Can micronised progesterone (a progestogen) cause mild transaminitis (elevations in liver enzymes such as alanine transaminase (ALT) and aspartate transaminase (AST)) in patients, particularly those with a history of liver disease?

Can Micronised Progesterone Cause Mild Transaminitis?

Yes, micronised progesterone can cause mild transaminitis, particularly when used at high doses during pregnancy, with elevations in ALT and AST documented in clinical studies and case reports. 1, 2, 3

Evidence from FDA Drug Label

The FDA-approved prescribing information for progesterone capsules explicitly lists hepatotoxicity as a recognized adverse effect 1:

• Gastrointestinal/Hepatic adverse reactions include: acute pancreatitis, cholestasis, cholestatic hepatitis, hepatic failure, hepatic necrosis, hepatitis, and increased liver function tests (including alanine aminotransferase increased, aspartate aminotransferase increased, gamma-glutamyl transferase increased) 1
• These reactions were identified through postmarketing surveillance, indicating they occur in real-world clinical practice 1

Clinical Evidence from Research Studies

High-Dose Use in Pregnancy

A prospective, double-blind, placebo-controlled study of 201 pregnant women provides the strongest evidence for progesterone-induced transaminitis 3:

• Women receiving micronised progesterone 900-1200 mg/day during the third trimester showed significantly more frequent transaminase elevations compared to placebo 3
• 6 patients (3.4%) developed elevated AST, all in the progesterone group (p < 0.001) 3
• 10 patients (5.6%) developed elevated ALT, all in the progesterone group (p < 0.001) 3
• 18 patients in the progesterone group versus 8 in placebo developed elevated total biliary acids >10 μmol/L (p = 0.004) 3

Case Series of Drug-Induced Hepatitis

A French case series documented 4 patients who developed drug-induced hepatitis while receiving micronised progesterone for preterm labor 2:

• Primary manifestation was pruritus 2
• After drug withdrawal, transaminase levels continued to rise for one week, then normalized within 10-30 days 2
• The causality assessment determined the adverse effect was "likely" related to progesterone 2

Clinical Pattern and Time Course

The hepatotoxicity pattern typically presents as: 2, 3

• Cholestatic and/or cytolytic hepatic disorders with elevated transaminases 3
• Pruritus as the predominant clinical symptom 2
• Transaminase elevations that may paradoxically continue to rise for approximately one week after drug discontinuation 2
• Resolution within 10-30 days after stopping the medication 2

Dose-Dependent Risk

The risk appears related to dosage 3:

• Standard doses (200-400 mg/day) used in postmenopausal hormone therapy showed minimal hepatic effects in clinical trials 1
• High doses (900-1200 mg/day) used for preterm labor prevention carry significantly higher risk 3
• This high-dose use is common in France but represents off-label prescribing beyond approved indications 2, 3

Clinical Implications for Monitoring

For patients with pre-existing liver disease or those receiving high-dose progesterone: 2, 3

• Monitor for pruritus as an early warning sign of hepatotoxicity 2
• Consider baseline and periodic liver enzyme monitoring, particularly with doses >400 mg/day 3
• Be aware that transaminase elevations may worsen transiently after drug discontinuation before improving 2
• Expect normalization within 2-4 weeks if progesterone is the causative agent 2

Important Caveats

The effectiveness of micronised progesterone for preventing preterm delivery remains unproven, making the risk-benefit calculation particularly important when considering high-dose use 2. The drug should be used cautiously, with heightened vigilance for hepatotoxicity, especially in patients presenting with pruritus 2.

In patients with unexplained transaminitis, progesterone should be included in the comprehensive medication review as part of the evaluation for drug-induced liver injury 1, 2.