{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T11:09:10Z","timestamp":1792840150855,"version":"4.5.0"},"reference-count":35,"publisher":"The Endocrine Society","issue":"2","license":[{"start":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T00:00:00Z","timestamp":1751500800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,1,21]]},"abstract":"Abstract<\/jats:title>\n \n Context<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>\n \n Objective<\/jats:title>\n We explored whether GC replacement correlates with FKBP5 methylation in patients with adrenal insufficiency (AI), aiming to assess the adequacy of therapy.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n In an explorative cross-sectional analysis, we analyzed 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).<\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n Significant negative correlations were found between methylation levels and GC dose, clinical GC replacement score, and 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.<\/jats:p>\n <\/jats:sec>\n \n Conclusion<\/jats:title>\n 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.<\/jats:p>\n <\/jats:sec>","DOI":"10.1210\/clinem\/dgaf383","type":"journal-article","created":{"date-parts":[[2025,7,3]],"date-time":"2025-07-03T07:57:12Z","timestamp":1751529432000},"page":"427-436","source":"Crossref","is-referenced-by-count":2,"title":["FKBP5<\/i>\n Methylation in Adrenal Insufficiency: New Insights Into Assessing the Quality of Glucocorticoid Replacement"],"prefix":"10.1210","volume":"111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6741-2689","authenticated-orcid":false,"given":"Irina","family":"Chifu","sequence":"first","affiliation":[{"name":"Department of Internal Medicine I, Division of Endocrinology and Diabetology, University Hospital of W\u00fcrzburg, University of W\u00fcrzburg , W\u00fcrzburg 97080 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna-Lena","family":"Richter","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Division of Endocrinology and Diabetology, University Hospital of W\u00fcrzburg, University of W\u00fcrzburg , W\u00fcrzburg 97080 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliane","family":"Lippert","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Division of Endocrinology and Diabetology, University Hospital of W\u00fcrzburg, University of W\u00fcrzburg , W\u00fcrzburg 97080 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1490-5575","authenticated-orcid":false,"given":"Mario","family":"Detomas","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Division of Endocrinology and Diabetology, University Hospital of W\u00fcrzburg, University of W\u00fcrzburg , W\u00fcrzburg 97080 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolin","family":"Scheuermann","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Division of Endocrinology and Diabetology, University Hospital of W\u00fcrzburg, University of W\u00fcrzburg , W\u00fcrzburg 97080 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"Herterich","sequence":"additional","affiliation":[{"name":"Clinical Chemistry and Laboratory Medicine, University Hospital of Wuerzburg , Wuerzburg 97080 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Birgit","family":"Harbeck","sequence":"additional","affiliation":[{"name":"III. Department of Medicine, University Medical Center Hamburg-Eppendorf , Hamburg 20251 ,","place":["Germany"]},{"name":"MVZ Amedes Experts, Endocrinology , Hamburg 20095 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janik","family":"Freytag","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Division of Endocrinology and Diabetology, University Hospital of W\u00fcrzburg, University of W\u00fcrzburg , W\u00fcrzburg 97080 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2616-3249","authenticated-orcid":false,"given":"Barbara","family":"Altieri","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Division of Endocrinology and Diabetology, University Hospital of W\u00fcrzburg, University of W\u00fcrzburg , W\u00fcrzburg 97080 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"Hahner","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine