In the Journals Plus

Glucocorticoid replacement doses tied to mortality risk in nonfunctioning pituitary adenoma

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June 27, 2017

Patients with nonfunctioning pituitary adenoma who receive daily hydrocortisone replacement doses greater than 20 mg are at increased risk for death from any cause vs. similar patients receiving lower doses and those without secondary adrenal insufficiency, according to findings published in the European Journal of Endocrinology.

“The previously demonstrated excess mortality in patients with adrenal insufficiency has been mainly attributable to cardiovascular, respiratory and infectious diseases as well as cancer,” Daniel S. Olsson, MSc, MD, PhD, of the Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden, and colleagues wrote. “It is likely that the degree of adrenal insufficiency is of importance for outcome and that patients who are completely insufficient may be more vulnerable to intercurrent illness, whereas patients with partial [adrenocorticotropic hormone] deficiency may be overtreated under normal unstressed conditions using conventional replacement doses. Hence, inadequate treatment of hypocortisolism remains a significant cause of death during stressful events and intercurrent illness in patients with hypopituitarism.”

Olsson and colleagues analyzed data from 392 patients treated or followed for nonfunctioning pituitary adenoma between 1997 and 2011, identified through the Swedish National Patient Register (252 men; mean age, 59 years; 80% with hypopituitarism; 49% with secondary adrenal insufficiency; mean follow-up time, 12.7 years). Within the cohort, 73% underwent surgical treatment; 19% also received pituitary radiation therapy; 26% did not receive any targeted therapy. The cohort was stratified by daily hydrocortisone dose (< 20 mg per day, 20 mg per day or 20 mg per day) and by daily hydrocortisone dose per kilogram body weight ( 0.25 mg/kg per day, > 0.25-30 mg/kg per day and > 0.3-0.55 mg/kg per day). For patients with secondary adrenal insufficiency not receiving hydrocortisone (n = 7), researchers calculated an equivalent dose. Researchers defined current replacement therapy as the treatment patients received at their last clinical visit before the end of the study; mortality information was obtained from the Swedish National Cause of Death Register. Researchers used Cox regression models to calculate HRs for mortality adjusted for baseline age, sex, treatment with radiotherapy and absolute or weight-adjusted hydrocortisone dose. Researchers also calculated HRs for patients with secondary adrenal insufficiency and with intact hypothalamic-pituitary-adrenal function.

Most patients received hydrocortisone; seven patients received cortisone acetate; mean daily hydrocortisone-equivalent dose was 20 mg; mean hydrocortisone-equivalent dose per kilogram body weight was 0.25 mg/kg per day.

During follow-up, 106 patients died; the most frequent cause of death was diseases of the circulatory system.

Researchers found that patients receiving a daily hydrocortisone-equivalent dose greater than 20 mg per day had a higher standardized mortality ratio (SMR; 1.42; 95% CI, 0.88-2.17) vs. patients who received a daily hydrocortisone-equivalent dose of 20 mg daily (0.71; 95% CI, 0.49-0.99). For patients receiving a daily hydrocortisone dose between 0.3 mg/kg per day and 0.55 mg/kg per day, SMR was higher (1.56; 95% CI, 1.01-2.3) compared with patients receiving a daily hydrocortisone-equivalent dose between 0.25 mg/kg per day and 0.3 mg/kg/day (0.65; 95% CI, 0.37-1.06).

In Cox regression analyses, patients receiving a daily hydrocortisone-equivalent dose greater than 20 mg had increased mortality compared with patients not receiving glucocorticoid replacement therapy (HR = 1.88; 95% CI, 1.06-3.33). However, patients receiving a daily hydrocortisone-equivalent dose of 20 mg and patients receiving less than 20 mg daily had mortality similar to patients not receiving glucocorticoid replacement therapy, according to the researchers. Results persisted after adjustment for treatment with radiotherapy and sex.

“We can show that [nonfunctioning pituitary adenoma] patients with secondary adrenal insufficiency with a daily [hydrocortisone-equivalent] replacement dose already higher than 20 mg or 0.3 mg/kg have an increased mortality both when compared to patients with [hydrocortisone-equivalent] doses 20 mg per day and in comparison with the background population,” the researchers wrote. “Our study also shows that daily replacement [hydrocortisone-equivalent] doses of 20 mg or less do not result in any premature mortality. Previous studies together with our data highlight the importance of using replacement treatment that results in a physiological cortisol exposure to prevent an excess mortality.” – by Regina Schaffer

Disclosures: One researcher reports receiving consultant fees from Ipsen, Novartis, Pfizer and Sandoz. Another researcher reports receiving consultant fees and honoraria from AstraZeneca, Eli Lilly, Merck, Novartis, Novo Nordisk, Otsuka, Pfizer and Shire.