To the Editor:
The article by Williams et al. (1), “Prednisolone Replacement Therapy Mimics the Circadian Rhythm More Closely Than Other Glucocorticoids,” published in the September 2016 issue of JALM, reports on an ultraperformance LC-MS/MS method to investigate pharmacokinetic profiles of prednisolone. Although the method is sound and convincing, the clinical conclusions are not supported by the data presented.
To date, there is no adrenal hemoglobin (Hb)1 A1c for monitoring glucocorticoid replacement therapy in primary and secondary adrenal insufficiency (AI). The optimal glucocorticoid dose must be determined by clinical judgment based on the patient's medical history, complaints, and clinical examination (2). Current guidelines and expert opinions recommend against measuring single corticotropin or cortisol levels, and cortisol day profiles, to monitor glucocorticoid replacement therapy. However, measurements can be helpful in the occasional case, especially when there is a discrepancy between the dose of glucocorticoid administered, clinical signs, and the patient's complaints. It is therefore surprising that the authors recommend monitoring hormone replacement therapy in AI patients using only a single 8-h postdose level of a given glucocorticoid. This method is not in keeping with the current standard of care.
The authors postulate that they have identified the optimal prednisolone replacement dose in AI when using 3.86 mg daily. However, this is not investigated or proven by any longitudinal clinical studies that include variables such as blood pressure, lipid profile, Hb A1c, waist-to-hip ratio, body mass index, quality of life, markers for osteoporosis, or, most importantly, the prevalence of adrenal crisis. Therefore, this statement is not supported from the data presented. Careful examination of the presented patient profiles shows an over twofold difference in peak prednisolone levels, which, when combined with a highly variable terminal half-life of 1.75–3.75 h, means that individual variability in prednisolone dose is likely to be large. It is also clear that those individuals with the shorter prednisolone half-lives (1.75 h) overlap with the half-life of hydrocortisone (1.9 h) and therefore would potentially require prednisolone administration 2 or 3 times daily (3), suggesting that prednisolone is not a true once-daily replacement therapy.
Furthermore, it is important to point out that we now have an improved understanding of how glucocorticoids bind to the glucocorticoid receptor (GR) and induce genomic and nongenomic effects. Genomic effects of activated GRs are mediated through 3 primary mechanisms: (a) direct binding of GR to DNA via the GR response elements and negative GR response elements to activate or repress transcription, (b) tethering to DNA-bound transcription factors to modulate transcription indirectly, and (c) composite activity of DNA binding and interaction with adjacent DNA-bound transcription factors to affect transcription (4, 5). Rapid nongenomic effects of GR ligation occur after ligand-induced dissociation of the GR multiprotein complex in the cytoplasm (4). This diversity of regulatory processes indicates that prednisolone is likely to regulate a different spectrum of genes compared with the physiological glucocorticoid hydrocortisone (6). This result demonstrates that the differences between the physiological effects of prednisolone and hydrocortisone do not relate simply to differences in dose equivalence.
Therefore, we strongly advocate that clinicians use the available natural glucocorticoid hormone (hydrocortisone = cortisol) and not the synthetic glucocorticoid prednisolone for hormone replacement therapy in AI until appropriate supportive clinical data are available.
↵1 Nonstandard abbreviations:
- adrenal insufficiency
- glucocorticoid receptor.
see article on page 152
Authors' Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form.
Employment or Leadership: None declared.
Consultant or Advisory Role: M. Quinkler, R.D. Murray, Members of the Scientific Steering Committee of the European Adrenal Insufficiency Registry (EU-AIR) funded by Shire Pharmaceuticals.
Stock Ownership: None declared.
Honoraria: M. Quinkler, R.D. Murray, Shire Pharmaceuticals.
Research Funding: M. Quinkler, R.D. Murray, Shire Pharmaceuticals.
Expert Testimony: None declared.
Patents: None declared.
- Received November 21, 2016.
- Accepted December 16, 2016.
- © 2017 American Association for Clinical Chemistry