Tissue glucocorticoid metabolism in adrenal insufficiency: a prospective study of dual-release hydrocortisone therapy

Dineen, RA, Martin-Grace, J, Ahmed, KMS, Taylor, AE, Shaheen, F, Schiffer, L, Gilligan, LC, Lavery, GG ORCID: https://orcid.org/0000-0001-5794-748X, Frizelle, I, Gunness, A, Garrahy, A, Hannon, AM, Methlie, P, Eystein, SH, Stewart, PM, Tomlinson, JW, Hawley, JM, Keevil, BG, O’Reilly, MW, Smith, D, McDermott, J, Healy, M-L, Agha, A, Pazderska, A, Gibney, J, Behan, L-A, Thompson, CJ, Arlt, W and Sherlock, M, 2023. Tissue glucocorticoid metabolism in adrenal insufficiency: a prospective study of dual-release hydrocortisone therapy. The Journal of Clinical Endocrinology and Metabolism, 108 (12), pp. 3178-3189. ISSN 0021-972X

Preview

Text 2554510_Lavery.pdf - Published version Download (900kB) | Preview

Abstract

Background: Patients with adrenal insufficiency (AI) require life-long glucocorticoid (GC) replacement therapy. Within tissues, cortisol (F) availability is under the control of the isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD). We hypothesize that corticosteroid metabolism is altered in patients with AI because of the nonphysiological pattern of current immediate release hydrocortisone (IR-HC) replacement therapy. The use of a once-daily dual-release hydrocortisone (DR-HC) preparation, (Plenadren®), offers a more physiological cortisol profile and may alter corticosteroid metabolism in vivo.

Study design and methods: Prospective crossover study assessing the impact of 12 weeks of DR-HC on systemic GC metabolism (urinary steroid metabolome profiling), cortisol activation in the liver (cortisone acetate challenge test), and subcutaneous adipose tissue (microdialysis, biopsy for gene expression analysis) in 51 patients with AI (primary and secondary) in comparison to IR-HC treatment and age- and BMI-matched controls.

Results: Patients with AI receiving IR-HC had a higher median 24-hour urinary excretion of cortisol compared with healthy controls (72.1 µg/24 hours [IQR 43.6-124.2] vs 51.9 µg/24 hours [35.5-72.3], P = .02), with lower global activity of 11β-HSD2 and higher 5-alpha reductase activity. Following the switch from IR-HC to DR-HC therapy, there was a significant reduction in urinary cortisol and total GC metabolite excretion, which was most significant in the evening. There was an increase in 11β-HSD2 activity. Hepatic 11β-HSD1 activity was not significantly altered after switching to DR-HC, but there was a significant reduction in the expression and activity of 11β-HSD1 in subcutaneous adipose tissue.

Conclusion: Using comprehensive in vivo techniques, we have demonstrated abnormalities in corticosteroid metabolism in patients with primary and secondary AI receiving IR-HC. This dysregulation of pre-receptor glucocorticoid metabolism results in enhanced glucocorticoid activation in adipose tissue, which was ameliorated by treatment with DR-HC.

Item Type:	Journal article
Publication Title:	The Journal of Clinical Endocrinology and Metabolism
Creators:	Dineen, R.A., Martin-Grace, J., Ahmed, K.M.S., Taylor, A.E., Shaheen, F., Schiffer, L., Gilligan, L.C., Lavery, G.G., Frizelle, I., Gunness, A., Garrahy, A., Hannon, A.M., Methlie, P., Eystein, S.H., Stewart, P.M., Tomlinson, J.W., Hawley, J.M., Keevil, B.G., O’Reilly, M.W., Smith, D., McDermott, J., Healy, M.-L., Agha, A., Pazderska, A., Gibney, J., Behan, L.-A., Thompson, C.J., Arlt, W. and Sherlock, M.
Publisher:	The Endocrine Society
Date:	December 2023
Volume:	108
Number:	12
ISSN:	0021-972X
Identifiers:	Number Type 10.1210/clinem/dgad370 DOI 2554510 Other
Rights:	© The Author(s) 2023. Published by Oxford University Press on behalf of the Endocrine Society. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Divisions:	Schools > School of Science and Technology
Record created by:	Laura Borcherds
Date Added:	09 Jan 2026 12:07
Last Modified:	09 Jan 2026 12:07
URI:	https://irep.ntu.ac.uk/id/eprint/55006

Actions (login required)

Edit View

Statistics

Views

Downloads