Can testosterone therapy in adult men elevate homocysteine levels?

Testosterone Therapy Can Elevate Homocysteine Levels in Adult Men

Testosterone therapy can increase plasma total homocysteine (tHcy) levels in adult men, which may potentially contribute to cardiovascular risk.

Evidence on Testosterone and Homocysteine

The relationship between testosterone therapy and homocysteine levels has been examined in several studies with varying populations:

• In men with Klinefelter's syndrome, supraphysiologic doses of testosterone administered for 6 months significantly increased plasma tHcy concentrations 1. This study provides the strongest evidence for a direct effect of testosterone therapy on homocysteine levels.

• A study in female-to-male transsexuals showed that testosterone administration increased plasma tHcy levels from 7.7 μmol/L to 9.0 μmol/L (p=0.005), while estrogen plus antiandrogen administration to male-to-female transsexuals decreased tHcy levels 2. This bidirectional effect supports the role of sex hormones in regulating homocysteine levels.

• However, short-term high-dose testosterone administration (3 weeks) did not significantly affect fasting tHcy levels in normal male weightlifters 3, suggesting that duration of therapy may be important.

Clinical Significance of Elevated Homocysteine

Elevated homocysteine levels are associated with:

• Increased risk for atherosclerotic cardiovascular disease 4
• Graded cardiovascular risk with no threshold 5
• Enhanced effect when combined with conventional risk factors 5
• Strong prediction of cardiovascular mortality 5

Cardiovascular Risk Considerations with Testosterone Therapy

The American College of Physicians guideline on testosterone treatment in adult men notes:

• Low-certainty evidence from 14 trials showed a small increase to no difference in adverse cardiovascular events (Peto odds ratio, 1.22 [CI, 0.66 to 2.23]) 6
• Most studies excluded men with recent cardiovascular disease, limiting generalizability to higher-risk populations 6, 7

Monitoring and Risk Assessment

When considering testosterone therapy, clinicians should:

• Assess baseline cardiovascular risk factors before initiating therapy
• Consider that the combination of testosterone-induced elevated homocysteine and other risk factors may increase cardiovascular risk
• Monitor for cardiovascular symptoms during treatment
• Consider periodic homocysteine level measurements in patients with pre-existing cardiovascular disease or risk factors

Practical Recommendations

1. Before initiating testosterone therapy:

   • Assess baseline cardiovascular risk
   • Consider measuring baseline homocysteine levels in high-risk patients

2. During testosterone therapy:

   • Monitor for cardiovascular symptoms
   • Consider periodic homocysteine measurements in high-risk patients
   • Be particularly vigilant in patients with Klinefelter's syndrome or other conditions predisposing to cardiovascular disease

3. Risk mitigation:

   • Ensure adequate folate and vitamin B12 status, as deficiencies can exacerbate hyperhomocysteinemia 5
   • Consider the lowest effective dose of testosterone to minimize potential effects on homocysteine

Caveats and Limitations

• The effect of testosterone on homocysteine may vary based on:

  • Duration of therapy (short-term vs. long-term)
  • Dose of testosterone (physiologic vs. supraphysiologic)
  • Route of administration (oral, transdermal, intramuscular)
  • Individual patient factors (genetic predisposition, baseline homocysteine levels)

• Long-term safety data on testosterone therapy targeting upper-normal levels is lacking 7