Allopregnanolone in premenstrual dysphoric disorder (PMDD): Evidence for dysregulated sensitivity to GABA-A receptor modulating neuroactive steroids across the menstrual cycle

Premenstrual dysphoric disorder (PMDD) is a severe mood disorder with core symptoms (affective lability, irritability, depressed mood, anxiety) and increased sensitivity to stress occurring in the luteal phase of the menstrual cycle. PMDD can be conceptualized as a disorder of suboptimal sensitivity to neuroactive steroid hormones (NASs). In this review, we describe the role of the NAS allopregnanolone (ALLO), a positive allosteric modulator of the GABA(A) receptor (GABA(A)-R), in PMDD's pathophysiology. We review evidence of impaired interaction between ALLO and GABA(A)-Rs in terms of affective symptom expression, with evidence from rodent and human studies. We discuss evidence of increased luteal phase stress sensitivity as a result of poor ALLO-GABA control of the HPA axis. Finally, we describe how treatments such as selective serotonin reuptake inhibitors (SSRIs) and new drugs targeting GABA(A)-Rs provide evidence for impaired ALLO-GABA function in PMDD. In sum, the literature supports the hypothesis that PMDD pathophysiology is rooted in impaired GABA(A)-R response to dynamic ALLO fluctuations across the menstrual cycle, manifesting in affective symptoms and poor regulation of physiologic stress response.