Clinical trial NCT00287586: Testosterone Replacement in Older Men and Atherosclerosis Progression
Official title: Effects of Testosterone Replacement on Atherosclerosis Progression in Older Men With Low Testosterone Levels
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Hypogonadism
Atherosclerosis
Keywords: Testosterone Replacement
Heart Disease
Vascular Disease
Risk Factors for Cardiovascular Disease
Cholesterol
Obesity
Blood pressure
Quality of Life
Lead sponsor: Brigham and Women's Hospital
Sponsor class: OTHER
Collaborators: name: Solvay Pharmaceuticals
First posted: 2006-02-07
Enrollment: 308
Sex: MALE
Minimum age (years): 60
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change From Baseline in Common Carotid Artery Intima-Media Thickness (IMT)
timeFrame: Baseline and Month 36
measure: Change From Baseline in Coronary Artery Calcium Score
timeFrame: Baseline and Month 36
Secondary outcomes:
measure: Change From Baseline in Lipid Profiles
timeFrame: Baseline and Month 36
measure: Changes in Biomarkers of Inflammation
timeFrame: Three years
measure: Changes in Blood Pressure
timeFrame: Three years
measure: Change From Baseline in Complex Figure (Immediate) and Complex Figure (Delayed)
timeFrame: Baseline and Month 36
measure: Change From Baseline in Paragraph Recall Test (Delayed)
timeFrame: Baseline and Month 36
measure: Change From Baseline in the Buschke Selective Reminding Test (Delayed)
timeFrame: Baseline and Month 36
measure: Change From Baseline in the Verbal Fluency Test
timeFrame: Baseline and Month 36
measure: Change From Baseline in the Category Fluency Test
timeFrame: Baseline and Month 36
measure: Change From Baseline in the Stroop Interference Test
timeFrame: Baseline and Month 36
measure: Change From Baseline in the Trail Making Test B
timeFrame: Baseline and Month 36
measure: Change From Baseline in Chest Press Strength and Leg Press Strength
timeFrame: Baseline and Month 36
measure: Change From Baseline in Unloaded Stair Climb Power and Loaded Stair Climb Power
timeFrame: Baseline and Month 36
measure: Change in Sexual Function as Assessed by the International Index of Erectile Function (IIEF)
timeFrame: Baseline and Month 36
measure: Change in Health Quality of Life (QoL) as Assessed by Short Form 36 (SF-36)
timeFrame: Baseline and Month 36
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Kronos Longevity Research Institute
state: Arizona
city: Los Angeles
country: United States
facility: Charles R. Drew University of Medicine and Science
state: California
city: Boston
country: United States
facility: Boston University / Boston Medical Center
state: Massachusetts
Study officials:
affiliation: Boston University / Boston Medical Center, Boston, MA
name: Shalender Bhasin, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Huang G, Pencina KM, Li Z, Basaria S, Bhasin S, Travison TG, Storer TW, Harman SM, Tsitouras P. Long-Term Testosterone Administration on Insulin Sensitivity in Older Men With Low or Low-Normal Testosterone Levels. J Clin Endocrinol Metab. 2018 Apr 1;103(4):1678-1685. doi: 10.1210/jc.2017-02545.
citation: Bhasin S, Travison TG, O'Brien L, MacKrell J, Krishnan V, Ouyang H, Pencina K, Basaria S. Contributors to the substantial variation in on-treatment testosterone levels in men receiving transdermal testosterone gels in randomized trials. Andrology. 2018 Jan;6(1):151-157. doi: 10.1111/andr.12428. Epub 2017 Oct 5.
citation: Gagliano-Juca T, Icli TB, Pencina KM, Li Z, Tapper J, Huang G, Travison TG, Tsitouras P, Harman SM, Storer TW, Bhasin S, Basaria S. Effects of Testosterone Replacement on Electrocardiographic Parameters in Men: Findings From Two Randomized Trials. J Clin Endocrinol Metab. 2017 May 1;102(5):1478-1485. doi: 10.1210/jc.2016-3669.
citation: Storer TW, Basaria S, Traustadottir T, Harman SM, Pencina K, Li Z, Travison TG, Miciek R, Tsitouras P, Hally K, Huang G, Bhasin S. Effects of Testosterone Supplementation for 3 Years on Muscle Performance and Physical Function in Older Men. J Clin Endocrinol Metab. 2017 Feb 1;102(2):583-593. doi: 10.1210/jc.2016-2771.
citation: Huang G, Wharton W, Bhasin S, Harman SM, Pencina KM, