Improved Urinary Cortisol Metabolome in Addison Disease: A Prospective Trial of Dual-Release Hydrocortisone

Stéphanie Espiard, Johanna McQueen, Mark Sherlock, Oskar Ragnarsson, Ragnhildur Bergthorsdottir, Pia Burman, Per Dahlqvist, Bertil Ekman, Britt Edén Engström, Stanko Skrtic, Jeanette Wahlberg, Paul M Stewart, Gudmundur Johannsson, Stéphanie Espiard, Johanna McQueen, Mark Sherlock, Oskar Ragnarsson, Ragnhildur Bergthorsdottir, Pia Burman, Per Dahlqvist, Bertil Ekman, Britt Edén Engström, Stanko Skrtic, Jeanette Wahlberg, Paul M Stewart, Gudmundur Johannsson

Abstract

Context: Oral once-daily dual-release hydrocortisone (DR-HC) replacement therapy has demonstrated an improved metabolic profile compared to conventional 3-times-daily (TID-HC) therapy among patients with primary adrenal insufficiency. This effect might be related to a more physiological cortisol profile, but also to a modified pattern of cortisol metabolism.

Objective: This work aimed to study cortisol metabolism during DR-HC and TID-HC.

Design: A randomized, 12-week, crossover study was conducted.

Intervention and participants: DC-HC and same daily dose of TID-HC were administered to patients with primary adrenal insufficiency (n = 50) vs healthy individuals (n = 124) as controls.

Main outcome measures: Urinary corticosteroid metabolites were measured by gas chromatography/mass spectrometry at 24-hour urinary collections.

Results: Total cortisol metabolites decreased during DR-HC compared to TID-HC (P < .001) and reached control values (P = .089). During DR-HC, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity measured by tetrahydrocortisol + 5α-tetrahydrocortisol/tetrahydrocortisone ratio was reduced compared to TID-HC (P < .05), but remained increased vs controls (P < .001). 11β-HSD2 activity measured by urinary free cortisone/free cortisol ratio was decreased with TID-HC vs controls (P < .01) but normalized with DR-HC (P = .358). 5α- and 5β-reduced metabolites were decreased with DR-HC compared to TID-HC. Tetrahydrocortisol/5α-tetrahydrocortisol ratio was increased during both treatments, suggesting increased 5β-reductase activity.

Conclusions: The urinary cortisol metabolome shows striking abnormalities in patients receiving conventional TID-HC replacement therapy, with increased 11β-HSD1 activity that may account for the unfavorable metabolic phenotype in primary adrenal insufficiency. Its change toward normalization with DR-HC may mediate beneficial metabolic effects. The urinary cortisol metabolome may serve as a tool to assess optimal cortisol replacement therapy.

Trial registration: ClinicalTrials.gov NCT00915343.

Keywords: 11β-hydroxysteroid dehydrogenase; Addison disease; cortisol metabolism; dual-release hydrocortisone; hydrocortisone; primary adrenal insufficiency.

© The Author(s) 2020. Published by Oxford University Press on behalf of the Endocrine Society.

Figures

Figure 1.
Figure 1.
Cortisol metabolism and its modification by DR-HC compared to TID-HC. Schematic representation of the different enzymatic steps of cortisol metabolism and metabolites changes as well as the changes of main enzyme activities (indicated by green arrows: pointed down indicates decrease and to right in no change) comparing TID-HC to DR-HC. 5α-THF, 5α-tetrahydrocortisol; 6β-OH-F, 6β-hydroxy-cortisol; 11β-HSD1, 11β-hydroxysteroid dehydrogenase type 1; 11β-HSD1, 11β-hydroxysteroid dehydrogenase type 2; 20α-HSD, 20α-hydroxysteroid dehydrogenase; 20β-HSD, 20β-hydroxysteroid dehydrogenase; CYP-3A, cytochrome P450A; DR-HC, dual-release hydrocortisone; THE, tetrahydrocortisone; THF, tetrahydrocortisol; TID-HC, 3-times-daily hydrocortisone.
Figure 2.
Figure 2.
Comparison of steroid excretion and urinary enzyme activity in controls and patients receiving TID-HC or DR-HC. Data are shown as box and whisker plots. The pink and blue lines represent individual changes in cortisol metabolites and enzyme activity for women and men, respectively, between TID-HC and DR-HC. Two patients (Nos. 004-057 and 004-0590) were excluded from the figure for the (THF + 5α-THF)/THE and THF/5α-THF ratios, respectively. The (THF + 5α-THF)/THE ratio evaluates 11β-HSD1 activity. The UFE/UFF ratio evaluates 11β-HSD2 activity. The THF/5α-THF ratio evaluates the balance of 5β-reductase and 5α-reductase activities. Statistical analysis: *P less than .05; **P less than .01; ***P less than .001. CTL vs patient comparisons adjusted for sex, weight, and age; and TID-HC vs DR-HC comparisons adjusted for treatment period. 5α-THF, 5α-tetrahydrocortisol; 11β-HSD1, 11β-hydroxysteroid dehydrogenase type 1; 11β-HSD2, 11β-hydroxysteroid dehydrogenase type 2; CONT, control; DR-HC, dual-release hydrocortisone; NS, not statistically significant; TCM, total cortisol metabolites; THE, tetrahydrocortisone; THF, tetrahydrocortisol; TID-HC, 3-times-daily hydrocortisone; UFE, urinary free cortisone; UFF, urinary free cortisol.
Figure 3.
Figure 3.
Percentage of change in the ratio (THF + 5α-THF)/THE between treatment with TID-HC and DR-HC for each individual patient. 5α-THF, 5α-tetrahydrocortisol; DR-HC, dual-release hydrocortisone; THE, tetrahydrocortisone; THF, tetrahydrocortisol; TID-HC, 3-times-daily hydrocortisone.

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