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

Abstract

Context: Methylation of FKBP5, a glucocorticoid(GC)-receptor co-chaperone, negatively correlates with cortisol levels in both healthy individuals and Cushing patients, potentially serving as an indicator of GC exposure.

Objective: We explored whether GC replacement correlates with FKBP5 methylation in patients with adrenal insufficiency (AI), aiming to assess the adequacy of therapy.

Design: Explorative cross-sectional analysis.

Methods: We analysed FKBP5 gene methylation at 54 CpG sites using bisulfite pyrosequencing in 120 patients with chronic primary (n=72) and secondary (n=48) AI on hydrocortisone replacement. Results were correlated with GC replacement, salivary cortisol, 24-hour urinary cortisol, FKBP5 polymorphisms, physician-guided therapy adjustments, and a predefined clinical score for assessment of GC exposure. Methylation levels were further compared with patients with cortisol-producing adrenal adenomas (CPA, n=64).Results: Significant negative correlations were found between methylation levels and GC dose, clinical GC-replacement score, salivary and urinary cortisol levels. Patients advised to increase their GC dose showed higher methylation levels than those recommended to reduce or maintain their dose. AI patients exhibited similar or lower methylation levels compared to those with CPA.

Conclusions: The correlation between FKBP5 methylation status, GC replacement dose, and clinical evaluation of therapy suggests a dose-dependent effect of GC replacement on FKBP5 methylation. This encourages further research into the added value of FKBP5 methylation analysis in assessing the quality of replacement therapy. The lower methylation levels in AI compared to CPA suggest a potential impact of the cortisol peaks arising under conventional GC treatment on FKBP5-methylation.

Keywords: FKBP5; adrenal insufficiency; glucocorticoid replacement; methylation.