ESPE Yearbook of Paediatric Endocrinology

J Clin Endocrinol Metab 2021; 106(3):814–825.https://pubmed.ncbi.nlm.nih.gov/33236103/

Here, the authors performed a randomized, 12-week, crossover study in order to assess cortisol metabolism during dual-release hydrocortisone (DR-HC) and conventional hydrocortisone (TID-HC) therapy in patients with primary adrenal insufficiency (n=50). Healthy controls (n=124) were included for comparison. DR-HC led to improvements in both 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) and 11β-HSD2 activities, as assessed by urinary metabolite profiles.

Treatment of adrenal insufficiency using conventional hydrocortisone (HC) therapy requires several doses to achieve sufficient coverage during the day, usually: a higher dose in the morning, a lower dose around midday, and a third dose late afternoon (1). However, patients with both primary and secondary adrenal insufficiency still demonstrate increased morbidity and mortality owing to cardiovascular diseases and infection (2, 3). It has been speculated that the exposure to supraphysiologic concentrations of cortisol and the non-physiologic cortisol profile are responsible for these adverse health outcomes. Two new modified release HC formulations have been designed to produce a more physiologic circadian cortisol exposure: a once-daily dual-release (DR-HC) tablet based on an immediate-release coating with an extended-release core (4); and a twice-daily modified-release tablet based on a multilayer design with an external coat providing delayed and sustained release of HC before final release of an inner HC coat, which is under development for the management of congenital adrenal hyperplasia (5) (see paper 8.3). The DR-HC formulation has been studied in primary and secondary adrenal insufficiency with observed improvement in cardiovascular risk factors and quality of life.

Urinary corticosteroid metabolites were measured by gas chromatography/mass spectrometry on 24-hour urinary collections. The results showed that patients receiving cortisol replacement therapy exhibit an alternate in cortisol metabolism profile. Total cortisol metabolites decreased during DR-HC compared to TID-HC (P<0.001) and reached control values. During DR-HC treatment, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) activity was reduced compared to TID-HC (P<0.05), but remained higher than in controls. 11β-HSD2 activity was decreased with TID-HC vs controls (P<0.01) but normalized with DR-HC. These findings demonstrate that the urinary cortisol metabolome shows significant abnormalities in patients receiving conventional TID-HC replacement therapy, with increased 11β-HSD1 activity, which relate to increased long-term exposure to glucocorticoids and may account for the unfavorable metabolic phenotype in patients with primary adrenal insufficiency. Its change toward normalization with DR-HC may mediate beneficial metabolic effects. Finally, the urinary cortisol metabolome may serve as a tool to assess optimal cortisol replacement therapy.

Reference: 1. Johannsson G, Falorni A, Skrtic S, Lennernäs H, Quinkler M, Monson JP, Stewart PM. Adrenal insufficiency: review of clinical outcomes with current glucocorticoid replacement therapy. Clin Endocrinol (Oxf). 2015; 82(1):2–11.2. Bergthorsdottir R, Leonsson-Zachrisson M, Odén A, Johannsson G. Premature mortality in patients with Addison’s disease: a population-based study. J Clin Endocrinol Metab. 2006; 91(12): 4849–4853.3. Burman P, Mattsson AF, Johannsson G, Höybye C, Holmer H, Dahlqvist P, Berinder K, Engström BE, Ekman B, Erfurth EM, Svensson J, Wahlberg J, Karlsson FA. Deaths among adult patients with hypopituitarism: hypocortisolism during acute stress, and de novo malignant brain tumors contribute to an increased mortality. J Clin Endocrinol Metab. 2013; 98(4): 1466–1475.4. Johannsson G, Lennernäs H, Marelli C, Rockich K, Skrtic S. Achieving a physiological cortisol profile with once-daily dual-release hydrocortisone: a pharmacokinetic study. Eur J Endocrinol. 2016; 175(1): 85–93.5. Whitaker M, Debono M, Huatan H, Merke D, Arlt W, Ross RJ. An oral multiparticulate, modified-release, hydrocortisone replacement therapy that provides physiological cortisol exposure. Clin Endocrinol (Oxf). 2014; 80(4): 554–561.