HIV-infection is increasing among women, who represent an understudied subpopulation of infected patients. Unique gender specific hormonal considerations are critical to the study of HIV-infected women. Over the past 4 years, significant progress has been made by our group in understanding the prevalence, pathophysiology and clinical consequences of androgen deficiency in women with AIDS wasting. Furthermore, we have recently completed a randomized, placebo-controlled 6-month study of physiologic testosterone in this population. Our data suggest that androgen deficiency is highly prevalent among women with AIDS wasting, occurring in over 50% of such patients. Detailed physiologic investigations of hormonal parameters in this population suggest relatively intact ovarian function, but decreased adrenal androgen production, and a relative shunting of androgen metabolism toward cortisol production and away from androgen production. Moreover, we-have shown for the first time, a significant reduction in bone density among androgen deficient women with AIDS wasting, characterized by relatively low bone formation rates. Furthermore, data from the 6 month randomized study demonstrates that testosterone at physiologic doses increases muscle function and bone formation indices in this population. Taken together, these data demonstrate a high prevalence and important clinical consequences of androgen deficiency in women with AIDS wasting. In the proposed grant renewal, we build on the data generated in the first grant hypothesizing that reversal of steroid shunting back toward androgen production and away from cortisol production will improve bone metabolism and increase markers of bone formation in HIV-infected women. Finally we will investigate the long-term effects of physiologic androgen replacement over 2 years. The novel studies outlined in this grant proposal will be the first to investigate long-term anabolic androgenic strategies on androgen sensitive endpoints, including bone, body composition and quality of life indices among the growing population of HIV-infected women. The studies outlined in this renewal constitute an important investigative initiative of a targeted, gender-specific therapy in this largely understudied population.
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