Circulating spexin levels in women with PCOS (PMOS): relationships with phoenixin, BMI and perceived stress

Polycystic ovary syndrome (PCOS), for which the term polyendocrine metabolic ovarian syndrome (PMOS) has recently been proposed to better reflect its complex endocrine and metabolic nature, is a common endocrine disorder associated with metabolic disturbances, including insulin resistance and obesity, chronic anovulation and impaired fertility. Its pathogenesis is complex and multifactorial, involving interrelated mechanisms such as impaired insulin action and compensatory hyperinsulinemia, neuroendocrine dysregulation, altered ovarian steroidogenesis and increased adrenal androgen production. Spexin and phoenixin are novel peptides, primarily produced in the hypothalamus, implicated in the regulation of energy homeostasis and reproductive function, but their role in PMOS remains insufficiently clarified. Emerging evidence suggests that women with PMOS experience higher levels of psychological distress, including anxiety, depression, and perceived stress, as assessed by validated instruments such as the Perceived Stress Scale (PSS). Chronic stress may contribute to dysregulation of the hypothalamic-pituitary-adrenal axis and reproductive neuroendocrine pathways. Given their involvement in both metabolic and neuroendocrine regulation, spexin and phoenixin may represent potential mediators linking metabolic dysfunction and psychological stress in PMOS. However, data on their association with perceived stress in this population remain limited. The aim of the study is to investigate serum spexin levels in women with and without PMOS, the association of the novel neuropeptide with body mass index (BMI), perceived stress and the potential interrelationship between spexin and phoenixin.

This cross-sectional study included 168 women of reproductive age, of whom 72 were diagnosed with PCOS and 96 served as controls. According to BMI, participants were classified as underweight (n = 20), normal weight (n = 73), overweight (n = 22), and obese (n = 53). Serum spexin and phoenixin concentrations were measured using enzyme-linked immunosorbent assay (ELISA). All blood samples were collected under fasting conditions. Perceived stress was assessed using the Bulgarian adaptation of the 14-item Perceived Stress Scale (PSS-14), with total scores calculated according to the adapted 1-5 scoring procedure. Group differences were analyzed using independent-samples t-tests and one-way ANOVA, while associations between variables were evaluated using Spearman correlation analysis.

Spexin levels showed a non-significant trend toward lower values in women with PMOS compared to controls (203.75 ± 226.06 vs. 260.90 ± 240.20), although the difference was not statistically significant (p = 0.120). A moderate positive correlation was found between spexin and phoenixin (r = 0.589, p < 0.001). Spexin demonstrated a weak negative correlation with BMI (r = - 0.135, p = 0.040). PSS scores were positively correlated with PMOS status (r = 0.274, p < 0.001). No significant correlation was found between spexin levels and the results of the Perceived Stress Scale (r r = - 0.110; p = 0.078).

Although no statistically significant difference was observed between groups, circulating spexin concentrations showed a trend toward lower values in women with PMOS compared to controls, which is consistent with and further supports previous research findings. To our knowledge, this research is among the first studies simultaneously evaluating spexin and phoenixin levels- a novel positive correlation between spexin and phoenixin suggests coordinated neuroendocrine regulation. Importantly, perceived stress, assessed by PSS, was significantly elevated in women with PMOS despite the lack of association with spexin levels, highlighting its independent clinical relevance with potential inclusion of PSS as a complementary tool in the diagnostic and therapeutic algorithm of PMOS. Further studies are warranted to clarify the role of these peptides in the complex metabolic and neuroendocrine mechanisms underlying PCOS.

Not applicable.