The role of progesterone and its metabolites in premenstrual disorders of affect

It is estimated that between 70% and 90% of women in their reproductive years experience some level of discomfort and experience affective and/or somatic symptoms during the premenstrual (luteal) phase of their menstrual cycle. These symptoms range from mild discomfort to severe emotional and somatic symptoms, with the latter seen particularly in women diagnosed with Premenstrual Dysphoric Disorder (PMDD). Although the neurobiological basis of the Premenstrual syndrome (PMS) and PMDD is still not completely understood, there appears to be a relationship between the levels of certain gonadal steroids and their metabolites on the development or exacerbation of these premenstrual disorders of affect. Here we review our current understanding of how progesterone, and its metabolite, allopregnanolone, may relate to such mood disturbances, focusing particularly on both conventional and more recently described, alternative mechanisms by which these neurosteroids exert their effects on the GABA_A receptor. Based on published reports and recent data from our laboratory, we propose that progesterone and its 5α-reduced metabolite, allopregnanolone, may have distinct effects on GABA-A receptor function, resulting from distinct mechanisms of action. This difference, we assert, may help explain the discrepant association between the levels of progesterone and/or its metabolites and the development of premenstrual disorders of affect, including PMDD.