The cause for the remarkable female to male ratio in Systemic Lupus Ersthematosus (SLE) and other autoimmune diseases is still unknown. In the present application we propose to evaluate the feasibility of a novel idea, namely that the sex hormonal involvement in SLE is at a stage proximal to the production of androgens. We will test the hypothesis that SLE females have low circulating levels of pregnenolone. To this end we will use state-of-the art techniques for measuring this steroid hormone precursor. Pregnenolone is a very important compound in I the pathway of steroid hormone biosynthesis in the adrenal, ovary and testis because it is the branching point that leads to formation of progesterone, androgens and estrogens. Since in females the ovaries are responsible for approximately 60% of total production of pregnenolone, compared to only 30% of pregnenolone produced by testes in males, a defect in the ovarian production of pregnenolone or its bioavailability might provide insight into female predominance in SLE. In addition, we hypothesize that manipulation of disease development can be achieved with Pregnenolone more efficiently and without the potential problems and side effects encountered by more distal androgen precursors such as DHEA which is presently under clinical trial. We propose to test the feasibility of this therapeutic approach in a well-established animal model of SLE. The results of these studies should lead to a novel direction in understanding the role sex steroids in this disease and to a new therapeutic approach in human SLE. This application combines expertise in autoimmune diseases biology (Dr. Jacob) with expertise in reproductive endocrinology (Dr. Stanczyk) and biochemistry of steroid hormones (Dr. Roberts). The project proposed represents a clear and distinct departure from the PI's and the other investigators ongoing research.