Premenstrual dysphoric disorder (PMDD), a severe form of premenstrual syndrome (PMS) afflicts 5-8 percent of women in their reproductive years. Despite more that 60 years of research, the physiological mechanisms contributing to this disorder remain elusive. Consistent with the heterogenous nature of PMDD, there may be different subgroups of women with different etiologic mechanisms. This study is designed to test the hypothesis that PMDD women with prior histories of major depression (MD) represent a large subgroup of PMDD women with unique pathophysiology. Specifically, it is hypothesized that PMDD women with prior MD will be more sensitive to the mood altering effects of gonadal steroid hormones, particularly progesterone (P), and that the increased sensitivity to P in PMDD women with prior MD will be associated with enhanced noradrenergic activation (indexed by greater beta-adrenergic receptor responsivity, greater plasma norepinephrine and MHPG, and greater cardiac reactivity to stress), relative not only to other PMDD women with no prior MD history, but also relative to controls with prior MD. It is predicted that it is dysregulation in noradrenergic systems that contribute to the greater premenstrual symptoms in PMDD women with prior MD. A second hypothesis is that regrardless of MD histories, all PMDD women will show blunted hypothalamic-pituitary-adrenal (HPA) axis activation (indexed via plasma cortisol and ACTH), and dysregulation in the neurosteroids allopregnanolone (ALLO) and 3alpha-21-dihydroxy-5alpha-pregnan-20 one (3alpha,5alpha-THDOC), relative to controls. After prospective confirmation of PMDD diagnosis, via daily mood ratings, 40 PMDD women and 40 matched controls will undergo structured clinical interview based on established psychiatric criteria in order to confirm that 50 percent of each group meets criteria for prior MD. Initial laboratory testing will occur in both the follicular and luteal phases of the menstrual cycle and will involve mood assessment via standardized questionnaires and exposure to standardized mental stressors, where groups will be compared for cardiac and blood pressure reactivity, and for plasma norepinephrine, MHPG, ACTH, cortisol and neurosteroid responses. Each subject will also be exposed to the standardized isoproterenol (beta-receptor agonist) sensitivity test in order to measure beta-adrenoceptor responsivity. Following this initial testing phase, subjects will be tested for progesterone-induced alterations in mood and neuroendocrine factors using a double-blind, placebo-controlled design. Specifically, subjects will be retested during the early follicular phase of 2 separate menstrual cycles, where, in each cycle, subjects will be exposed to the identical testing and sampling procedures described above, once before and once 2.5 hours after ingestion of oral, micronized P (600mg or placebo). Order of P vs. placebo will be randomly determined for each subject. The results of this study are intended to provide important new insights into the pathophysiological significance of gonadal hormones and neuroendocrine dysregulation in different subgroups of PMDD women (i.e. with versus without prior MD), yielding implications for clinical treatments.
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