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

Abstract

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.

Keywords: Cluster analysis; Functional hypothalamic amenorrhea; Oligo/amenorrhea; Polycystic ovarian morphology; Polycystic ovary syndrome; Psychological stress.

Graphical abstract

Fig. 1

Correlation Heatmap of Psychological Stress Scales. Correlation coefficients between the Perceived Stress Scale (PSS10), State-Trait Anxiety Inventory (STAI State, STAI Trait), and Hospital Anxiety and Depression Scale (HADS) subscales (Anxiety, Depression) and total score (HADS Total). The color scale ranges from blue (weak correlations) to red (strong correlations), with values closer to 1.0 indicating a strong positive correlation.

Fig. 2

– Unraveling the overlap between FHA and PCOS: Synthesis of cluster analysis. This figure illustrates three distinct clinical profiles among women with OA – PCOM, identified using cluster analysis based on E2, STAI–Trait, HADS, and cfT. The analysis reveals an overlap between PCOS and FHA within the PCOM population. This overlap manifests as two profiles associated with different types of stress: “Psychological Stress-Associated PCOM” and “Metabolic Stress-Associated PCOM” with each profile meeting the Rotterdam Criteria for PCOS.