Cushing's disease patients retain distinct neurosteroid signature and mood symptoms post-remission, dissociating from classical HPA axis markers.

Patients with Cushing's disease (CD), characterized by chronic hypercortisolism due to pituitary tumors, frequently experience high rates of depression and anxiety. These debilitating psychological symptoms often persist even after achieving biochemical remission, suggesting that the underlying mechanisms extend beyond simple cortisol normalization. The precise role of neurosteroids (NS), which are synthesized in the brain and peripheral tissues and modulate neuronal excitability and mood, in the persistent psychopathology of CD remains poorly understood, representing a critical gap in patient care.

This cross-sectional study investigated neurosteroid profiles and psychological symptoms in 37 patients with CD (22 active, 15 in remission) and 21 nonfunctioning pituitary adenoma (NFA) controls. Circulating neurosteroid levels were precisely quantified using mass spectrometry. Psychological symptoms, including depression, anxiety, and stress, were assessed via the 21-item Depression Anxiety Stress Scale (DASS-21). Discriminatory neurosteroids were identified using partial least squares discriminant analysis (PLS-DA), with a variable importance in projection (VIP) score > 1.0 serving as the selection threshold.

Patients with CD demonstrated significantly higher depression (14 vs. 7.5, p = 0.03) and stress scores (17 vs. 8.5, p = 0.03) compared to NFA controls. PLS-DA identified five key discriminatory neurosteroids: 4-androstenedione (VIP = 2.0), 11-deoxycorticosterone (DOC) (VIP = 1.8), 7-OH-pregnenolone (VIP = 1.8), corticosterone (VIP = 1.7), and androsterone (VIP = 1.1). The first four were elevated, while androsterone was decreased in CD patients. Notably, most of these neurosteroid alterations persisted despite biochemical remission, with 7-OH-pregnenolone paradoxically increasing further in remission (121 vs. 22.5 ng/mL, p = 0.008). Mood symptoms did not correlate with classical HPA axis markers like cortisol, ACTH, or urinary free cortisol (UFC). However, dehydroepiandrosterone (DHEA) correlated positively with depression (r = 0.4, p = 0.02) and stress (r = 0.4, p = 0.02), while allopregnanolone correlated negatively with depression (r = -0.4, p = 0.03) and stress (r = -0.4, p = 0.04). Among the discriminatory neurosteroids, only 7-OH-pregnenolone correlated with stress (r = 0.3, p = 0.04). These specific neurosteroid-mood associations were absent in NFA controls.

The persistence of altered neurosteroid profiles and their dissociation from classical HPA axis markers in CD remission highlights a distinct, enduring steroid signature contributing to mood dysregulation.