Is Clomifene (Clomid) hepatotoxic?

Clomifene (Clomid) Hepatotoxicity

Clomifene citrate is contraindicated in patients with liver disease or a history of liver dysfunction due to its potential hepatotoxic effects. 1

Mechanism and Evidence of Hepatotoxicity

Clomifene citrate, commonly known as Clomid, is a selective estrogen receptor modulator used primarily for ovulation induction in women and to increase semen production in men. The FDA drug label explicitly lists liver disease as a contraindication for clomifene use, indicating recognition of its potential hepatotoxic effects 1.

The mechanism of liver injury caused by clomifene citrate is not fully understood, but case reports have documented its hepatotoxic potential:

• A case report described a 31-year-old male who developed significant liver injury after just 5 days of clomifene treatment, presenting with elevated AST and ALT levels, upper abdominal pain, and reddish-brown urine 2
• The patient's liver function tests normalized after discontinuation of clomifene and supportive care

Risk Assessment

The risk of hepatotoxicity from clomifene appears to be rare but significant enough to warrant caution. Several factors should be considered:

• Most patients tolerate clomifene without liver-related adverse effects
• A study examining liver function in women with polycystic ovary syndrome (PCOS) found that clomifene did not adversely affect liver function and actually showed modest improvements in liver transaminase levels in some patients 3
• However, individual susceptibility may vary, possibly related to genetic polymorphisms in drug-metabolizing enzymes such as CYP2D6 2

Recommendations for Clinical Practice

1. Pre-treatment evaluation:

   • Obtain baseline liver function tests before initiating clomifene therapy
   • Thoroughly screen for any history of liver dysfunction or disease

2. Absolute contraindications:

   • Active liver disease
   • History of liver dysfunction
   • Abnormal baseline liver function tests

3. Monitoring during treatment:

   • Monitor for symptoms of liver injury (abdominal pain, jaundice, dark urine)
   • Consider periodic liver function testing, especially in patients with risk factors
   • Immediately discontinue clomifene if signs of liver injury develop

4. Patient education:

   • Inform patients about potential symptoms of liver injury
   • Advise immediate medical attention if such symptoms develop

Special Considerations

For patients with other risk factors for liver disease (such as alcohol use, obesity, or concurrent hepatotoxic medications), extra caution is warranted. The principles applied to other potentially hepatotoxic medications should be followed, including:

• Avoiding concurrent use of other hepatotoxic drugs
• More frequent monitoring of liver function
• Lower threshold for discontinuation if abnormalities develop

Conclusion

While clomifene-induced hepatotoxicity appears to be uncommon, its potential for causing liver injury is recognized in the FDA labeling as a contraindication. Clinicians should follow the contraindication guidance and avoid prescribing clomifene to patients with existing liver disease or dysfunction to prevent potentially serious adverse outcomes affecting morbidity and mortality.