Tissue Glucocorticoid Metabolism in Adrenal Insufficiency: A Prospective Study of Dual-release Hydrocortisone Therapy

Rosemary A Dineen; Julie Martin-Grace; Khalid Mohamed Saeed Ahmed; Angela E Taylor; Fozia Shaheen; Lina Schiffer; Lorna C Gilligan; Gareth G Lavery; Isolda Frizelle; Anjuli Gunness; Aoife Garrahy; Anne Marie Hannon; Paal Methlie; Sverre Husebye Eystein; Paul M Stewart; Jeremy W Tomlinson; James M Hawley; Brian G Keevil; Michael W O’reilly; Diarmuid Smith; John Mcdermott; Marie-Louise Healy; Amar Agha; Agnieszka Pazderska; James Gibney; Lucy-Ann Behan; Christopher J Thompson; Wiebke Arlt; Mark Sherlock

doi:10.1210/clinem/dgad370

Tissue Glucocorticoid Metabolism in Adrenal Insufficiency: A Prospective Study of Dual-release Hydrocortisone Therapy

Rosemary A Dineen, Julie Martin-Grace, Khalid Mohamed Saeed Ahmed, Angela E Taylor, Fozia Shaheen, Lina Schiffer, Lorna C Gilligan, Gareth G Lavery, Isolda Frizelle, Anjuli Gunness, Aoife Garrahy, Anne Marie Hannon, Paal Methlie, Sverre Husebye Eystein, Paul M Stewart, Jeremy W Tomlinson, James M Hawley, Brian G Keevil, Michael W O’reilly, Diarmuid SmithJohn Mcdermott, Marie-Louise Healy, Amar Agha, Agnieszka Pazderska, James Gibney, Lucy-Ann Behan, Christopher J Thompson, Wiebke Arlt, Mark Sherlock^*

^*Corresponding author for this work

Metabolism and Systems Research

Research output: Contribution to journal › Article › peer-review

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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.

Original language	English
Pages (from-to)	3178–3189
Number of pages	12
Journal	Journal of Clinical Endocrinology and Metabolism
Volume	108
Issue number	12
Early online date	20 Jun 2023
DOIs	https://doi.org/10.1210/clinem/dgad370
Publication status	Published - Dec 2023

Bibliographical note

Funding:
R.D. is funded by the Irish Research Council, The Meath Foundation, and The Irish Endocrine Society. M.S. has received funding for this Investigator-Initiated Study from Shire (IE). The funders of the study had no role in the study design, data collection, data analysis, data interpretation, writing of the report, or the decision to submit for publication. The corresponding author had full access to all the data in the study and had the final responsibility for the decision to submit for publication.

Keywords

cortisol
adrenal insufficiency
11beta-hydroxysteroid dehydrogenase
metabolism

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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., ... Sherlock, M. (2023). Tissue Glucocorticoid Metabolism in Adrenal Insufficiency: A Prospective Study of Dual-release Hydrocortisone Therapy. Journal of Clinical Endocrinology and Metabolism, 108(12), 3178–3189. https://doi.org/10.1210/clinem/dgad370

@article{a00ba64b4e954dc8883e8acc91ac1720,

title = "Tissue Glucocorticoid Metabolism in Adrenal Insufficiency: A Prospective Study of Dual-release Hydrocortisone Therapy",

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{\textregistered}), 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.",

keywords = "cortisol, adrenal insufficiency, 11beta-hydroxysteroid dehydrogenase, metabolism",

author = "Dineen, {Rosemary A} and Julie Martin-Grace and Ahmed, {Khalid Mohamed Saeed} and Taylor, {Angela E} and Fozia Shaheen and Lina Schiffer and Gilligan, {Lorna C} and Lavery, {Gareth G} and Isolda Frizelle and Anjuli Gunness and Aoife Garrahy and Hannon, {Anne Marie} and Paal Methlie and Eystein, {Sverre Husebye} and Stewart, {Paul M} and Tomlinson, {Jeremy W} and Hawley, {James M} and Keevil, {Brian G} and O{\textquoteright}reilly, {Michael W} and Diarmuid Smith and John Mcdermott and Marie-Louise Healy and Amar Agha and Agnieszka Pazderska and James Gibney and Lucy-Ann Behan and Thompson, {Christopher J} and Wiebke Arlt and Mark Sherlock",

