrogen) and 225mg progesterone daily?

Cancer Risk with 8mg Estriol and 225mg Progesterone Daily

Taking 8mg estriol with 225mg progesterone daily carries significant cancer risks, including potential increased risk of breast cancer with combined estrogen-progestin therapy and possible ovarian cancer risk, which likely outweigh benefits for most women using this regimen for chronic disease prevention. 1, 2

Cancer Risks Associated with Hormone Therapy

Breast Cancer Risk

• Combined estrogen and progestin therapy significantly increases the risk of invasive breast cancer (HR 1.25,95% CI 1.07-1.46) and potentially breast cancer deaths (HR 1.96,95% CI 1.00-4.04) 3
• The FDA warning for progesterone explicitly states that estrogen plus progestin therapy demonstrated an increased risk of invasive breast cancer in the Women's Health Initiative (WHI) study 2
• The risk appears to increase with duration of use, with relative risk increasing by 0.08 (95% CI 0.02-0.16) with each year of estrogen-progestin use 4
• This risk is particularly pronounced in women with lower BMI (≤24.4 kg/m²) 4

Endometrial Cancer Risk

• Unopposed estrogen (without progestin) significantly increases endometrial cancer risk in a dose and duration-dependent manner (OR 6.2-6.6 after 5+ years of use) 5
• Adding progesterone to estrogen therapy reduces this risk compared to estrogen alone 5
• The pattern of progesterone administration matters:
  • Cyclic progestin use (fewer than 16 days per cycle) still carries increased risk (OR 2.9,95% CI 1.8-4.6 for 5+ years of use)
  • Continuous progestin use may actually reduce risk (OR 0.2,95% CI 0.1-0.8 for 5+ years) 5

Ovarian Cancer Risk

• Combined estrogen-progestin therapy may increase ovarian cancer risk (HR 1.58,95% CI 0.77-3.24), though this finding was not statistically significant in the WHI trial 6
• Two cohort studies reported increased risks (RR 1.8-2.2) for ovarian cancer among women who had taken HRT for 10 years or more 3

Other Significant Health Risks

Cardiovascular Risks

• Estrogen plus progestin therapy increases risk of:
  • Deep vein thrombosis
  • Pulmonary embolism
  • Stroke (HR 1.41,95% CI 0.86-2.31)
  • Myocardial infarction 3, 2
• The FDA black box warning explicitly states that estrogen plus progestin therapy should not be used for prevention of cardiovascular disease 2

Other Risks

• Increased risk of gallbladder disease (RR 1.8,95% CI 1.6-2.0 for current users) 3
• Potential increased risk of dementia in women over 65 years 2
• Venous thromboembolism risk is doubled with hormone therapy (RR 2.14,95% CI 1.64-2.81) 3

Risk Mitigation Considerations

1. Dose and Duration: Use the lowest effective dose for the shortest duration necessary 1
2. Route of Administration: Transdermal estradiol has lower VTE risk compared to oral formulations 1
3. Continuous vs. Cyclic Progesterone: Continuous progesterone administration appears to have a more favorable endometrial cancer risk profile 5
4. Individual Risk Factors: Women with pre-existing risk factors (smoking, history of breast cancer, cardiovascular disease, etc.) face even higher risks 1

Conclusion

The 8mg estriol with 225mg progesterone daily regimen carries substantial cancer and cardiovascular risks. The dose of 8mg estriol is significantly higher than recommended doses in standard hormone therapy regimens (typically 0.025-0.0375mg/day for transdermal estradiol or 0.625mg/day for conjugated equine estrogen) 1, which may further increase these risks. The high progesterone dose (225mg) also exceeds standard recommendations (typically 2.5mg/day of medroxyprogesterone acetate) 1.

For most women, especially those seeking chronic disease prevention rather than short-term symptom management, these risks likely outweigh potential benefits.