Gonadal steroids are major neuroregulators and presumably underlie gender-related differences (sexual dimorphisms) 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 disturbance. 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) In preliminary metabolomic data, menstrual cycle effects on plasma levels of tyramine significantly differ in women with PMD and controls. 3) A differential reward-related activation of the orbital frontal cortex and the amygdala was observed in the luteal compared with the follicular phase of the menstrual cycle. 4) 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. 5) 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. 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.
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