Effects of testosterone replacement on cardiovascular risk factors and atherosclerosis progression, physical function, and health-related quality of life, in older men with low testosterone levels
Principal Investigator: Shalendar Bhasin, MD
Co-investigators: S. Mitchell Harman, MD, PhD, Panayiotis D. Tsitouras, MD, Thomas Storer, PhD, Tinna Traustadóttir, PhD
Aging-associated loss of muscle mass and function (sarcopenia) has emerged as an important public health problem that contributes to decreased functional mobility, increased risk of falls and fractures, and a poor quality of life in the elderly. Although sarcopenia is a multifactorial process resulting from perturbations in multiple hormonal axes (including the growth hormone/insulin like growth factor-I:GH/IGF-I axis), decreased physical activity, chronic illness, and, probably, unknown factors as well, a potentially correctable cause of age-related sarcopenia is the decrease in serum testosterone concentrations characteristic of older men. Both cross-sectional and longitudinal studies have demonstrated that total and free plasma testosterone (T) levels decline with advancing age in normal men, with a significant number of men meeting usual criteria for hypogonadism by the sixth to seventh decades. Androgen-deficiency in young men is associated with decreased muscle mass and impaired sexual function and low testosterone levels are associated with decreased muscle mass and lower extremity strength in older men. Testosterone replacement increases lean body mass, muscle strength, and muscle protein synthesis in androgen-deficient, young men and in older men with low testosterone levels. However, the effects of testosterone supplementation on other health-related outcomes have not been well studied, and therefore, the risks and benefits of long-term androgen administration in elderly men remain unknown. Moreover, we do not know whether testosterone replacement in older men improves physical function.
Although short-term administration of testosterone in replacement doses is relatively safe, the risks of long-term testosterone administration to older men remain poorly understood. The two major areas of concern with regard to risk are the potential for acceleration of atherosclerotic heart disease and exacerbation of a pre-existing, subclinical prostate cancer. There is a widespread perception that testosterone supplementation adversely affects the plasma lipoprotein profile and increases the risk of atherosclerotic heart disease. However, review of the available data does not support this premise. Thus, the long-term consequences of testosterone supplementation on these risks remain unknown. Physiologic testosterone replacement in older men has been associated with only a modest or no decrease in plasma HDL-cholesterol and small or no increases in plasma LDL cholesterol. Testosterone supplementation of middle-aged men with central obesity is associated with a reduction in visceral fat volume, serum glucose concentration, blood pressure, and an improvement in insulin sensitivity. Recently studies have even found that low testosterone levels in older men is associated with increases in the "metabolic syndrome" and mortality. These data suggest that serum testosterone levels in the range that is mid-normal for healthy young men may be consistent with an optimal cardiovascular risk profile at any age, and that testosterone concentrations either above or below the physiologic male range may increase the risk of atherosclerotic heart disease. The effects of testosterone replacement on overall cardiovascular risk have never been directly examined in men over 60.
Therefore, we are carrying out a randomized controlled trial to determine how testosterone replacement with a transdermal gel in men 60-85 years of age with low to low-normal testosterone levels affects progression of atherosclerosis assessed by changes over time in common carotid artery intima-media thickness (CCA IMT) by ultrasound and coronary artery calcification (CAC) by X-ray tomography. We are also measuring both conventional and non-conventional cardiovascular risk factors. In addition we are examining body composition, muscle mass and strength, physical function, cognitive function, and health-related quality of life. This multi-center study will recruit a total of 320 participants (180 at KLRI and 140 at the Los Angeles and Boston centers) over a four-year period, and the selected men will be treated for three years.
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Underway |
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At baseline, men have blood and urine testing for cardiovascular risk factors, hormone levels, and measures of oxidative stress, body composition and bone density measurements by DEXA, assessments of functional capacity and quality of life using validated and standardized procedures, and CCA-IMT and EBT measurements for degree of atherosclerosis. Men are randomized to either physiologic testosterone replacement using an FDA approved transdermal gel preparation, testosterone plus an oral aromatase inhibitor (which prevents conversion of testosterone to estrogens), or placebo gel. At scheduled intervals over a three year period, we then obtain blood levels of testosterone, estrogens, IGF-I, cardiovascular risk factors, and measures of oxidative stress, DEXA body composition, strength and physical function testing, health related quality of life assessments, and CCA-IMT and EBT studies. |
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