MON-136 - Beyond Hypercortisolism: Cortisol Dysregulation in Premenstrual Dysphoric Disorder and Treatment Modulation of the HPA Axis

Objective:
To synthesize existing literature on PMDD, focusing on neuroendocrine markers of cortisol regulation and the impact of focused treatment modalities.

Background:
PMDD is a debilitating endocrine-related disorder distinct from major depressive disorder, marked by a cyclic link to the menstrual cycle and remission by menopause. PMDD’s pathophysiology involves a heightened neural sensitivity to normal ovarian hormone fluctuations rather than a consistently elevated hormonal state. Cortisol, a crucial steroid of the HPA axis and a biomarker for stress reactivity, is maladaptive to stress levels in PMDD patients rather than hypersecreted. Understanding the neuroendocrine sensitivity towards cortisol and its modulators, including allopregnanolone, is critical for refining targeted therapeutic interventions.

Methods
A systematic PubMed search identified studies on HPA axis function in PMDD. Included studies were reviews, observational studies, stress paradigms, or randomized controlled trials reporting cortisol measures, circadian or sleep biomarkers, stress reactivity, or treatment effects. Studies with comorbid psychiatric or endocrine disorders and without relevant neuroendocrine outcomes were excluded. Data was extracted and synthesized qualitatively.

Results
Across studies, the observed pattern suggests that PMDD results from impaired stress recovery or heightened stress sensitivity rather than hypercortisolism. Unlike MDD, which is characterized by elevated cortisol and HPA hyperactivity, women with PMDD often display normal cortisol levels but blunted responses to stress, highlighting a phase-dependent, maladaptive stress-responsivity pattern rather than generalized hypercortisolism.

In line with this model of dysregulated HPA axis activity, emerging treatment studies have identified selective serotonin reuptake inhibitors (SSRIs) and phosphatidylserine/phosphatidic acid supplementation (PAS) as potentially effective interventions to normalize stress responsivity in PMDD. SSRIs appear to balance HPA axis responsivity by increasing allopregnanolone, thereby modulating cortisol response and stabilizing the stress reactivity in PMDD. PAS was observed to reduce cortisol peaks and mitigate luteal-phase stress, indicated by a decrease in overall serum cortisol levels.

Conclusion
Collectively, this review reframes PMDD as a disorder of neuroendocrine stress-system dysregulation rather than cortisol excess alone. Cortisol dynamics, particularly the cortisol awakening response, serve as a quantifiable biomarker linking symptom severity to treatment response. Targeting HPA axis regulation offers a mechanism-based framework for personalized interventions for PMDD.

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