ArticleFrontiers in endocrinology2026
Psychological distress, but not single-time endocrine stress markers, is associated with unexplained infertility: a prospective case-control study.
Article in Frontiers in endocrinology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: Psychological distress is common among women with unexplained infertility and may interact with neuroendocrine stress pathways. However, the relevance of single-time endocrine stress markers such as cortisol and dehydroepiandrosterone sulfate (DHEAS) in reflecting chronic emotional burden remains uncertain. Objective: To investigate the association between psychological distress and single-time endocrine stress markers in women with unexplained infertility and to compare psychometric assessment with synchronized hormonal measurements. Methods: In this prospective case-control study, consecutive women with primary unexplained infertility (n = 50) and age-matched fertile controls (n = 52) were enrolled from the same tertiary gynecology outpatient clinic. Psychological distress was assessed using the Hospital Anxiety and Depression Scale (HADS). Clinically relevant psychological distress was defined as HADS-Anxiety ≥8 and/or HADS-Depression ≥8. Serum cortisol and DHEAS concentrations were measured under standardized morning fasting conditions during the early follicular phase. Multivariable logistic regression analysis was performed using a parsimonious adjusted model including age, body mass index, smoking status, residential environment, cortisol level, and HADS-defined psychological distress. Results: Women with unexplained infertility demonstrated significantly higher HADS-Anxiety and HADS-Depression scores compared with fertile controls (p < 0.05 for both comparisons). Based on predefined HADS subscale cut-off values (HADS-A ≥8 and/or HADS-D ≥8), HADS-defined psychological distress was significantly more prevalent in the unexplained infertility group (76.0% vs. 42.3%, p = 0.001). Although follicle-stimulating hormone and estradiol levels differed significantly between groups, all measured values remained within physiological reference ranges. No statistically significant between-group differences were observed for cortisol, dehydroepiandrosterone sulfate (DHEAS), or anti-Müllerian hormone levels. In the final parsimonious multivariable logistic regression model adjusted for age, body mass index, smoking status, residential environment, cortisol level, and HADS-defined psychological distress, psychological distress remained independently associated with unexplained infertility (adjusted OR 3.907, 95% CI 1.610-9.478, p = 0.003). Exploratory ROC analyses demonstrated limited discriminatory performance of isolated single-time cortisol and DHEAS measurements for identifying HADS-defined psychological distress. Conclusion: Psychological distress was more prevalent among women with unexplained infertility, whereas single-time serum endocrine stress markers were not significantly different between groups. These findings support the relevance of psychological assessment in women with unexplained infertility; however, the cross-sectional case-control design does not allow causal inference regarding the direction of this association.
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