Testosterone Replacement in Older Men and Atherosclerosis Progression
Testosterone Replacement in Older Men and Atherosclerosis Progression
As men grow older, their testosterone levels decrease with age. One-third of men, 70 years of
 age or older, have low testosterone levels. It is known that short-term testosterone
 replacement is safe, and can increase muscle strength and physical function, but the risks of
 long-term testosterone replacement in older men with low testosterone levels are incompletely
 understood.

 Atherosclerosis is characterized by thickening of the artery walls, and the narrowing of the
 blood vessels as cholesterol is deposited in the lining of the arteries. It is the major
 cause of cardiovascular disease including ischemic heart disease (heart attacks) and stroke.
 Although, historically, there has been a widespread perception that higher levels of
 testosterone might increase the risk of atherosclerosis, the evidence from research does not
 support this. In observational studies, higher testosterone levels have been correlated with
 more favorable cardiovascular risk factors, and supplementation with testosterone to bring
 older men into the normal range for healthy younger men appears to improve several
 cardiovascular risk factors, and may slow the progression of atherosclerosis.

 The primary purpose of this study is to look at the effects of testosterone replacement on
 the progression of atherosclerosis in older men. This study is also being done to find out
 whether replacement with testosterone in older men with low testosterone levels improves
 their health-related quality of life.
Although short-term administration of testosterone in replacement doses is relatively safe,
 the risks of long-term testosterone administration in older men remain poorly understood. The
 two major areas of concern include the potential for increased risk of atherosclerotic heart
 disease and exacerbation of a pre-existing, subclinical prostate cancer. There is a
 widespread perception that testosterone supplementation adversely affects plasma lipoprotein
 profile and increases the risk of atherosclerotic heart disease; this premise is not
 supported by data. Thus, the long-term consequences of testosterone supplementation on the
 risk of atherosclerosis progression remain unknown. While supraphysiological doses of
 testosterone and non-aromatizable androgens frequently employed by body-builders undoubtedly
 decrease plasma high density lipoprotein (HDL)-cholesterol levels, physiologic testosterone
 replacement in older men has been associated with only a modest or no decrease in plasma
 HDL-cholesterol. Cross-sectional studies of middle-aged men find a direct, rather than an
 inverse, relationship between serum testosterone levels and plasma HDL-cholesterol
 concentrations as well as an inverse correlation between serum testosterone levels and
 visceral fat volume. Testosterone supplementation of middle-aged men with truncal obesity is
 associated with a reduction in visceral fat volume, serum glucose concentration, blood
 pressure, and an improvement in insulin sensitivity. All of these changes are associated with
 lower risk for atherosclerosis. These data suggest that serum testosterone levels in the
 range that is mid-normal for healthy young men are 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. Studies in a
 low density lipoprotein (LDL)-receptor deficient mice provide compelling evidence that
 testosterone retards early atherogenesis, and that testosterone effects on atherogenesis are
 mediated through its conversion to estradiol by the action of aromatase enzyme that is
 expressed in the vessel wall. The effects of testosterone replacement on cardiovascular risk
 in humans have never been directly examined. Therefore, the primary objective of this study
 is to examine directly the effects of testosterone replacement on atherosclerosis progression
 in men by measuring common carotid artery intima-media thickness (CCA IMT) and coronary
 artery calcification (CAC) by multidetector computed tomography (MDCT), two independent
 measurements of generalized atherosclerosis.

 The second objective of this study is to determine whether physiologic testosterone
 replacement of older men with low testosterone levels improves health-related quality of
 life. Aging-associated decline in physical, sexual, and cognitive functions contributes to
 diminished quality of life in older men. Although the pathophysiology of impairment in each
 of these subdomains of health-related quality of life is complex and multifactorial, one
 correctable cause of the diminished quality of life in older men is the decrease in serum
 testosterone concentrations. Total and free 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. Spontaneous and experimentally-induced androgen-deficiency
 in young men is associated with decreased muscle mass and strength and impaired sexual
 function. Because loss of muscle mass and function contributes to diminished health-related
 quality of life (HRQOL) in older men, anabolic therapies such as testosterone that increase
 muscle mass and strength, would be expected to improve physical function. In older men with
 low testosterone levels, testosterone might also improve sexual function and marital
 interaction. A growing body of literature suggests that testosterone impacts neuronal
 functioning and may affect cognitive performance. Because physical, sexual, and cognitive
 functions are important determinants of health-related quality of life, testosterone
 replacement of older men with low testosterone levels would be expected to improve general
 health perceptions.

 The aging of humans is a recent evolutionary event. Of the thousand generations of men and
 women who have lived on this planet, only the humans of the last two generations could have
 hoped to live past the age of 50. The population is getting proportionally older. The number
 of people 85 years of age and older today is substantially greater than at the beginning of
 the 20th century. Advancing age is associated with decreased muscle mass and strength, and
 impairment of physical, sexual, and cognitive functions. Diminished muscle mass and strength
 increases the risk of falls, disability and poor quality of life. Age-related impairment of
 sexual and cognitive functions also contributes to overall reduction in quality of life.
 Testosterone replacement, by improving some aspects of physical, sexual and cognitive
 functions, would be expected to improve health-related quality of life.

