GDF15 Is Elevated in Conditions of Glucocorticoid Deficiency and Is Modulated by Glucocorticoid Replacement

• Published in: The journal of clinical endocrinology and metabolism 2020-05, Vol.105 (5), p.1427-1434
• Main Authors: Melvin, Audrey, Chantzichristos, Dimitrios, Kyle, Catriona J, Mackenzie, Scott D, Walker, Brian R, Johannsson, Gudmundur, Stimson, Roland H, O’Rahilly, Stephen
• Format: Article
• Language: English
• Subjects: Addison Disease - blood; Addison Disease - drug therapy; Adolescent; Adrenal Hyperplasia, Congenital - blood; Adrenal Hyperplasia, Congenital - drug therapy; Adrenal insufficiency; Adrenal Insufficiency - blood; Adrenal Insufficiency - drug therapy; Adult; Aged; Animal models; Anorexia; Appetite; Autoimmune diseases; Body weight; Body weight loss; Care and treatment; Clinical; Cohort Studies; Complications and side effects; Corticosteroids; Cross-Over Studies; Endocrine disorders; Endocrinology and Diabetes; Endokrinologi och diabetes; Female; Food intake; Glucocorticoids; Glucocorticoids - blood; Glucocorticoids - deficiency; Glucocorticoids - therapeutic use; Growth Differentiation Factor 15 - blood; Health aspects; Hindbrain; Hormone Replacement Therapy; Humans; Hydrocortisone; Hydrocortisone - blood; Hydrocortisone - deficiency; Hydrocortisone - therapeutic use; Hyperplasia; Intravenous administration; Male; Middle Aged; Nausea; Neural circuitry; Neural networks; Physiological aspects; Single-Blind Method; Transforming growth factors; Up-Regulation; Vomiting; Young Adult
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/clinem/dgz277

Abstract Context GDF15 is a stress-induced hormone acting in the hindbrain that activates neural circuitry involved in establishing aversive responses and reducing food intake and body weight in animal models. Anorexia, weight loss, nausea and vomiting are common manifestations of glucocorticoid deficiency, and we hypothesized that glucocorticoid deficiency may be associated with elevated levels of GDF15. Objective To determine the impact of primary adrenal insufficiency (PAI) and glucocorticoid replacement on circulating GDF15 levels. Methods and Results We measured circulating concentrations of GDF15 in a cohort of healthy volunteers and Addison’s disease patients following steroid withdrawal. Significantly higher GDF15 (mean ± standard deviation [SD]) was observed in the Addison’s cohort, 739.1 ± 225.8 pg/mL compared to healthy controls, 497.9 ± 167.7 pg/mL (P = 0.01). The effect of hydrocortisone replacement on GDF15 was assessed in 3 independent PAI cohorts with classical congenital adrenal hyperplasia or Addison’s disease; intravenous hydrocortisone replacement reduced GDF15 in all groups. We examined the response of GDF15 to increasing doses of glucocorticoid replacement in healthy volunteers with pharmacologically mediated cortisol deficiency. A dose-dependent difference in GDF15 (mean ± SD) was observed between the groups with values of 491.0 ± 157.7 pg/mL, 427.0 ± 152.1 pg/mL and 360 ± 143.1 pg/mL, in the low, medium and high glucocorticoid replacement groups, respectively, P < .0001. Conclusions GDF15 is increased in states of glucocorticoid deficiency and restored by glucocorticoid replacement. Given the site of action of GDF15 in the hindbrain and its effects on appetite, further study is required to determine the effect of GDF15 in mediating the anorexia and nausea that is a common feature of glucocorticoid deficiency.