The Endocrine Society guideline on Androgen Deficiency in Men emphasized that accurate measurement of testosterone (T) levels is central to the diagnosis of androgen deficiency. However, the accuracy of direct radioimmunoassays for the measurement of total T levels has been questioned. Furthermore, reference limits for total and free T levels generated in a population-based sample of community-dwelling men are not available. In the absence of standardized reference limits, the partitioning of total and free T levels into normal or low values is fraught with substantial risk of misclassification. The objective of this collaboration among investigators from BUMC, Framingham Heart Study (FHS), CDC, and Mayo Clinic is to generate reference limits for total and free T levels in a sample of healthy young men in the community- based FHS third generation (Gen 3) cohort. Total T levels will be measured by liquid chromatography tandem mass spectrometry (LC-MS/MS), using a CDC calibrator. We will calculate free T from total T and SHBG, by using law of mass action equation, in accordance with Endocrine Society's position statement. We will generate reference limits for total and free T levels using nonparametric methods stratifying by age and apply the reference limits generated in Gen 3 sample to the distribution of values in a broad sample of men in both Gen 3 and Offspring (Gen 2) cohorts. We will evaluate the cross-sectional clinical correlates of total and free T levels in the broad sample using multivariable regression. adjusting for age, BMI, co-morbid conditions, smoking, and physical activity. Longitudinally, we will relate total and free T levels at baseline (examination 7) to the incidence of adverse outcomes (primary: mortality, diabetes mellitus, cardiovascular disease events (CVD);secondary: progression of functional limitations and disability) over a follow-up of 10 years. We will develop recommendations for partitioning of men into those with low or normal levels, based on considerations of statistical distribution of total and free T values and the association of outcomes with varying degree of deviations from the reference limits. The proposed study will provide a framework for the interpretation of serum T levels and enhance the comprehensibility of circulating T values to practicing clinicians. These steps will facilitate the development of rational criteria for classifying men into androgen-deficient and androgen-replete categories.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG031206-03
Application #
7796684
Study Section
Aging Systems and Geriatrics Study Section (ASG)
Program Officer
Sherman, Sherry
Project Start
2008-04-15
Project End
2012-02-28
Budget Start
2010-03-15
Budget End
2012-02-28
Support Year
3
Fiscal Year
2010
Total Cost
$479,805
Indirect Cost
Name
Boston Medical Center
Department
Type
DUNS #
005492160
City
Boston
State
MA
Country
United States
Zip Code
02118
Travison, Thomas G; Vesper, Hubert W; Orwoll, Eric et al. (2017) Harmonized Reference Ranges for Circulating Testosterone Levels in Men of Four Cohort Studies in the United States and Europe. J Clin Endocrinol Metab 102:1161-1173
Travison, Thomas G; O'Donnell, Christopher J; Bhasin, Shalender et al. (2016) Circulating Sex Steroids and Vascular Calcification in Community-Dwelling Men: The Framingham Heart Study. J Clin Endocrinol Metab 101:2160-7
Travison, T G; Zhuang, W V; Lunetta, K L et al. (2014) The heritability of circulating testosterone, oestradiol, oestrone and sex hormone binding globulin concentrations in men: the Framingham Heart Study. Clin Endocrinol (Oxf) 80:277-82
Jasuja, Guneet Kaur; Travison, Thomas G; Davda, Maithili et al. (2013) Circulating estrone levels are associated prospectively with diabetes risk in men of the Framingham Heart Study. Diabetes Care 36:2591-6
Jasuja, Guneet Kaur; Travison, Thomas G; Davda, Maithili et al. (2013) Age trends in estradiol and estrone levels measured using liquid chromatography tandem mass spectrometry in community-dwelling men of the Framingham Heart Study. J Gerontol A Biol Sci Med Sci 68:733-40
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Coviello, Andrea D; Haring, Robin; Wellons, Melissa et al. (2012) A genome-wide association meta-analysis of circulating sex hormone-binding globulin reveals multiple Loci implicated in sex steroid hormone regulation. PLoS Genet 8:e1002805
Bhasin, Shalender; Jasjua, Guneet K; Pencina, Michael et al. (2011) Sex hormone-binding globulin, but not testosterone, is associated prospectively and independently with incident metabolic syndrome in men: the framingham heart study. Diabetes Care 34:2464-70
Bhasin, Shalender; Pencina, Michael; Jasuja, Guneet Kaur et al. (2011) Reference ranges for testosterone in men generated using liquid chromatography tandem mass spectrometry in a community-based sample of healthy nonobese young men in the Framingham Heart Study and applied to three geographically distinct cohorts. J Clin Endocrinol Metab 96:2430-9
Ohlsson, Claes; Wallaschofski, Henri; Lunetta, Kathryn L et al. (2011) Genetic determinants of serum testosterone concentrations in men. PLoS Genet 7:e1002313

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