What are the side effects of progesterone?

Side Effects of Progesterone

Progesterone can cause significant side effects including drowsiness, dizziness, venous thromboembolism, and mood changes, with severity varying based on administration route and dosage. 1, 2

Common Side Effects

• Neurological effects: Drowsiness and dizziness are among the most common side effects, particularly with oral administration. These can be severe enough to impair driving ability and daily functioning 1, 3

• Gastrointestinal symptoms: Nausea, vomiting, abdominal cramps, and bloating 1

• Reproductive system effects: Irregular vaginal bleeding or spotting, breast pain/tenderness 1

• Other common effects: Fluid retention, hair loss, vaginal yeast infections 1

Serious Side Effects

• Thromboembolism: Progesterone increases risk of blood clots, stroke, and heart attack, particularly when combined with estrogen 4

• Cardiovascular effects: Progesterone can have cardio-depressive effects involving modulation of calcium handling 4

• Mood disturbances: Some patients experience poor mood and psychological side effects 4, 5

Route-Specific Considerations

Oral Administration

Oral micronized progesterone undergoes significant first-pass metabolism (>90%) in the liver, which:

• Results in high levels of progesterone metabolites, particularly those reduced at the 5-alpha position 3
• Causes more pronounced drowsiness and dizziness compared to other routes 3, 2
• May be minimized by taking the medication at bedtime 2, 5

Transdermal/Vaginal Administration

• Generally associated with fewer systemic side effects than oral administration 3
• Vaginal administration provides better uterine uptake with lower systemic levels, resulting in fewer side effects 3

Special Populations

Postmenopausal Women

• When combined with estrogen for hormone replacement therapy, progesterone increases risk of:
  • Breast cancer (though natural progesterone may have lower risk than synthetic progestins) 4, 6
  • Venous thromboembolism 4
  • Stroke 4
  • Cholecystitis (gallbladder inflammation) 4

Pregnant Women

• Progesterone can cause relaxation of the lower esophageal sphincter, facilitating gastroesophageal reflux and heartburn during pregnancy 4
• It can inhibit gastrointestinal and small bowel motility, leading to delayed gastric emptying 4

Risk Mitigation

• Take oral progesterone at bedtime to minimize drowsiness during waking hours 1, 2
• Use caution when driving or operating machinery due to potential dizziness and drowsiness 1
• Consider vaginal administration when appropriate, as it may cause fewer systemic side effects 3
• Monitor for signs of thromboembolism (sudden severe headaches, chest pain, leg pain, vision changes) 1
• Regular follow-up with healthcare providers for monitoring side effects, especially in long-term use 4

Contraindications

Progesterone should not be used in patients with:

• History of breast cancer or certain other cancers 1
• History of stroke or heart attack 1
• Current or past blood clots 1
• Liver problems 1
• Unusual vaginal bleeding 1
• Peanut allergy (specific to some formulations) 1

Comparative Safety Profile

• Natural progesterone appears to have a better safety profile compared to synthetic progestins, particularly regarding:
  • Metabolic effects 2, 5
  • Breast cancer risk 6
  • Venous thromboembolism risk 2
  • Cardiovascular effects 2, 5