Does progesterone increase the risk of breast cancer?

Progesterone and Breast Cancer Risk

Combined estrogen-progestin hormone therapy increases breast cancer risk, while progesterone alone appears to have minimal risk or may even be protective, particularly when using micronized progesterone rather than synthetic progestins. 1, 2, 3

Different Types of Progesterone and Their Risk Profiles

Combined Hormone Therapy

• Estrogen plus progestin therapy significantly increases breast cancer risk:
  • Women's Health Initiative (WHI) study showed a 26% increased risk (HR 1.26; 95% CI, 1.00 to 1.59) 4, 1
  • Absolute risk increase of approximately 8 additional breast cancer cases per 10,000 women-years 1, 2
  • Risk becomes apparent earlier with combined therapy compared to estrogen-alone therapy 2

Progesterone Types and Risk Differentiation

• Synthetic progestins carry higher breast cancer risk (OR 1.28; 95% CI 1.22-1.35) 3
• Micronized progesterone appears significantly safer (OR 0.99; 95% CI 0.55-1.79) 3
• A meta-analysis of studies involving 86,881 postmenopausal women found natural progesterone associated with significantly lower breast cancer risk compared to synthetic progestins 5

Duration of Use and Risk

• Short-term use (<5 years) of estrogen with micronized progesterone does not appear to increase breast cancer risk 6
• Long-term use (>5 years) shows limited evidence of increased risk even with micronized progesterone 6
• Risk increases with duration of use for combined estrogen-progestin therapy 2, 7

Clinical Recommendations

For Women Without a Uterus

• Estrogen-only therapy is preferred as it carries lower breast cancer risk 1
• WHI study showed estrogen-only therapy associated with a 23% reduction in invasive breast cancer risk (HR 0.77; 95% CI, 0.62 to 0.95) 1

For Women With an Intact Uterus

• If hormone therapy is necessary, consider using micronized progesterone rather than synthetic progestins 3
• Use the lowest effective dose for the shortest duration needed 2
• FDA recommends: "estrogens with or without progestins should be prescribed at the lowest effective doses and for the shortest duration consistent with treatment goals and risks for the individual woman" 2

Important Caveats and Considerations

• Hormone therapy is contraindicated in women with a history of breast cancer, including those with hormone receptor-negative disease 4
• Women with BRCA1/2 mutations should be counseled about the potential additional breast cancer risk with HRT 4
• Breast cancer risk with HRT is higher in:
  • Older women
  • Women with low BMI in menopause (<25 kg/m²)
  • Women with increased mammographic breast density 7
• Continuous use of hormone therapy is associated with higher breast cancer risk compared to sequential therapy 7

Monitoring Recommendations

• All women on hormone therapy should receive yearly breast examinations and perform monthly breast self-examinations 2
• Mammography examinations should be scheduled based on patient age, risk factors, and prior mammogram results 2
• Monitor for abnormal vaginal bleeding, which may require further evaluation 2

When considering hormone therapy, the risk of breast cancer must be weighed against other potential benefits and risks, including effects on cardiovascular disease, venous thromboembolism, stroke, and quality of life.