FKBP5 methylation in adrenal insufficiency: New insights into assessing the quality of glucocorticoid replacement

Irina Chifu; Anna-Lena Richter; Juliane Lippert; Mario Detomas; Carolin Scheuermann; Sabine Herterich; Janik Freytag; Barbara Altieri; Stefanie Hahner

doi:10.1530/endoabs.99.OC11.6

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Endocrine Abstracts (2024) 99 OC11.6 | DOI: 10.1530/endoabs.99.OC11.6

ECE2024 Oral Communications Oral Communications 11: Adrenal and Cardiovascular Endocrinology | Part II (6 abstracts)

FKBP5 methylation in adrenal insufficiency: New insights into assessing the quality of glucocorticoid replacement

Irina Chifu ¹ , Anna-Lena Richter ¹ , Juliane Lippert ¹ , Mario Detomas ¹ , Carolin Scheuermann ¹ , Sabine Herterich ² , Janik Freytag ¹ , Barbara Altieri ¹ & Stefanie Hahner ¹

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¹University Hospital of Würzburg, Endocrinology and Diabetes, Würzburg; ²University Hospital of Würzburg, Clinical Chemistry and Laboratory Medicine, Würzburg

Introduction: Methylation of FKBP5, a glucocorticoid(GC)-receptor co-chaperone, negatively correlates with cortisol levels in both healthy and hypercortisolaemic individuals, and may serve as an indicator of GC exposure. We explored whether GC replacement correlates with FKBP5 methylation levels in patients with adrenal insufficiency (AI), aiming to assess the adequacy of substitution therapy.

Methods: In 122 patients with chronic primary (n=73) and secondary (n=49) AI on hydrocortisone replacement, we analyzed FKBP5 gene methylation at 54 CpG sites in introns, promoters, and proximal enhancers using bisulfite pyrosequencing. 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 between AI patients, patients with cortisol-producing adenomas (CPA, n=64) and patients with non-functioning adrenal adenomas (NFA, n=46).

Results: Significant negative correlations were found between FKBP5 methylation levels in various regions and GC dose, clinical GC-replacement score, salivary/urinary cortisol levels, persisting after adjusting for sex and FKBP5 polymorphisms. 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 and NFA.

Conclusion: Findings suggest a dose-dependent impact of GC replacement on FKBP5 methylation. The alignment between methylation and clinical evaluation encourages further investigations with regard to an additional benefit in the assessment of replacement therapy. The unexpected observation of partially lower methylation in patients with AI compared to CPA and NFA raises the hypothesis that cortisol peaks in AI patients under conventional treatment have a relevant impact on FKBP5-methylation.