Gonadal steroids are major neuroregulators and are presumed to underlie many sex-related differences in brain structure and function. We have studied reproductive endocrine-related mood disorders as well as developed endocrine models for these disorders in order to characterize the role of gonadal steroids in affective regulation and mood disorders. Our major research findings are as follows: 1) We provide the first demonstration of an association between polymorphic genetic variants and premenstrual dysphoric disorder (PMD). Four single nucleotide polymorphisms in the estrogen receptor alpha gene positively associate with the disorder, and evidence for epistasis exists with the BDNF gene. 2) A differential reward-related pattern of brain activation in the orbital frontal cortex and the amygdala was observed in the luteal compared with the follicular phase of the menstrual cycle. 3) Administration of the Cambridge Neuropsychological Test Automated Battery and the Emotional Processing Battery to women with PMD identified impaired emotional coding and recognition, increased susceptibility to affective interference, and decreased capacity for emotional reappraisal and recovery compared with controls. 4) Application of chaos-based Approximate Entropy modeling to mood rating data yielded a suite of statistical descriptors that have very high sensitivity and specificity for PMD compared with recurrent brief depression and controls. 5) Administration of the 5 alpha reductase inhibitor, dutasteride, a medication that inhibits neurosteroid synthesis has no effect on symptoms of PMDD. 6) We have documented for the first time the hourly change in symptom ratings in women with PMDD after treatment with the selective serotonin reuptake inhibitor fluoxetine. In most women response occurs within 48 hours. These observations are of both theoretical and practical importance, as they both identify promising endophenotypes and suggest the physiological basis for the susceptibility to experience menstrual cycle-related mood disorders.
