FKBP5 Methylation in Adrenal Insufficiency: New Insights Into Assessing the Quality of Glucocorticoid Replacement.

FKBP5 methylation negatively correlates with glucocorticoid replacement dose in patients with adrenal insufficiency.

• Analysis performed at 54 CpG sites using bisulfite pyrosequencing in 120 patients with chronic AI on hydrocortisone replacement.
• Cohort included 72 patients with primary AI and 48 with secondary AI.
• Significant negative correlations were found between methylation levels and GC dose.
• The correlation suggests a dose-dependent effect of GC replacement on FKBP5 methylation.

FKBP5 methylation negatively correlates with both salivary cortisol and 24-hour urinary cortisol levels in AI patients.

• Results were correlated with salivary cortisol and 24-hour urinary cortisol as part of the cross-sectional analysis.
• Significant negative correlations were found between methylation levels and salivary cortisol levels.
• Significant negative correlations were found between methylation levels and urinary cortisol levels.
• This pattern is consistent with findings in healthy individuals and Cushing patients where cortisol levels negatively correlate with FKBP5 methylation.

FKBP5 methylation negatively correlates with a predefined clinical score for assessment of glucocorticoid exposure.

• A predefined clinical GC replacement score was used to assess adequacy of therapy.
• Significant negative correlations were found between methylation levels and the clinical GC replacement score.
• This correlation aligns with physician-guided therapy assessments.

Patients advised to increase their GC dose showed higher FKBP5 methylation levels than those recommended to reduce or maintain their dose.

• Physician-guided therapy adjustments were used as a clinical benchmark for comparing methylation levels.
• Patients with higher methylation levels were more likely to be recommended a dose increase, suggesting under-replacement.
• Patients recommended to reduce or maintain their dose had lower methylation levels, suggesting adequate or over-replacement.

AI patients exhibited similar or lower FKBP5 methylation levels compared to patients with cortisol-producing adrenal adenomas (CPA).

• Methylation levels were compared between 120 AI patients and 64 patients with cortisol-producing adrenal adenomas.
• AI patients showed similar or lower methylation compared to CPA patients.
• Lower methylation levels in AI patients compared to CPA suggest a potential impact of cortisol peaks arising under conventional GC treatment on FKBP5 methylation.
• The authors suggest that pulsatile cortisol peaks from conventional GC treatment may drive demethylation of FKBP5.

FKBP5 polymorphisms were assessed as part of the analysis of factors influencing methylation levels.

• FKBP5 polymorphisms were included as a variable in correlations with methylation status.
• The explorative cross-sectional analysis assessed methylation at 54 CpG sites using bisulfite pyrosequencing.
• The study design was cross-sectional and exploratory in nature.