Cortisol and ACTH response to Dex/CRH testing and 24-hour urine free cortisol levels in women with and without premenstrual dysphoric disorder

Hyperactive and hyperreactive HPA axis functions are frequently reported in depressive disorders, particularly in major depression. However, research into HPA axis function in women with premenstrual dysphoric disorder (PMDD), which is also classified as a depressive disorder, has shown inconsistent results. This study aimed to characterize the HPA axis in women with PMDD using the combined dexamethasone suppression and CRH stimulation (Dex/CRH) test, alongside measurements of 24-hour urine free cortisol (UFC). We enrolled 26 women with prospectively confirmed PMDD and 25 asymptomatic controls (ACs), testing them during the mid-follicular and luteal phases of the menstrual cycle. The primary outcomes included serial plasma cortisol and ACTH levels, their area-under-the-curve (AUC), and 24-hour UFC levels. We utilized a mixed model to compare serial cortisol and ACTH levels, and the Wilcoxon Signed Rank test for comparing UFC levels and cortisol and ACTH AUC. No significant effects related to diagnosis or menstrual cycle phase were observed on plasma cortisol or ACTH levels (from time 0 to +75 minutes), nor on the AUCs of plasma cortisol or ACTH (p > 0.05 for all comparisons). Notably, the PMDD group displayed significantly lower 24-hour UFC levels compared to the AC group during both the follicular and luteal phases (p = 0.0004 and p = 0.0007, respectively). The observed hyposecretion of cortisol in the PMDD group suggests a pathophysiology distinct from other depressive disorders, possibly aligning more closely with stress disorders such as PTSD. The unique symptom profile of PMDD, marked by significant irritability and a more rapid response to antidepressant treatment than is typical in major depression, further supports considering an alternative classification.