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., 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.
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 due to the non-physiological pattern of current immediate release hydrocortisone (IR-HC) replacement therapy. The use of 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 cross-over study assessing the impact of 12 weeks of DR-HC on systemic GC metabolism (urinary steroid metabolome profiling) and 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 to healthy controls [72.1 µg/24 hrs (IQR 43.6-124.2) vs 51.9 µg/24 hrs (35.5-72.3), p = 0.02], 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.