I, Division of Endocrinology and Diabetology, University Hospital of W\u00fcrzburg, University of W\u00fcrzburg , W\u00fcrzburg 97080 ,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2025,7,3]]},"reference":[{"issue":"12","key":"2026012101520356000_dgaf383-B1","doi-asserted-by":"crossref","first-page":"4849","DOI":"10.1210\/jc.2006-0076","article-title":"Premature mortality in patients with Addison's disease: a population-based study","volume":"91","author":"Bergthorsdottir","year":"2006","journal-title":"J Clin Endocrinol Metab"},{"key":"2026012101520356000_dgaf383-B2","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1159\/000443918","article-title":"Quality of life and life expectancy in patients with adrenal insufficiency: what is true and what is urban myth?","volume":"46","author":"Burger-Stritt","year":"2016","journal-title":"Front Horm Res"},{"issue":"12","key":"2026012101520356000_dgaf383-B3","doi-asserted-by":"crossref","first-page":"4882","DOI":"10.1210\/jc.2009-1368","article-title":"Clinical, immunological, and genetic features of autoimmune primary adrenal insufficiency: observations from a Norwegian registry","volume":"94","author":"Erichsen","year":"2009","journal-title":"J Clin Endocrinol Metab"},{"issue":"5","key":"2026012101520356000_dgaf383-B4","doi-asserted-by":"crossref","first-page":"1284","DOI":"10.1210\/clinem\/dgab063","article-title":"Cardiovascular disease in patients with primary and secondary adrenal insufficiency and the role of comorbidities","volume":"106","author":"Ngaosuwan","year":"2021","journal-title":"J Clin Endocrinol Metab"},{"issue":"7","key":"2026012101520356000_dgaf383-B5","doi-asserted-by":"crossref","first-page":"e2759","DOI":"10.1210\/clinem\/dgab096","article-title":"Increased mortality risk in patients with primary and secondary adrenal insufficiency","volume":"106","author":"Ngaosuwan","year":"2021","journal-title":"J Clin Endocrinol Metab"},{"issue":"10","key":"2026012101520356000_dgaf383-B6","doi-asserted-by":"crossref","first-page":"3954","DOI":"10.1210\/jc.2006-0524","article-title":"The impact of glucocorticoid replacement regimens on metabolic outcome and comorbidity in hypopituitary patients","volume":"91","author":"Filipsson","year":"2006","journal-title":"J Clin Endocrinol Metab"},{"issue":"6","key":"2026012101520356000_dgaf383-B7","doi-asserted-by":"crossref","first-page":"2031","DOI":"10.1210\/jc.2018-02298","article-title":"Sex-specific risk of cardiovascular disease in autoimmune addison disease-a population-based cohort study","volume":"104","author":"Skov","year":"2019","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"2026012101520356000_dgaf383-B8","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1111\/cen.13609","article-title":"Mortality data from the European adrenal insufficiency registry-patient characterization and associations","volume":"89","author":"Quinkler","year":"2018","journal-title":"Clin Endocrinol (Oxf)"},{"issue":"12","key":"2026012101520356000_dgaf383-B9","doi-asserted-by":"crossref","first-page":"4843","DOI":"10.1210\/jc.2016-2221","article-title":"Exploring inpatient hospitalizations and morbidity in patients with adrenal insufficiency","volume":"101","author":"Stewart","year":"2016","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"2026012101520356000_dgaf383-B10","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1111\/gbb.12104","article-title":"Gene-environment interactions at the FKBP5 locus: sensitive periods, mechanisms and pleiotropism","volume":"13","author":"Zannas","year":"2014","journal-title":"Genes Brain Behav"},{"issue":"1","key":"2026012101520356000_dgaf383-B11","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/npp.2015.235","article-title":"Gene-stress-epigenetic regulation of FKBP5: clinical and translational implications","volume":"41","author":"Zannas","year":"2016","journal-title":"Neuropsychopharmacology"},{"issue":"3","key":"2026012101520356000_dgaf383-B12","doi-asserted-by":"crossref","first-page":"bvaa202","DOI":"10.1210\/jendso\/bvaa202","article-title":"Potential transcriptional biomarkers to guide glucocorticoid replacement in autoimmune Addison's