From metabolic network to brain loop: unraveling the neuro-metabolic correlates in PCOS-related depression

Polycystic ovary syndrome(PCOS) is increasingly recognized for its substantial depressive burden, however, the underlying mechanism remains unclear. In this study, the neuro-metabolic pathway was explored to unravel the mechanism in PCOS-related depression.

Participants recruited from the UK Biobank comprised a cross-sectional population, the outcome as female depression, with 2,826 individuals among whom 471 diagnosed with PCOS. Progressive regression, interaction and mediation analyses, linearity and threshold examinations, relative weight analysis and principal component analysis(PCA), as well as stratified analyses were conducted in this study.

The two brain magnetic resonance imaging(MRI) metrics as volume of grey matter in frontal orbital cortex(FOC GMVol) and mean thickness of caudalanteriorcingulate(CaudalAntCing Thk) showed prominent links with PCOS-related depression, with CaudalAntCing Thk serving as the final common executor to depression. FOC GMVol and CaudalAntCing Thk interacted with PCOS in a metabolic-dependent and a metabolic-independent way respectively. A PCOS×free androgen index(FAI)×FOC GMVol three-way interaction was observer only in normal body mass index(BMI) individuals with high FAI. The FOC GMVol-CaudalAntCing Thk association, correlated with concurrent increases in BMI and FAI, existed exclusively in non-PCOS. Metabolic factors exhibited mediating effects (BMI and FAI) and formed a network among which BMI served as a hub linking the antagonistic FAI and the auxiliary triglyceride-glucose index(TyG), while systemic immune-inflammation index(SII) acted as an independent risk factor irrelevant to PCOS. A two-tiered brain protective hypothesis was proposed against depression: neural compensation reflected the protective FOC GMVol-CaudalAntCing Thk coupling in non-PCOS, and protective threshold patterns of both FOC GMVol and CaudalAntCing Thk in PCOS, with FAI playing pivotal and distinct roles at both peripheral and central levels across the entire pathways.

Given the intricate neuro-metabolic correlates underlying PCOS-related depression, further studies were warranted and a synergistic therapeutic strategy of androgen suppression plus weight management might be considered.