Glucocorticoid (“stress hormone”) deficiency, as with other neuroendocrine hormone deficiencies, is managed by exogenous replacement. The importance of replacement in situations of deficiency is clear — adrenal insufficiency is a potentially fatal disease, unless treated with replacement. However, in contrast to other hormonal replacement regimens, such as thyroid function testing for thyroid hormone replacement, there is no set of laboratory tests to serve as a guideline for per-patient appropriate glucocorticoid replacement. The goal is to give enough, but not too much.
As reflected in the EU-AIR experience, there are several options for glucocorticoid replacement. Of note, the medications are not 1:1 equivalent, so the relevance of a particular daily dose depends entirely on which corticosteroid is used (eg, hydrocortisone, prednisolone). The total dosages reported by Murray and colleagues pertain to hydrocortisone, not prednisolone or dexamethasone. While a small number of studies have looked at potential different effects of different glucocorticoids, there is no definitive best replacement regimen. The choice of glucocorticoid largely reflects individual clinician familiarity. Evidence from other studies suggests that the choice may also reflect regional variation, with higher percentage use of prednisone in the U.S. than in the UK (Forss M, et al. BMC Endocr Disord. 2012;doi:10.1186/1472-6823-12-8).
The article by Murray and colleagues references other registry data suggesting higher morbidity and mortality in patients with adrenal insufficiency. It is not clear to what this association is due. The EU-AIR registry that was the basis for this study included patients with very different illnesses — both adrenal insufficiency (primary and secondary) and congenital adrenal hyperplasia, which was appropriately exclude.
The authors highlight the existing range of treatment regimens in use for glucocorticoid replacement, while acknowledging limitations of conclusions from an open registry.
The association between replacement doses totaling more than 30 mg daily (upper limit of general guidelines) and frequency of elevated BMI, diabetes and hypertension is worth noting, and later data may offer additional insights into rates of events suggesting under-replacement (adrenal crisis) or the possibility of over-replacement (BMI, fracture). The association between adrenal crisis and lack of stress dosing is particularly interesting if unsurprising, as it suggests an opportunity for intervention and study of different patient education approaches. Importantly, and as noted by the authors, the registry is by its nature without a control group, and thus definitive conclusions as to causality cannot be drawn; in addition, individual needs may vary and the absence of a biochemical barometer, leaving physicians to rely on patient feedback and clinical judgement.
The paper suggests areas for further analysis. Given the prevalence of hydrocortisone use among the included cohort, it would be of potential clinical benefit to examine the impact on quality of life and other parameters of multi-dose hydrocortisone regimens vs. single-dose prednisone, in a randomized fashion. In addition, including in analyses the particular diagnostic method for adrenal insufficiency would be of use: Are there more patients diagnosed by low early morning cortisol who are over-replaced than patients diagnosed by cosyntropin stimulation testing? It would be interesting to note differences in specific quality-of-life parameters across regimens and across diagnostic method.
Disclosure: Wexler reports no relevant financial disclosures.
Gary D. Hammer
Adrenal insufficiency (AI) is a rare but life-threatening disorder resulting from glucocorticoid deficiency in secondary (ACTH-dependent) AI with additional mineralocorticoid deficiency in primary AI. Despite a paucity of controlled studies, clinicians are well aware of the need for adequate glucocorticoid dosing regimens for patients with AI and the need for increased dosing during intercurrent illness with concomitant physiologic stress. The recent Endocrine Society guidelines for the diagnosis and treatment of AI suggest regimens that aim to mimic the endogenous diurnal secretion of cortisol using 15 to 25 mg/day in two or three divided doses.
The current study by Murray and colleagues of the European Adrenal Insufficiency Registry (EU-AIR) confirms what most endocrinologists know empirically: that many patients are treated with doses and regimens that are not aligned with expert opinion regarding optimal management of AI. In this report, the EU-AIR team reports that while the majority of patients in the cohort were taking daily doses of 15 to 25 mg in two to three divided doses in keeping with the guidelines, over 10% of patients were taking more than 30 mg/day, and a smaller but significant number of patients (7.2%) were under-replaced (< 15 mg/day). Moreover, significant heterogeneity in the frequency of administration of was observed. This is an important study.
While numerous prior studies have detailed the health risks associated with supra-physiologic endogenous or exogenous glucocorticoids, the optimization of therapy in patients with AI remains challenging. This report is an important first step toward better management of this disease. While some consider steroid hormone replacement relatively easy (ie, hydrocortisone and fludrocortisone in AI) compared with peptide hormone replacement (ie, insulin in diabetes), without good parameters to define optimal dosing regimens, clinicians rely mostly on patient “sense of well-being” to titrate dosing accordingly. The ongoing data collection of the EU-AIR should over time provide observational data, metabolic parameters and patient outcome that is predicted to provide evidence-based information to determine best practice for the management of AI. We look forward to translating these and related studies into the next iteration of clinical practice guidelines.
Disclosure: Hammer reports serving as a consultant or advisory board member for Embera NeuroTherapeutics, HRA Pharma, Ionis Pharmaceuticals, Millendo and Orphagen Pharmaceuticals, and holding equity ownership or options in Embera, NeuroTherapeutics and Millendo.