Robin Lengton1, Susanne Kuckuck1,2, Mariëtte R. Boon1, Johanneke E. Oosterman1, Sjoerd A.A. van den Berg1,3, Clemens Kirschbaum4, Brenda W.J.H. Penninx5, Maryam Kavousi2, Elisabeth F.C. van Rossum1
1Obesity Center CGG, Department of Internal Medicine, Division of Endocrinology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
2Department of Epidemiology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
3Department of Clinical Chemistry, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
4Institute of Biological Psychology, Faculty of Psychology, Technische Universität Dresden, Dresden, Germany
5Department of Psychiatry and Amsterdam Public Health, Amsterdam UMC, Vrije Universiteit, Amsterdam, The Netherlands
Introduction: Dysregulation of the hypothalamic-pituitary-adrenal (HPA)-axis is implicated in cardiometabolic diseases. We examined whether glucocorticoid sensitivity, assessed with a very low-dose 0.25mg dexamethasone suppression test (DST), is associated with cardiometabolic outcomes cross-sectionally and prospectively, and whether changes over time relate to cardiometabolic health.
Methods: We included 1814 participants (59% female, median age 58) of the Rotterdam Study (RS-III, initiated in 2006), with follow-up data available for 1049 participants after 5.7 years. Post-dexamethasone cortisol levels and cortisol suppression ratios were calculated as markers of glucocorticoid sensitivity. Incident disease outcomes were recorded until January 1, 2020.
Results: Cross-sectionally, each 1 nmol/L increase in post-dexamethasone cortisol was associated with lower odds of obesity (OR:0.97, 95%CI:0.94;1.00), CHD (OR:0.88, 95%CI:0.80;0.96) and diabetes (OR:0.95, 95%CI:0.91;1.00), whereas each 1-unit increase in cortisol suppression ratio was associated with greater odds of CHD (OR:1.03, 95%CI:1.01;1.05). Prospectively, neither baseline cortisol marker predicted incident CHD or heart failure. Longitudinal change in post-dexamethasone cortisol (Δ = Follow-up – baseline) showed that each 1 nmol/L increase was associated with decreases in BMI (β:–0.02 kg/m², 95%CI:–0.03;–0.00) and triglycerides (β:–0.01 mmol/L, 95%CI:–0.02;–0.00), and increase in systolic blood pressure (β:0.17 mmHg, 95%CI:0.02;0.32).
Conclusion: Cross-sectional findings suggest that lower post-dexamethasone cortisol levels and higher cortisol suppression ratios, indicative of increased glucocorticoid sensitivity, are linked to adverse cardiometabolic profiles. However, baseline glucocorticoid sensitivity did not predict incident disease. Longitudinal reductions in glucocorticoid sensitivity were associated with favorable metabolic changes, highlighting the dynamic role of HPA-axis regulation in cardiometabolic health.