Premenstrual dysphoric disorder is a disabling complex of mood and physical symptoms that affects 5-8% of premenopausal women. Because symptoms are limited to the luteal phase of the menstrual cycle, fluxes in reproductive hormones during the cycle are thought to precipitate symptoms. However, the mechanisms through which hormonal fluctuations produce symptoms of PMDD remain unclear. To date, there has been little study of the role of androgen hormones in PMDD. Although circulating levels of androgen hormones do not rise in the luteal phase, androgen precursors, including progesterone and pregnenolone, do rise in the luteal phase and can be converted to androgens in brain and other tissues. Increased sensitivity to locally synthesized androgens in women with PMDD could lead to several prominent PMDD symptoms, including irritability, mood lability, and bloating. In this R34 exploratory treatment development application, we propose to clarify the role of androgen hormones in PMDD by conducting a pilot treatment efficacy study. The efficacy of a specific androgen receptor antagonist, flutamide, for treatment of PMDD will be tested in a placebo-controlled study. 64 subjects will be recruited who meet DSM-IV criteria for PMDD, confirmed by two months of prospective daily ratings. Subjects will be randomized to two months of treatment with either flutamide or placebo. This study will enable determination of an effect size for this treatment, which is necessary for design of a larger scale clinical trial, and will also provide data regarding the tolerability of this treatment. If there is preliminary evidence of efficacy of this anti-androgen treatment, and the treatment is well-tolerated, a full-scale clinical trial will be planned. If the treatment shows evidence of efficacy, but is not well-tolerated, alternative methods of blocking androgen hormone activity will be investigated. This study will also provide evidence as to whether androgen hormones, acting through androgen receptors, play a role in the pathophysiology of PMDD.
