To characterize circulating neurosteroid profiles in Cushing’s disease and examine their associations with psychological symptoms.
Approach:
Study Design: Cross-sectional study of 37 patients with Cushing’s disease (22 active, 15 remission) and 21 nonfunctioning pituitary adenoma controls.
Methods: Neurosteroid levels quantified by mass spectrometry; psychological symptoms assessed using the DASS-21.
Data Analysis: Discriminatory neurosteroids identified by partial least squares discriminant analysis with a VIP score > 1.0.
Key Findings:
Patients with Cushing’s disease exhibited higher depression scores (14 vs. 7.5, p = 0.03) and stress scores (17 vs. 8.5, p = 0.03) compared to controls.
Five discriminatory neurosteroids were identified: 4-androstenedione, 11-deoxycorticosterone, 7-OH-pregnenolone, corticosterone, and androsterone.
Most neurosteroid alterations persisted despite biochemical remission, with 7-OH-pregnenolone levels increasing (121 vs. 22.5 ng/mL, p = 0.008).
Mood symptoms did not correlate with cortisol, ACTH, or urinary free cortisol, but DHEA correlated positively with depression and stress, while allopregnanolone correlated negatively.
Interpretation:
The findings suggest that neurosteroid profiles in patients with Cushing’s disease are significantly altered, even after achieving biochemical remission. The persistence of elevated levels of certain neurosteroids, particularly 7-OH-pregnenolone, may contribute to ongoing psychological symptoms such as depression and stress. The lack of correlation between mood symptoms and traditional markers of cortisol activity indicates that neurosteroids may play a distinct role in the psychological sequelae of Cushing’s disease, independent of the hypothalamic-pituitary-adrenal (HPA) axis activity.
Limitations:
The study's cross-sectional design limits causal inferences.
Sample size may restrict the generalizability of findings.
Conclusion:
This study highlights the importance of understanding neurosteroid alterations in Cushing’s disease, particularly in the context of psychological health. The identification of specific neurosteroids associated with mood symptoms underscores the need for further research to explore therapeutic interventions targeting these neurosteroid pathways, which may improve the quality of life for patients even after biochemical remission is achieved.
