Steroid alterations in Cushing's disease persist after remission: ACTH-driven steroid changes dissociate from mood-regulatory neurosteroids.

OBJECTIVE

Cushing's disease (CD) is associated with high rates of depression and anxiety that often persist despite biochemical remission, yet the underlying mechanisms remain unclear. This study aims to characterize circulating neurosteroid (NS) profiles in CD and examine their associations with psychological symptoms.

DESIGN AND

METHODS

This is a cross-sectional study of 37 patients with CD (22 active, 15 remission) and 21 nonfunctioning pituitary adenoma (NFA) controls. NS levels were quantified by mass spectrometry; psychological symptoms were assessed using the 21-item Depression Anxiety Stress Scale (DASS-21). Discriminatory NS were identified by partial least squares discriminant analysis (PLS-DA), with a variable importance in projection (VIP) score > 1.0 used as the selection threshold.

RESULTS

Patients with CD exhibited higher depression (14 vs. 7.5, p = 0.03) and stress scores (17 vs. 8.5, p = 0.03) than NFA. PLS-DA identified five discriminatory NS: 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, and androsterone decreased in CD. Despite biochemical remission, most NS alterations persisted, with 7-OH-pregnenolone paradoxically increasing further (121 vs. 22.5 ng/mL, p = 0.008). Mood symptoms did not correlate with cortisol, adrenocorticotropic hormone (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), whereas allopregnanolone correlated negatively with depression (r = -0.4, p = 0.03) and stress (r = -0.4, p = 0.04). Among discriminatory NS, only 7-OH-pregnenolone correlated with stress (r = 0.3, p = 0.04). These NS-mood associations were absent in NFA.

CONCLUSIONS

CD is characterized by a distinct and persistent steroid signature that persists beyond biochemical remission, reflecting hypercortisolism-driven epigenetic remodeling of steroidogenic pathways. The dissociation between ACTH-driven steroid alterations and mood-associated NS suggests that cortisol reduction alone may inadequately address psychiatric symptoms, warranting investigation of NS-targeted therapies.