Beyond ovarian Morphology: Integrative stress profiling for distinguishing polycystic ovary syndrome from functional hypothalamic amenorrhea

Introduction

Polycystic Ovary Syndrome (PCOS) and Functional Hypothalamic Amenorrhea (FHA) are two prevalent causes of secondary oligo/amenorrhea (OA) in women. Women with polycystic ovarian morphology (PCOM) frequently exhibit features of both PCOS and FHA, creating diagnostic challenges in clinical practice. This exploratory study explores how psychological and metabolic stress markers, combined with hormonal profiling, can distinguish FHA-PCOM from PCOS-PCOM.

Methods

In this prospective observational exploratory study, ninety-one women with OA were recruited from the general population. They were classified into PCOM and non-PCOM groups using transvaginal ultrasonography (antral follicle number per ovary ≥20 or ovarian volume ≥10 cm³). Psychological stress was assessed using Perceived Stress Scale (PSS-10), Hospital Anxiety and Depression Scale (HADS), and State-Trait Anxiety Inventory (STAI). Clinical evaluations included physical examinations, transvaginal ultrasonography, and comprehensive biochemical analyses. Cluster analysis was performed to identify distinct phenotypic profiles.

Results

All women in the PCOM group met the Rotterdam Criteria for PCOS and two-thirds of them exhibited overlapping features of both FHA and PCOS. The cluster analysis identified three PCOM subgroups: PCOM–CL1 displayed classic PCOS traits, including elevated androgens and insulin resistance; PCOM–CL2 exhibited psychological stress with FHA-like features; PCOM–CL3 showed metabolic stress with higher engagement in physical activity (both in duration and intensity), low leptin, and reduced insulin resistance. Additionally, PCOM-CL3 exhibited the lowest levels of psychological stress compared to the other two clusters. Non-PCOM women formed two clusters, one dominated by psychological stress and the other by metabolic stress. STAI-Trait and HADS were validated as reliable tools for assessing psychological stress in OA-PCOM cases.

Conclusions

This study highlights the significant overlap between PCOS and FHA phenotypes in women with PCOM and emphasizes the utility of psychological assessments, physical activity metrics, and leptin levels in differential diagnosis. Integrating these diagnostic tools into clinical practice may enhance personalized management strategies for OA-PCOM women, addressing both hormonal and stress-related dimensions.