 Previous studies have established that testosterone replacement in older men with low
 testosterone levels increases muscle mass and strength. However, lack of information in two
 areas has prevented formulation of general recommendations about wider use of testosterone
 replacement in older men. First, the effectiveness of testosterone in improving physical
 function, quality of life, and other health-related outcomes has not been demonstrated.
 Second, while there is agreement that short-term administration of testosterone in
 replacement doses is safe, the long-term risks of testosterone supplementation in older men
 remain unknown. The areas of major concern are the risks of prostate cancer and heart
 disease. Because of the high prevalence, even small increases in the incidence rates of
 atherosclerotic heart disease associated with testosterone supplementation will have
 significant impact on overall morbidity and mortality, and health care costs. The study will
 evaluate one important aspect of the long-term safety of testosterone administration by
 directly examining its effects on the rate of progression of atherosclerosis. If the study
 demonstrates that testosterone retards atherosclerosis progression, then that would provide
 one additional reason for testosterone supplementation of older men with low testosterone
 levels. If the study demonstrates a neutral effect of testosterone on atherosclerosis
 progression, that information would also be reassuring and useful to regulatory agencies.
 This study will establish the efficacy of testosterone replacement in improving physical,
 sexual and cognitive functions that are major determinants of health-related quality of life
 in older men.

 In spite of the paucity of efficacy and safety data, the sales of testosterone and other
 androgenic products have witnessed explosive growth because of increased media attention and
 public interest. During the summer of 2000, testosterone-related stories were on the cover of
 Time, Newsweek, New York Times, and Los Angeles Times. The prescription sales of testosterone
 that had been growing at 25-30% annual rate since 1993, almost doubled in the year 2000, and
 have cumulatively increased 500% since 1993 (Source: IMS Sales Data, provided by Reed Selby,
 Marketing Director for ALZA Corporation). The growing testosterone use in older men, without
 a clear understanding of its benefits or long-term risks, has raised concern among regulatory
 agencies. The proposed study by providing definitive information on the effects of
 testosterone replacement on several measures of efficacy and safety in older men would
 facilitate an analysis of its risk:benefit ratio.
Inclusion Criteria:

 -  Age 60 years or greater

 -  Hypogonadism, Testosterone 100-400 ng/dl or Free Testosterone < 50 pg/ml

 -  Generally good health

 -  At least 8 years of primary school education

 -  Able to pass screening test for dementia

 -  Able to give informed consent

 Exclusion Criteria:

 -  Testosterone level < 100 ng/dl (these individuals will be referred for evaluation of
 severe hypogonadism)

 -  Use of testosterone or other androgens [dehydroepiandrosterone (DHEA),
 Androstenedione] in last year

 -  Use of growth hormone in the last year

 -  Current alcohol of drug dependence [Alcohol Use Disorders Identification Test (AUDIT)
 Score > 8]

 -  Diseases known to affect gonadal function

 -  Medications known to affect gonadal function eg. anticonvulsants, glucocorticoids such
 as prednisone

 -  Prostate cancer, breast cancer

 -  Any cancer that may limit life expectancy to less than 5 years

 -  Limiting neuromuscular, joint or bone disease

 -  History of stroke with residual neurologic deficit

 -  Neurologic condition that would impair cognitive function including:

 epilepsy, multiple sclerosis, human immunodeficiency virus (HIV), Parkinson's disease,
 stroke

 -  Psychiatric disorder in the last year meeting Diagnostic and Statistical Manual of
 Mental Disorders, 4th edition (DSMIV) Axis 1 criteria

 -  Use of psychotropic medicine for at least 6 months

 -  Dementia as assessed by (Telephone Interview for Cognitive Status modified score less
 than 31)

 -  Severe symptoms of benign prostatic hyperplasia (BPH) (American Urological Association
 symptom index score greater than 21)

 -  Prostate nodule or induration of digital rectal exam (DRE)

 -  Prostate specific antigen (PSA) greater than 4 unless participant has had a negative
 transrectal biopsy within last 3 months

 -  Limiting heart disease in including New York (NY) Class III or IV - congestive heart
 failure, unstable angina, or myocardial infarction (MI) in last 3 months

 -  Liver function tests [aspartate aminotransferase (AST) and alanine
 aminotransferase(ALT)] greater than 3 times the upper limit of the reference range

 -  Serum creatinine (Cr) greater than 2.5 mg/dl

 -  Hematocrit greater than 48%

 -  Hemoglobin (Hb)A1c greater than 9.0%

 -  Untreated thyroid disease

 -  Uncontrolled hypertension (systolic blood pressure greater than 160 mmHg or diastolic
 blood pressure greater than 100 mmHg)

 -  Body mass index (BMI greater than 35 kg/m2)

 -  Untreated severe obstructive sleep apnea

 -  Development of electrocardiogram (EKG) changes consistent with myocardial ischemia or
 changes in blood pressure during cardiopulmonary exercise testing will be excluded
 from testing of muscle strength and physical function.