Testosterone Dose-Response on Cardiometabolic Outcomes in Surgically Menopausal W

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DESCRIPTION (provided by applicant): The overall goal of this proposal is to evaluate the potential adverse effects of testosterone therapy at varying doses on cardiovascular risk profile in surgically menopausal women. Testosterone dose-response relationships on changes in body fat distribution and metabolic outcomes in women have not been established previously. In women with PCOS, testosterone levels have been positively associated with fat mass, dyslipidemia and insulin resistance. Testosterone formulations are being developed for the treatment of sexual dysfunction in post-menopausal women. However, the data from PCOS women demonstrating the association of higher testosterone levels with fat mass, proatherogenic dyslipidemia, and insulin resistance suggest that exogenous androgens may worsen metabolic and cardiovascular risk outcomes in women. As a result, there has been significant controversy in the medical community about the long term safety of androgen supplementation in women with sexual dysfunction. We propose a study in which: 1) we will compare changes in abdominal fat distribution, insulin resistance, lipid profile and inflammatory markers in surgically menopausal women with low serum testosterone levels receiving a range of testosterone doses over a 6-month time period, and 2) we will assess the associations of these various metabolic and inflammatory markers with changes in abdominal fat distribution in response to testosterone administration. A dose-response analysis will help us identify a therapeutic range of testosterone concentrations that can achieve beneficial effects on sexual function without having significant adverse effects on cardiovascular risk profile. This proposed study, in addition to advancing our understanding of mechanisms underlying effects of physiologic and supraphysiologic doses of testosterone on cardiovascular markers, is likely to lay the groundwork for future long-term intervention trials assessing cardiovascular safety of androgen therapy in women.