What are the potential side effects of progesterone, especially in women with a history of cardiovascular disease, liver disease, or breast cancer?

Side Effects of Progesterone

Progesterone when combined with estrogen increases the risk of breast cancer, cardiovascular events, stroke, and venous thromboembolism, but these risks are substantially lower with natural micronized progesterone compared to synthetic progestins like medroxyprogesterone acetate. 1

Serious Cardiovascular and Thrombotic Side Effects

Combined estrogen-progestin therapy carries significant cardiovascular risks that led to early termination of major clinical trials:

• 8 additional strokes per 10,000 women-years (RR 1.39,95% CI 1.09-2.09) 2
• 8 additional pulmonary emboli per 10,000 women-years (RR 2.03,95% CI 1.55-6.64) 2
• 7 additional coronary heart disease events per 10,000 women-years (RR 1.29,95% CI 1.02-1.63) 2
• Deep vein thrombosis risk increases 2-3 fold, with highest risk in the first year of use 2

The FDA explicitly warns that estrogen plus progestin therapy should not be used for cardiovascular disease prevention, as the WHI trial demonstrated increased risks of myocardial infarction, stroke, and venous thromboembolism in postmenopausal women aged 50-79 years. 1

Breast Cancer Risk

The addition of progestin to estrogen therapy significantly increases breast cancer risk:

• 8 additional invasive breast cancers per 10,000 women-years with combined estrogen-progestin (RR 1.26,95% CI 1.00-1.59) 2, 1
• Risk increases with duration beyond 5 years (RR 1.23-1.35 for long-term users) 2
• Critically, estrogen-alone therapy shows NO increased breast cancer risk and may even be protective (RR 0.80), demonstrating that the progestin component drives the breast cancer risk 2, 3

Natural micronized progesterone appears safer than synthetic progestins: A meta-analysis of 86,881 postmenopausal women found natural progesterone associated with significantly lower breast cancer risk compared to synthetic progestins like medroxyprogesterone acetate. 4

Neurological and Cognitive Side Effects

Progesterone causes significant central nervous system effects:

• Extreme drowsiness and dizziness requiring bedtime dosing 1
• Blurred vision, difficulty speaking, difficulty walking, and feeling abnormal in some cases 1
• Caution required when driving or operating machinery 1
• Increased risk of probable dementia in women ≥65 years taking estrogen plus progestin (based on WHIMS trial) 1

The FDA label explicitly warns that progesterone capsules should be taken at bedtime due to these effects, and patients experiencing severe symptoms should discuss them with their provider immediately. 1

Common but Less Serious Side Effects

Frequently reported side effects include:

• Headaches 1
• Breast pain and tenderness 1
• Irregular vaginal bleeding or spotting 1
• Stomach or abdominal cramps and bloating 1
• Nausea and vomiting 1
• Hair loss 1
• Fluid retention 1
• Vaginal yeast infection 1

Special Population Risks

In women with cardiovascular disease history:

• Absolute contraindication: History of myocardial infarction, coronary heart disease, stroke, or venous thromboembolism 3, 1
• The HERS trial in women with established CHD showed no cardiovascular benefit and potential early harm with estrogen-progestin therapy 2

In women with liver disease:

• Active liver disease is an absolute contraindication to progesterone therapy 3, 1
• Increased risk of gallbladder disease (RR 1.48-1.8) with hormone therapy 3

In women with breast cancer history:

• Hormone-sensitive cancers are a strong contraindication to systemic progesterone therapy 3, 1
• Women with current or prior breast cancer should not take progesterone 1

Fetal and Pregnancy Risks

Progesterone poses teratogenic risks if taken during pregnancy:

• Cases of cleft palate, cleft lip, hypospadias 1
• Ventricular septal defect, patent ductus arteriosus, and other congenital heart defects 1
• Contraindicated if pregnancy is suspected 1

Critical Pitfalls to Avoid

Do not assume all progestins carry equal risk profiles - natural micronized progesterone has substantially better safety data than synthetic progestins (particularly medroxyprogesterone acetate) for breast cancer and cardiovascular outcomes. 3, 5, 4

Do not prescribe progesterone-containing products to patients with peanut allergies - progesterone capsules contain peanut oil and are absolutely contraindicated. 1

Do not continue progesterone therapy beyond symptom management needs - risks including breast cancer increase significantly with duration beyond 5 years. 2, 3

Do not initiate progesterone therapy in women over 65 for chronic disease prevention - this is explicitly contraindicated as it increases morbidity and mortality without benefit. 3, 6