__________________________________________________Principal Investigator: COVIELLO, ANDREAABSTRACTWomen with polycystic ovary syndrome, a known disorder of androgen excess, are at increased risk formetabolic syndrome, type 2 diabetes, dyslipidemia and hypertension raising concern for increasedcardiovascular disease risk as well. However, the relation of circulating testosterone levels with women'shealth outcomes in the general population is poorly understood and the subject of this investigation.Preliminary data from the women in the Offspring Cohort of the Framingham Heart Study (FHS) revealed astrong positive association between higher free testosterone and metabolic syndrome, type 2 diabetes,dyslipidemia, and high blood pressure. However, studies of the association of testosterone levels withoutcomes in women have been hampered by the inaccuracy of the platform-based immunoassays in the lowrange prevalent in women. The overall objective of this proposal is to characterize circulating testosteronelevels in women across a broad age range from a community-based population using state of the art liquidchromatography tandem mass spectrometry (LC-MS/MS) method. The Framingham Heart Study (FHS)cohorts are ideally suited for this project given the study's community-based sample population, stored serum,and extensive clinical phenotyping. Furthermore, LC-MS/MS method provides accurate and precisemeasurement of testosterone concentrations in the low range found in women. We will assess the associationbetween circulating testosterone levels and health outcomes in ~4500 women, focusing on metabolic andcardiovascular disease, in cross-sectional and longitudinal analyses over a 5-10 year period. We will firstformulate a population-based reference range for total and free testosterone in women with the FraminghamHeart Study cohorts measuring total testosterone by LC-MS/MS and calculating free testosterone by usingupdated law of mass action equations (specific aim 1). We will determine the cross-sectional clinicalcorrelates of testosterone, including relations to prevalent metabolic dysfunction (type 2 diabetes, dyslipidemia/ atherogenic lipid profiles, hypertension, metabolic syndrome, and cardiovascular disease) in women across abroad age range (specific aim 2). We will evaluate the relations of circulating total testosterone, freetestosterone, sex-hormone binding globulin (SHBG) and incident metabolic (type 2 diabetes mellitus,dyslipidemia / atherogenic lipid profiles, metabolic syndrome), hypertension, and cardiovascular disease inwomen longitudinally (specific aim 3). We will generate reference limits for total and free testosterone levelsin women based on the results of the longitudinal analysis. The proposed investigation, by furthering ourknowledge of the health consequences of high testosterone levels in women, a potentially modifiable hormonalfactor, will facilitate the identification of high risk individuals as well as the development of effective riskreduction strategies for metabolic dysfunction and cardiovascular disease for women across a broad agerange.
Principal Investigator: COVIELLO, ANDREA PROJECT NARRATIVE The effect of testosterone on women's health in the general population is unclear but of increasing concern clinically. Women with polycystic ovary syndrome, a known disorder of androgen excess, are at increased risk for metabolic syndrome, type 2 diabetes, dyslipidemia and hypertension raising concern for increased cardiovascular disease risk as well. There is also increasing evidence of adverse health conditions in women with low androgen states including low bone density, sexual dysfunction, and depression. Thus, there may be a critical range of testosterone levels in women associated with health. Determination of the adverse health effects of androgen excess and deficiency is crucially dependent upon knowledge of normal androgen states in women across the lifespan. Our overall objective is to characterize circulating testosterones in women across a broad age range from a community-based population;the Framingham Heart Study (FHS) cohorts are ideally suited for this project given the study's community-based sample population, stored serum, and extensive clinical phenotyping. Testosterone will be measured using state of the art assay methodology, liquid chromatography tandem mass spectrometry (LC-MS/MS) that provides accurate and precise measurement of testosterone concentrations in the low range found in women. We will assess the association between circulating testosterone levels and health outcomes in women, focusing on metabolic and cardiovascular disease.
