There has never been an evidence base for the use of hydrocortisone or any other steroid for replacement in patients with adrenal insufficiency, and there are no data demonstrating superiority of hydrocortisone over prednisolone. Patients on oral hydrocortisone are still admitted with Addisonian crises, and deaths still occur (1). The concentration of hydrocortisone falls rapidly after oral administration, and patients need to have more than 1 dose daily (2). Infections such as norovirus reduce cortisol absorption, and the short half-life of cortisol is particularly dangerous with gastrointestinal infections. Many patients are treated with 30 mg hydrocortisone daily (given as 20 mg in the morning and 10 mg in the afternoon), but this is overall too high a dose. The overall morbidity and mortality is higher than it should be because of our imperfect replacement strategy (2). Pulsatile secretion of cortisol is matched by rapid metabolism in healthy volunteers (3), and the resulting plasma profile is similar to that obtained from a single dose of prednisolone.
Specific enzymes have evolved for the rapid metabolism of endogenous hormones so that concentrations are rapidly altered by changes in the secretory rate. Native hormones such as cortisol, aldosterone, and insulin are hormones with a short half-life, where a rapid change in concentration might be required for physiological changes in the environment. During fasting, the concentration of insulin falls rapidly to prevent hypoglycemia. When administering exogenous replacements in patients with hormone deficiency, the native hormones have too short a half-life for once-daily administration and we therefore use analogs. Insulin analogs with longer half-lives such as glargine insulin are now used instead of insulin, and fludrocortisone is used instead of aldosterone for the same reason. Similarly, the half-life of cortisol is increased by inserting a double bond between positions 1 and 2, giving prednisolone (Fig. 1).
The diversity of genomic and regulatory effects of prednisolone referenced by Quinkler and Murray (4) relate to high-dose glucocorticoids that have immunosuppressive and antiinflammatory effects not seen with replacement doses. High doses of prednisolone (30–75 mg daily) demonstrated the diversity of regulatory processes compared to physiological replacement. This result has no relevance to replacement doses, although similar gene expression studies with lower doses might confirm that 3 mg prednisolone is equivalent to a normal replacement dose. Such studies are needed to find complementary evidence of dose equivalence.
Whether the difference in avidity of prednisolone for the glucocorticoid receptor is an advantage or a disadvantage is not known. It is possible that the increased avidity will reduce the risk of an Addisonian crisis in a patient who has taken prednisolone as a normal replacement dose but then goes on to develop norovirus. In such a situation, the increased binding and the slower dissociation of already-absorbed prednisolone may help prevent a crisis, whereas oral hydrocortisone with norovirus may not be safe (1).
Growth rates in patients with congenital adrenal hyperplasia give us some insight into longitudinal glucocorticoid replacement. Once-daily prednisolone improved growth rates compared to 3 times daily hydrocortisone (5). The relative potency of prednisolone to hydrocortisone was between 6:1 and 8:1, which is additional evidence for prednisolone 3 mg daily being equivalent to hydrocortisone 20 mg (10 mg in the morning, 5 mg at noon, and 5 mg in the afternoon).
The article by Quinkler and Murray reassuringly demonstrates no difference between prednisolone and hydrocortisone in several measures that would be worsened by steroid excess, including hemoglobin A1c, high-density lipoprotein and triglyceride levels, body mass index, systolic and diastolic blood pressure, and waist circumference (6). They only found a difference in total and LDL cholesterol, not known to be affected by steroids, and the title of this audit does not reflect the data accurately. Shire Pharmaceuticals markets Plenadren®, for which prednisolone is a direct competitor, and it is important to judge their comments in this light.
Longitudinal data is required to inform our decisions, but until such data exists, the choice should be left to the individual clinician.
see letter on page 753
Authors' Disclosures or Potential Conflicts of Interest: No authors declared any potential conflicts of interest.
- Received December 18, 2016.
- Accepted February 6, 2017.
- © 2017 American Association for Clinical Chemistry