disease","volume":"5","author":"S\u00e6vik","year":"2021","journal-title":"J Endocr Soc"},{"key":"2026012101520356000_dgaf383-B13","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.psyneuen.2018.11.033","article-title":"Temporal dynamics of cortisol-associated changes in mRNA expression of glucocorticoid responsive genes FKBP5, GILZ, SDPR, PER1, PER2 and PER3 in healthy humans","volume":"102","author":"Yurtsever","year":"2019","journal-title":"Psychoneuroendocrinology"},{"issue":"12","key":"2026012101520356000_dgaf383-B14","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1002\/da.22430","article-title":"HPA axis related genes and response to psychological therapies: genetics and epigenetics","volume":"32","author":"Roberts","year":"2015","journal-title":"Depress Anxiety"},{"key":"2026012101520356000_dgaf383-B15","doi-asserted-by":"crossref","first-page":"118","DOI":"10.3389\/fpsyt.2013.00118","article-title":"Epigenetic biomarkers as predictors and correlates of symptom improvement following psychotherapy in combat veterans with PTSD","volume":"4","author":"Yehuda","year":"2013","journal-title":"Front Psychiatry"},{"issue":"1","key":"2026012101520356000_dgaf383-B16","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/npp.2015.235","article-title":"Gene\u2013stress\u2013epigenetic regulation of FKBP5: clinical and translational implications","volume":"41","author":"Zannas","year":"2016","journal-title":"Neuropsychopharmacology"},{"issue":"9","key":"2026012101520356000_dgaf383-B17","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1080\/15592294.2021.1980688","article-title":"Methylation of FKBP5 is associated with accelerated DNA methylation ageing and cardiometabolic risk: replication in young-adult and middle-aged black Americans","volume":"17","author":"Beach","year":"2022","journal-title":"Epigenetics"},{"issue":"23","key":"2026012101520356000_dgaf383-B18","doi-asserted-by":"crossref","first-page":"11370","DOI":"10.1073\/pnas.1816847116","article-title":"Epigenetic upregulation of FKBP5 by aging and stress contributes to NF-\u03baB-driven inflammation and cardiovascular risk","volume":"116","author":"Zannas","year":"2019","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2026012101520356000_dgaf383-B19","doi-asserted-by":"crossref","first-page":"44445","DOI":"10.1038\/srep44445","article-title":"Reduced DNA methylation and psychopathology following endogenous hypercortisolism\u2014a genome-wide study","volume":"7","author":"Glad","year":"2017","journal-title":"Sci Rep"},{"key":"2026012101520356000_dgaf383-B20","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.psyneuen.2018.07.003","article-title":"DNA methylation and sex-specific expression of FKBP5 as correlates of one-month bedtime cortisol levels in healthy individuals","volume":"97","author":"Lee","year":"2018","journal-title":"Psychoneuroendocrinology"},{"issue":"5","key":"2026012101520356000_dgaf383-B21","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1093\/ejendo\/lvad149","article-title":"Predisposing factors for adrenal crisis in chronic adrenal insufficiency: a case-control study","volume":"189","author":"Chifu","year":"2023","journal-title":"Eur J Endocrinol"},{"issue":"1","key":"2026012101520356000_dgaf383-B22","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1186\/s13148-019-0682-5","article-title":"Identification of dynamic glucocorticoid-induced methylation changes at the FKBP5 locus","volume":"11","author":"Wiechmann","year":"2019","journal-title":"Clin Epigenetics"},{"issue":"10","key":"2026012101520356000_dgaf383-B23","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.2217\/epi-2017-0057","article-title":"FKBP5 methylation as a possible marker for cortisol state and transient cortisol exposure in healthy human subjects","volume":"9","author":"Winkler","year":"2017","journal-title":"Epigenomics"},{"key":"2026012101520356000_dgaf383-B24","unstructured":"Chifu I RA, Lippert J, Detomas M, et al \u00a0Supplementary material. Dataset. Figshare. 2025. 