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

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.

• Authors: Audrey Melvin, Dimitrios Chantzichristos, Catriona J Kyle, Scott D Mackenzie, Brian R Walker, Gudmundur Johannsson, Roland H Stimson, Stephen O'Rahilly
• Journal: The Journal of clinical endocrinology and metabolism (J Clin Endocrinol Metab) Vol. 105 Issue 5 (05 01 2020) ISSN: 1945-7197 [Electronic] United States
• PMID: 31853550 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: © Endocrine Society 2019.

Chemical References

• GDF15 protein, human
• Glucocorticoids
• Growth Differentiation Factor 15
• Hydrocortisone

Topics

• Addison Disease (blood, drug therapy)
• Adolescent
• Adrenal Hyperplasia, Congenital (blood, drug therapy)
• Adrenal Insufficiency (blood, drug therapy)
• Adult
• Aged
• Cohort Studies
• Cross-Over Studies
• Female
• Glucocorticoids (blood, deficiency, therapeutic use)
• Growth Differentiation Factor 15 (blood)
• Hormone Replacement Therapy
• Humans
• Hydrocortisone (blood, deficiency, therapeutic use)
• Male
• Middle Aged
• Single-Blind Method
• Up-Regulation
• Young Adult