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Editorials

Glucocorticoid replacement

BMJ 2014; 349 doi: https://doi.org/10.1136/bmj.g4843 (Published 30 July 2014) Cite this as: BMJ 2014;349:g4843

Re: Glucocorticoid replacement: Do we really have enough evidence to recommend the use of prednisolone as first line therapy?

The debate as to the optimal glucocorticoid replacement has been fuelled by the emergence of the dual release hydrocortisone preparation, Plenadren® [1]. There remains a paucity of data supporting the relative advantage of the use of one glucocorticoid over an alternate. In this environment Amin and colleagues suggest we should be using prednisolone as first line glucocorticoid replacement in a health system with finite resources, based on cost and absence of evidence for inferiority compared with hydrocortisone [2]. Within the UK, endocrinologists have favoured the use of hydrocortisone (cortisol) in treatment of both primary and secondary adrenal insufficiency. Cortisol production rates calculated from stable isotope dilution are well documented and confirm the appropriateness of current daily replacement hydrocortisone doses [3]. Furthermore, levels of cortisol are measureable in patients on hydrocortisone and support serum levels approximating those observed physiologically, or can be used to confirm or refute low levels at times during the day when patients are symptomatic.
In contrast the physiological dose of prednisolone is less certain. For anti-inflammatory effects prednisolone is four-fold more potent than hydrocortisone. Whether this relative potency is also true for the glucocorticoid and mineralocorticoid effects is less clear. Using luciferase transactivation assay in CV-1 cells transfected with the human glucocorticoid receptor, prednisolone is 1.7 fold more potent than hydrocortisone. When transfected with the human mineralocorticoid receptor hydrocortisone is 4.2 fold more potent than prednisolone [4]. Bioequivalence of prednisolone and hydrocortisone derived from growth data in patients with congenital adrenal hyperplasia suggest prednisolone to be 6 - 8 fold more potent than hydrocortisone [5]. Amid this confusion it is difficult to know how measurement of serum prednisolone levels during treatment will aid management of adrenal insufficiency. Clinical long term data suggests glucocorticoid replacement therapy with prednisolone is likely to have a selective adverse impact on bone, but not quality of life, relative to hydrocortisone [6, 7].
A European observational study of adrenal insufficiency management and outcomes (EU-AIR) is currently in progress and should provide further data on the relative benefits of hydrocortisone and prednisolone [8]. Until this, and additional data are available, clinicians will continue to individualise glucocorticoid replacement to the patient’s symptoms whilst attempting to avoid steroid-related side-effects.

1. Johannsson, G., et al., Improved cortisol exposure-time profile and outcome in patients with adrenal insufficiency: a prospective randomized trial of a novel hydrocortisone dual-release formulation. J Clin Endocrinol Metab, 2012. 97(2): p. 473-81.
2. Amin, A., A.H. Sam, and K. Meeran, Glucocorticoid replacement. BMJ, 2014. 349: p. g4843.
3. Kraan, G.P., et al., The daily cortisol production reinvestigated in healthy men. The serum and urinary cortisol production rates are not significantly different. J Clin Endocrinol Metab, 1998. 83(4): p. 1247-52.
4. Grossmann, C., et al., Transactivation via the human glucocorticoid and mineralocorticoid receptor by therapeutically used steroids in CV-1 cells: a comparison of their glucocorticoid and mineralocorticoid properties. Eur J Endocrinol, 2004. 151(3): p. 397-406.
5. Caldato, M.C., V.T. Fernandes, and C.E. Kater, One-year clinical evaluation of single morning dose prednisolone therapy for 21-hydroxylase deficiency. Arq Bras Endocrinol Metabol, 2004. 48(5): p. 705-12.
6. Koetz, K.R., et al., Bone mineral density is not significantly reduced in adult patients on low-dose glucocorticoid replacement therapy. J Clin Endocrinol Metab, 2012. 97(1): p. 85-92.
7. Bleicken, B., et al., Impaired subjective health status in chronic adrenal insufficiency: impact of different glucocorticoid replacement regimens. Eur J Endocrinol, 2008. 159(6): p. 811-7.
8. Ekman, B., et al., European Adrenal Insufficiency Registry (EU-AIR): a comparative observational study of glucocorticoid replacement therapy. BMC Endocr Disord, 2014. 14: p. 40.

Competing interests: Dr Nikolaos Kyriakakis has no conflicts of interest. Dr Robert D Murray and Dr Marcus Quinkler are on the Scientific Steering Committee of the EU-AIR study which is funded by Shire Pharmaceuticals, and have received honoraria from Shire Pharmaceuticals as a member of advisory boards for adrenal insufficiency and Plenadren®.

04 October 2014
Robert D Murray
Consultant Endocrinologist & Honorary Associate Professor
Marcus Quinkler, Nikolaos Kyriakakis
Leeds Teaching Hospitals NHS Trust
Leeds Centre for Diabetes & Endocrinology, St James's University Hospital, Beckett Street, Leeds LS9 7TF