Estradiol treatment of stress-related psychiatric disorders in Veterans

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Stress is a major risk factor for the development of various neuropsychiatric conditions, including depression, anxiety, and post-traumatic stress disorder (PTSD), which disproportionately affect our military personnel and Veterans. We have discovered that brain conversion of 17β-estradiol (E2) from circulating testosterone promotes a maladaptive response to stress in male mice. We have found that the absence of E2 in brain, but not testosterone per se, underlies this susceptibility. Our preliminary data provides evidence for the effectiveness of E2 as a novel antidepressant and have established a circuit-based mechanism through which stress interacts with hypogonadism to mediate depressive-like behavior in males. We hope to translate these basic scientific discoveries into tangible benefits for military personnel and Veterans of both sexes who urgently need improved care for stress-related disorders. While E2 is not a viable treatment in human male populations due to its peripheral side effects, the E2 bioprecursor 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED) overcomes this limitation by delivering E2 directly to the brain after conversion by NADPH-dependent reductase. Unfortunately, DHED has poor oral bioavailability, which limits its potential use as a novel therapeutic in patients. We propose to advance knowledge regarding the role of targeting E2 signaling as a treatment mechanism for stress-induced neuropsychiatric disorders, and further the discovery of a brain-selective and orally bioavailable prodrug of DHED based on the previously characterized structure of the molecule. In Specific Aim #1, we will use rodent models of psychiatric disease treatment effectiveness to further determine the role of E2 signaling in mediating stress susceptibility in males. These studies will address hypogonadism- and age-dependent mechanisms of enhanced susceptibility to stress and pathological fear, relevant to neuropsychiatric conditions that disproportionately affect those who have served in the military. This will help identify which psychiatric disorders, in addition to depression, may be most amenable to E2-mediated treatment. In Specific Aim #2, we will assess candidate prodrugs for improved oral bioavailability. We will determine the oral bioavailability of DHED prodrugs by comparing levels of DHED and E2 in the brain following intravenous and oral administration in male and female rodents. Those prodrugs that exhibit favorable oral bioavailability and E2 production in the brain will be tested for in vivo response to E2-related biomarkers and therapeutic efficacy for stress-related phenotypes. At completion of our experiments, we will have an improved understanding of the role of estrogen signaling in depression, PTSD, and other stress-influenced neuropsychiatric conditions in males and have better defined a novel treatment approach for both males and females with estrogen responsive disorders. Additionally, we will generate preclinical data that will support a future treatment for military personnel and Veterans suffering from stress-induced neuropsychiatric conditions.