10.6084\/m9.figshare.28924529 (Data available at Figshare: https:\/\/figshare.com\/s\/d48de9f74823eca74686)"},{"issue":"10","key":"2026012101520356000_dgaf383-B25","doi-asserted-by":"crossref","first-page":"2892","DOI":"10.1210\/clinem\/dgac470","article-title":"Prognostic role of targeted methylation analysis in paraffin-embedded samples of adrenocortical carcinoma","volume":"107","author":"Lippert","year":"2022","journal-title":"J Clin Endocrinol Metab"},{"issue":"6","key":"2026012101520356000_dgaf383-B26","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1530\/EJE-19-0872","article-title":"Reference intervals of salivary cortisol and cortisone and their diagnostic accuracy in Cushing's syndrome","volume":"182","author":"B\u00e4cklund","year":"2020","journal-title":"Eur J Endocrinol"},{"issue":"4","key":"2026012101520356000_dgaf383-B27","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1111\/j.1365-2265.2006.02473.x","article-title":"Quality of glucocorticoid replacement in adrenal insufficiency: clinical assessment vs. timed serum cortisol measurements","volume":"64","author":"Arlt","year":"2006","journal-title":"Clin Endocrinol (Oxf)"},{"issue":"3","key":"2026012101520356000_dgaf383-B28","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1530\/EJE-22-0396","article-title":"Non-invasive assessment of tissue sodium content in patients with primary adrenal insufficiency","volume":"187","author":"Chifu","year":"2022","journal-title":"Eur J Endocrinol"},{"issue":"3","key":"2026012101520356000_dgaf383-B29","doi-asserted-by":"crossref","first-page":"768","DOI":"10.1007\/s12020-016-1083-6","article-title":"Reduced DNA methylation of FKBP5 in Cushing's syndrome","volume":"54","author":"Resmini","year":"2016","journal-title":"Endocrine"},{"issue":"1","key":"2026012101520356000_dgaf383-B30","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1038\/nn.3275","article-title":"Allele-specific FKBP5 DNA demethylation mediates gene-childhood trauma interactions","volume":"16","author":"Klengel","year":"2013","journal-title":"Nat Neurosci"},{"issue":"7","key":"2026012101520356000_dgaf383-B31","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1055\/a-1719-5381","article-title":"Diurnal salivary cortisol profiles in patients with Cushing's syndrome","volume":"130","author":"Braun","year":"2022","journal-title":"Exp Clin Endocrinol Diabetes"},{"issue":"2","key":"2026012101520356000_dgaf383-B32","first-page":"230","article-title":"The 24-h cortisol secretory pattern in Cushing's syndrome","volume":"112","author":"Tourniaire","year":"1986","journal-title":"Acta Endocrinol (Copenh)"},{"issue":"2","key":"2026012101520356000_dgaf383-B33","first-page":"319","article-title":"Plasma cortisol profiles in Cushing's syndrome","volume":"91","author":"Yoshida","year":"1979","journal-title":"Acta Endocrinol (Copenh)"},{"issue":"7","key":"2026012101520356000_dgaf383-B34","first-page":"2468","article-title":"Effects of gender and age on the levels and circadian rhythmicity of plasma cortisol","volume":"81","author":"Van Cauter","year":"1996","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"2026012101520356000_dgaf383-B35","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1186\/s13148-022-01347-y","article-title":"Whole blood methylome-derived features to discriminate endocrine hypertension","volume":"14","author":"Armignacco","year":"2022","journal-title":"Clin Epigenetics"}],"container-title":["The Journal of Clinical Endocrinology & Metabolism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jcem\/advance-article-pdf\/doi\/10.1210\/clinem\/dgaf383\/63662073\/dgaf383.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcem\/article-pdf\/111\/2\/427\/63662073\/dgaf383.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcem\/article-pdf\/111\/2\/427\/63662073\/dgaf383.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T06:52:15Z","timestamp":1768978335000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/111\/2\/427\/8185527"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,3]]},"references-count":35,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2025,7,3]]},"published-print":{"date-parts":[[2026,1,21]]}},"URL":"https:\/\/doi.org\/10.1210\/clinem\/dgaf383","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,2]]},"published":{"date-parts":[[2025,7,3]]}}}