note = "Funding: R.D. is funded by the Irish Research Council, The Meath Foundation, and The Irish Endocrine Society. M.S. has received funding for this Investigator-Initiated Study from Shire (IE). The funders of the study had no role in the study design, data collection, data analysis, data interpretation, writing of the report, or the decision to submit for publication. The corresponding author had full access to all the data in the study and had the final responsibility for the decision to submit for publication.",

year = "2023",

month = dec,

doi = "10.1210/clinem/dgad370",

language = "English",

volume = "108",

pages = "3178–3189",

journal = "Journal of Clinical Endocrinology and Metabolism",

issn = "0021-972X",

publisher = "Endocrine Society",

number = "12",

}

Dineen, RA, Martin-Grace, J, Ahmed, KMS, Taylor, AE, Shaheen, F, Schiffer, L , Gilligan, LC, Lavery, GG, 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 & Sherlock, M 2023, 'Tissue Glucocorticoid Metabolism in Adrenal Insufficiency: A Prospective Study of Dual-release Hydrocortisone Therapy', Journal of Clinical Endocrinology and Metabolism, vol. 108, no. 12, pp. 3178–3189. https://doi.org/10.1210/clinem/dgad370

TY - JOUR

T1 - Tissue Glucocorticoid Metabolism in Adrenal Insufficiency

T2 - A Prospective Study of Dual-release Hydrocortisone Therapy

AU - Dineen, Rosemary A

AU - Martin-Grace, Julie

AU - Ahmed, Khalid Mohamed Saeed

AU - Taylor, Angela E

AU - Shaheen, Fozia

AU - Schiffer, Lina

AU - Gilligan, Lorna C

AU - Lavery, Gareth G

AU - Frizelle, Isolda

AU - Gunness, Anjuli

AU - Garrahy, Aoife

AU - Hannon, Anne Marie

AU - Methlie, Paal

AU - Eystein, Sverre Husebye

AU - Stewart, Paul M

AU - Tomlinson, Jeremy W

AU - Hawley, James M

AU - Keevil, Brian G

AU - O’reilly, Michael W

AU - Smith, Diarmuid

AU - Mcdermott, John

AU - Healy, Marie-Louise

AU - Agha, Amar

AU - Pazderska, Agnieszka

AU - Gibney, James

AU - Behan, Lucy-Ann

AU - Thompson, Christopher J

AU - Arlt, Wiebke

AU - Sherlock, Mark

N1 - Funding: R.D. is funded by the Irish Research Council, The Meath Foundation, and The Irish Endocrine Society. M.S. has received funding for this Investigator-Initiated Study from Shire (IE). The funders of the study had no role in the study design, data collection, data analysis, data interpretation, writing of the report, or the decision to submit for publication. The corresponding author had full access to all the data in the study and had the final responsibility for the decision to submit for publication.

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

KW - cortisol

KW - adrenal insufficiency

KW - 11beta-hydroxysteroid dehydrogenase

KW - metabolism

U2 - 10.1210/clinem/dgad370

DO - 10.1210/clinem/dgad370

M3 - Article

SN - 0021-972X

VL - 108

SP - 3178

EP - 3189

JO - Journal of Clinical Endocrinology and Metabolism

JF - Journal of Clinical Endocrinology and Metabolism

IS - 12

ER -

Tissue Glucocorticoid Metabolism in Adrenal Insufficiency: A Prospective Study of Dual-release Hydrocortisone Therapy

Abstract

Bibliographical note

Keywords

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