Research suggests there are alterations in the cortisol awakening response (CAR) in patients with premenstrual dysphoric disorder (PMDD), as demonstrated by delayed cortisol peaks and flatter diurnal cortisol slopes compared to healthy controls. While inconsistent, previous work also demonstrates a relation between alterations in CAR, prefrontal serotonin transporter (5-HTT) binding and severity of depressive symptoms.

This longitudinal study explores CAR in relation to midbrain and prefrontal 5-HTT binding and depressive symptoms in patients with PMDD and in healthy controls across the menstrual cycle.

Thirty patients with PMDD and 29 controls each provided 3 saliva samples for assessment of CAR (awakening, +30 min, +60 min) and 5 to assess the diurnal cortisol slope (09.00, 12.00, 15.00, 18.00, 21.00 h) during the periovulatory and premenstrual phases. [11C]DASB positron emission tomography scans were performed to measure 5-HTT non-displaceable binding potential (BPND). Depressive symptoms were assessed using the Hamilton Depression Rating Scale. Associations between cortisol measures, 5-HTT BPND and depressive symptoms were examined using linear mixed-effects models, independent t-tests, mixed analysis of variance (ANOVA) and Spearman rank correlations.

A significant interaction effect between group and cycle phase was found for cortisol peak concentrations (estimate = 0.78, p = 0.05, d = 0.62, 95% CI: [0.01, 1.56]; and corrected for awakening cortisol concentration: estimate = 0.90, p = 0.02, d = 0.77, 95% CI: [0.15, 1.66]). Cortisol peak concentrations correlated negatively with both midbrain 5-HTT BPND (r = −0.34, p < 0.01, R2 = 0.12) and depressive symptoms (r = −0.30, p = 0.02, R2 = 0.09) during the premenstrual phase.

Patients with PMDD showed attenuated cortisol peaks in the periovulatory phase compared with healthy controls, who demonstrated plastic changes across the cycle. Results point towards an interplay between the stress and the serotonergic system, as well as to the severity of depressive symptoms during the premenstrual phase.