Psychological distress, but not single-time endocrine stress markers, is associated with unexplained infertility: a...

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.

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.

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.

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.

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.