Is progesterone (a hormone replacement therapy (HRT) medication) dangerous?

Progesterone Safety in Hormone Replacement Therapy

Progesterone carries significant risks when used in hormone replacement therapy (HRT), including increased risks of venous thromboembolism, breast cancer, and cardiovascular events. 1

Cardiovascular and Thrombotic Risks

• Progesterone, when used in combination with estrogen (as in most HRT regimens), is associated with a statistically significant 2-fold greater rate of venous thromboembolism compared to placebo (35 versus 17 per 10,000 women-years) 1
• The increased risk of venous thromboembolism is highest during the first year of therapy and persists with continued use 2
• Stroke risk is increased with bioidentical HRT, with a relative risk of 1.12 (95% CI, 1.01 to 1.23) according to meta-analyses 2
• HRT may increase rather than decrease the risk of coronary heart disease, contrary to earlier beliefs 2

Cancer Risks

• Combined estrogen-progestin therapy has shown increased breast cancer incidence (RH, 1.26 [95% CI, 1.00 to 1.59]) in the Women's Health Initiative study 1
• Breast cancers in women taking combined estrogen-progestin therapy were larger, more likely to be node positive, and diagnosed at a more advanced stage compared to placebo 1
• Unopposed estrogen significantly increases endometrial cancer risk (RR, 2.3 [95% CI, 2.1 to 2.5]), with risk increasing with duration of use (RR, 9.5 for 10 years of use) 3
• While progesterone is added to estrogen to prevent endometrial hyperplasia and cancer in women with an intact uterus, this combination introduces other risks 1

Other Significant Risks

• Increased risk of cholecystitis among current HRT users (RR, 1.8 [95% CI, 1.6 to 2.0]) and long-term users (>5 years) (RR, 2.5 [95% CI, 2.0 to 2.9]) 2
• The WHI estrogen plus progestin study found an increased risk of probable dementia in women aged 65-79 years (relative risk 2.05,95% CI, 1.21-3) 1

Formulation Considerations

• Natural micronized progesterone may have a more favorable cardiovascular and thrombotic risk profile compared to synthetic progestins 4
• Transdermal administration of estrogen is associated with lower thrombotic risk compared to oral routes 2
• Different progesterone formulations have varying side effect profiles - synthetic progestins (like medroxyprogesterone acetate) may cause fatigue, fluid retention, lipid alterations, and dysphoria 4

Clinical Recommendations

• The U.S. Preventive Services Task Force recommends against routine use of hormone therapy for primary prevention of chronic conditions in postmenopausal women 5, 6
• For women who choose to use HRT for management of menopausal symptoms, the lowest effective dose should be used for the shortest possible time 5
• Women with an intact uterus must use progestogen in combination with estrogen to protect the endometrium from hyperplasia and cancer 2
• Annual clinical reviews are recommended for women using HRT 2

Important Caveats

• The risk-benefit profile of progesterone varies significantly based on:
  • Whether it's used alone or in combination with estrogen 1
  • The specific formulation (natural vs. synthetic) 4
  • Route of administration (oral, transdermal, etc.) 2
  • Duration of use (risks increase with longer use) 3, 2
• Some research suggests natural progesterone may have a better safety profile than synthetic progestins, particularly regarding breast cancer risk 7
• HRT should be discontinued at least 4-6 weeks before surgeries with increased thromboembolism risk 1