Progesterone Side Effects
Progesterone carries significant risks including cardiovascular complications (stroke, heart attack, blood clots), breast cancer when combined with estrogen, and common symptoms like drowsiness, dizziness, headaches, and menstrual irregularities, with the severity and type of side effects varying by formulation and route of administration. 1, 2
Serious Cardiovascular and Thromboembolic Risks
Monitor closely for signs of thromboembolism, as progesterone increases risk of blood clots, stroke, and heart attack, particularly when combined with estrogen. 1 The FDA drug label specifically warns about abnormal blood clotting including stroke, heart attack, pulmonary embolus, and visual loss or blindness. 2
Warning Signs Requiring Immediate Medical Attention:
- Changes in vision or speech 2
- Sudden new severe headaches 2
- Severe chest or leg pains with or without shortness of breath 2
- Dizziness and faintness 2
- Weakness and fatigue 2
In postmenopausal women using combined estrogen-progesterone therapy, there is good evidence for increased risk of venous thromboembolism and breast cancer, plus fair-to-good evidence for increased coronary heart disease risk. 3, 1
Neurological and Cognitive Effects
Progesterone commonly causes extreme drowsiness and dizziness, particularly during initial therapy, which can be severe enough to impair driving or operating machinery. 2, 4 The FDA label reports that some women experience blurred vision, difficulty speaking, difficulty walking, and feeling abnormal. 2
To minimize these effects, progesterone capsules should be taken as a single daily dose at bedtime while standing with a glass of water. 2 Despite these precautions, drowsiness and dizziness remain more frequent with micronized progesterone compared to synthetic progestins. 4
Common Side Effects (Less Serious but Frequent)
The FDA label identifies these common adverse effects: 2
- Headaches 2
- Breast pain 2
- Irregular vaginal bleeding or spotting 2
- Stomach or abdominal cramps and bloating 2
- Nausea and vomiting 2
- Hair loss 2
- Fluid retention 2
- Vaginal yeast infection 2
Cancer Risks
Estrogen-alone therapy increases the chance of endometrial hyperplasia that may lead to uterine cancer; progesterone is added specifically to reduce this risk. 2 However, when estrogen and progesterone are combined, there is good evidence for increased breast cancer risk. 3, 1
Pregnancy and Reproductive Risks
Progesterone is contraindicated in pregnancy due to documented fetal risks. 2 The FDA label reports cases of cleft palate, cleft lip, hypospadias, ventricular septal defect, patent ductus arteriosus, and other congenital heart defects. 2
Gastrointestinal Effects
In pregnant women, progesterone can relax the lower esophageal sphincter, facilitating gastroesophageal reflux and heartburn, and inhibit gastrointestinal motility, leading to delayed gastric emptying. 1
Formulation-Specific Considerations
Synthetic progestins (Provera, PremPro, Cycrin) produce more significant side effects than natural progesterone, including fatigue, fluid retention, lipid alterations, dysphoria, hypercoagulant states, and increased androgenicity. 5
Micronized natural progesterone has better bioavailability and fewer side effects than non-micronized natural progesterone, making it the preferred formulation for most clinical applications. 5, 4 It presents a better safety profile regarding metabolic effects, breast cancer risk, and venous thromboembolism risk compared to synthetic progestins. 4
Mood and Psychiatric Effects
Progesterone's effects on mood are complex and potentially bidirectional. 6 While its metabolite allopregnanolone has proven useful for treating postpartum depression, it may trigger negative symptoms in women with premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD). 6
Bone Health Concerns (Depot Formulations)
Depot medroxyprogesterone acetate (DMPA) causes reductions in bone mineral density, though substantial recovery occurs after discontinuation. 3 Current guidelines do not recommend limiting DMPA use to 2 years or routinely monitoring bone density, but all patients should receive counseling about calcium (1300 mg daily), vitamin D (600 IU daily), and weight-bearing exercise. 3
Absolute Contraindications
Do not prescribe progesterone if the patient has: 2
- Peanut allergy (for capsule formulations) 2
- Unusual vaginal bleeding 2
- Current or history of certain cancers 2
- History of stroke or heart attack 2
- Current or history of blood clots 2
- Current or history of liver problems 2
- Pregnancy or suspected pregnancy 2
Monitoring Recommendations
Regular follow-up with healthcare providers is essential for monitoring side effects, especially with long-term use. 1 Patients should have annual pelvic exams, breast exams, and mammograms unless otherwise directed, with more frequent breast surveillance if there is family history of breast cancer or previous breast abnormalities. 2