Can testosterone supplementation cause low alkaline phosphatase levels?

Testosterone Supplementation Can Affect Alkaline Phosphatase Levels

Yes, testosterone supplementation can cause changes in alkaline phosphatase (ALP) levels, with studies showing that liver enzyme measurements including ALP shift toward the affirmed gender reference range when individuals are on gender-affirming hormone therapy. 1

Mechanism and Evidence

Testosterone administration affects liver function parameters in several ways:

• According to the 2025 guidelines from the Multinational Association of Supportive Care in Cancer, liver enzyme measurements (including alkaline phosphatase) shift toward the affirmed gender when individuals are on gender-affirming testosterone for at least 12 months 1

• The shift in alkaline phosphatase appears to be related to the hormonal effects of testosterone on hepatic cells:

  • Testosterone exerts epigenetic changes on cell behavior through DNA acetylation and methylation
  • These changes affect human physiology and drug metabolism mechanisms in hepatic cells 1

• Laboratory values are dynamic and depend on whether the individual is receiving hormone therapy at the time of testing, with values typically returning to baseline within 3 months after discontinuation 1

Clinical Implications

When interpreting alkaline phosphatase results in patients on testosterone therapy:

• For patients on testosterone for less than 12 months:

  • Put results in context of type, dose, and duration of therapy
  • Values may change over time as treatment continues 1

• For patients on testosterone for 12 months or longer:

  • Interpret results within the reference range for the affirmed gender 1

• If testosterone has been stopped for 3 months or more:

  • Interpret results using reference range for sex assigned at birth 1

Monitoring Recommendations

The New England Journal of Medicine guidelines on testosterone replacement therapy note:

• Intramuscular injections and transdermal preparations do not appear to be associated with significant hepatic dysfunction 1
• Routine monitoring with liver function tests is not considered necessary for men receiving these forms of testosterone supplementation 1
• However, oral forms of testosterone available in the US are strongly discouraged due to associated hepatotoxicity 1

Important Considerations

When evaluating abnormal alkaline phosphatase levels in patients on testosterone:

• Consider the timing of testosterone administration relative to laboratory testing
• Be aware that discontinuation of testosterone or modifications in dosing over time will likely influence reference ranges 1
• Clinical judgment should be used when interpreting laboratory values that fall outside reference ranges, considering:
  • The implications of potentially aberrant values
  • The possibility of monitoring the laboratory value over time
  • The best interests of the patient 1

Potential Confounding Factors

• Assay interference can occur with certain medications that affect alkaline phosphatase
• When laboratory results are discordant or don't match clinical impression, consider the possibility of assay interference 2
• Alternative laboratory methods free of interference should be selected to evaluate these patients when necessary 2

Remember that the categorical nature of reference ranges for gender-diverse patients should not undermine the non-binary nature of gender itself, and GAHT dosing is not standardized, which might also influence reference ranges 1.