How to supplement the real adrenal fatigue

Results of the article suggest that longer-acting cortisol-equivalent supplementation is more beneficial than conventional therapy with multiple daily doses of hydrocortisone in adults with adrenal insufficiency.  Advantages are reduced body weight, heightened immunity, less recurrent infections, and improved quality of life. A group of 89 participants were followed for 6 months.


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March 2018


Conventional treatment of patients with adrenal insufficiency involves administration of glucocorticoids multiple times a day and has been associated with weight gain and metabolic impairment.

The optimal glucocorticoid replacement therapy for these patients is highly debated because of the scarcity of evidence from randomised trials. We aimed to establish whether the timing and pharmacokinetics of glucocorticoid replacement therapy affect the metabolism and immune system of patients with adrenal insufficiency.


We did a single-blind randomised controlled trial at two reference university hospitals in Italy. Eligible patients, aged 18–80 years, with adrenal insufficiency were on conventional glucocorticoid therapy and had been stable for at least 3 months before enrolment.

Patients were randomly assigned (1:1) with a computer-generated random sequence stratified by type of adrenal insufficiency and BMI to continue conventional glucocorticoid therapy (standard treatment group) or to switch to an equivalent dose of once-daily, modified-release oral hydrocortisone (switch treatment group). Outcome assessors were masked to treatment allocation.

Primary outcome was bodyweight change from baseline to 24 weeks.

Secondary outcomes included immune cell profiles, susceptibility to infections, and quality of life. Efficacy analyses included all patients who received at least one dose of the study drug.


Between March 1, 2014, and June 30, 2016, 89 patients with adrenal insufficiency were randomly assigned to continue standard glucocorticoid therapy (n=43) or to switch to once-daily, modified-release hydrocortisone (n=46).

At 24 weeks, bodyweight reduction was superior in patients in the once-daily hydrocortisone group compared with those in the standard treatment group (–2.1 kg vs. +1.9 kg treatment difference −4·0 kg, p=0·008).

Additionally, patients in the once-daily hydrocortisone group had more normal immune cell profiles, reduced susceptibility to infections, and improved quality of life compared with the standard glucocorticoid therapy group.

We observed no difference in frequency or severity of adverse events between the two intervention groups, although a lower cumulative number of recurrent upper respiratory tract infections was observed with once-daily hydrocortisone than with standard treatment (17 vs 38; p=0·016). Most adverse events were mild; three serious adverse events occurred in each group, of which one adverse advent (arthritis) in the switch treatment group could be considered drug related.


Patients with adrenal insufficiency on conventional glucocorticoid replacement therapy multiple times a day exhibit a pro-inflammatory state and weakened immune defence.

Restoration of a more physiological circadian glucocorticoid rhythm by switching to a once-daily, modified-release regimen reduces bodyweight, normalises the immune cell profile, reduces recurrent infections, and improves the quality of life of patients with adrenal insufficiency.