ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: Lancet Diabetes Endocrinol. 2018; 6(3): 173-185

Adrenal insufficiency (AI), caused by adrenal failure (primary) or hypothalamo-pituitary failure (secondary), has a prevalence of 250–450 per 1 million (16). AI is potentially life-threatening and requires lifelong glucocorticoid replacement therapy. Modified-release hydrocortisone preparations have been developed to mimic the physiological cortisol rhythm and improve compliance (17, 18). The once-daily, modified-release hydrocortisone tablet was developed to prevent the afternoon peaks seen with conventional therapies given in multiple daily doses. Use of once-daily, modified-release hydrocortisone improves cardiovascular disease risk factors, glucose metabolism, and quality of life in controlled trials (19-21). However, the mechanisms involved remain unexplained.

This study is the first non-sponsored, randomised controlled trial to investigate the effect of once-daily, modified-release hydrocortisone versus standard therapy on metabolism in patients with primary or secondary AI. Patients with AI on standard therapy had impaired cell immunity and increased frequency of infections, probably due to disruption of normal circadian rhythm of cortisol by use of multiple daily hydrocortisone doses. They also showed that two of the most deleterious effects of glucocorticoid overtreatment—weight gain and increased HbA1c—can be prevented by changing the timing of administration without altering the dose. In addition, switching from multiple-daily to once-daily glucocorticoid administration restored immune-cell homoeostasis and reduced the frequency of infections. They also provided a molecular mechanism: low-grade inflammation leads to selective depletion of the immunoglobulin receptor, CD16, from the surface of natural killer cells. Such low-grade inflammation could also account for some of the symptoms reported by patients with adrenal insufficiency on standard glucocorticoid therapy (e.g. fatigue, impaired quality of life) and the increased risk of atherosclerosis even in the absence of the usual predisposing factors.

16. Charmandari E, Nicolaides NC, Chrousos GP. Adrenal insufficiency. Lancet 2014; 383: 2152–67.

17. Debono M, Ghobadi C, Rostami-Hodjegan A, Huatan H, Campbell MJ, Newell-Price J, Darzy K, Merke DP, Arlt W, Ross RJ. Modified-release hydrocortisone to provide circadian cortisol pro les. J Clin Endocrinol Metab 2009; 94: 1548–54.

18. Johannsson G, Bergthorsdottir R, Nilsson AG, Lennernas H, Hedner T, Skrtic S. Improving glucocorticoid replacement therapy using a novel modified-release hydrocortisone tablet: a pharmacokinetic study. Eur J Endocrinol 2009; 161: 119–30.

19. Johannsson G, Nilsson AG, Bergthorsdottir R, Burman P, Dahlqvist P, Ekman B, Engström BE, Olsson T, Ragnarsson O, Ryberg M, Wahlberg J, Biller BM, Monson JP, Stewart PM, Lennernäs H, Skrtic S. Improved cortisol exposure-time pro le and outcome in patients with adrenal insu ciency: a prospective randomized trial of a novel hydrocortisone dual-release formulation. J Clin Endocrinol Metab 2012; 97: 473–81.

20. Giordano R, Guaraldi F, Marinazzo E, Fumarola F, Rampino A, Berardelli R, Karamouzis I, Lucchiari M, Manetta T, Mengozzi G, Arvat E, Ghigo E. Improvement of anthropometric and metabolic parameters, and quality of life following treatment with dual-release hydrocortisone in patients with Addison’s disease. Endocrine 2016; 51: 360–68.

21. Quinkler M, Miodini Nilsen R, Zopf K, Ventz M, Oksnes M. Modified-release hydrocortisone decreases BMI and HbA1c in patients with primary and secondary adrenal insufficiency. Eur J Endocrinol 2015; 172: 619–26.