Cortisol Metabolism in Depressed Patients and Healthy Controls

Abstract

Background: Chronic stress as well as major depressive disorders are associated with hypercortisolemia and impaired hypothalamic-pituitary-adrenocortical axis functioning. The aim of this study was to determine whether in major depression changes in the activity patterns of local modulators of glucocorticoid action might contribute to an increase in cortisol bioavailability and if they change during antidepressant treatment and clinical response. Methods: Concentrations of urinary total cortisol (UFF), urinary total cortisone (UFE), tetrahydrocortisone (THE), tetrahydrocortisol (THF) and allo-THF (5α-THF) were measured in 10-hour nocturnal urine samples of 19 depressed patients and 15 healthy controls. The activity of 11β-hydroxysteroid dehydrogenases (11β-HSD) as well as 5α- and 5β-reductases was assessed by calculating the ratios of glucocorticoid metabolites. Patients were treated for 28 days with either mirtazapine or venlafaxine. Enzyme activity was observed during the course of treatment and compared to healthy controls. Responders to treatment were selected for this analysis. Results: Depressed patients showed reduced 5α-reductase activity manifested as a significantly lower amount of 5α-THF (102.8 ± 167.2 vs. 194.6 ± 165.8 μg, p = 0.019). The increase in the UFF/UFE ratio (0.73 ± 0.32 vs. 0.29 ± 0.13, p < 0.0001) indicates reduced activity of renal 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). During pharmacological treatment, 5α-reductase activity in patients returned to the level of the control group, while the decrease in 11β-HSD2 activity persisted until day 28. Conclusions: Our results show changes in activity of intracellular modulators of steroid action in major depressive disorders, particularly a reduced activity of the intracellular cortisol-deactivating enzymes 5α-reductase and 11β-HSD2. These changes suggest an increase in cortisol bioavailability within tissues.

Suppression of Neuroinflammatory and Apoptotic Signaling Cascade by Curcumin Alone and in Combination with Piperine in Rat Model of Olfactory Bulbectomy Induced Depression

“…Chronic stress activates hypothalamic–pituitary–adrenal (HPA) axis [39] and increases the levels of blood corticosterone in rats [40], similar to the human cortisol [41]. In our study, chronic stress induced by removal of olfactory bulbs resulted in significant rise in the serum corticosterone levels indicating hyperactivity of the HPA-axis [42].…”

Approach to patients with pseudo-Cushing’s states

“…Data regarding the pulsatile release of cortisol and ACTH in depressed patients are ambiguous, with reports of increased (23), unchanged (24), or reduced (25) frequencies. Analyzing these conflicting findings of different studies suggests that the prevalence of abnormalities in cortisol and ACTH levels might depend partly on how they are measured and the type of depressed patients examined.…”

Prenatal Excess Glucocorticoid Exposure and Adult Affective Disorders: A Role for Serotonergic and Catecholamine Pathways

“…Support of the notion that altered 11β-HSD2 activity contributes to affective behaviour has also been found clinically. Thus, measurements of urinary glucocorticoids and their metabolites in depressed patients reveal changes in the intracellular regulation of glucocorticoid activity, in particular 11β-HSD2, in comparison to healthy controls [90,91]. It is unclear, however, if this alteration in steroid metabolism is a consequence or cause of depression.…”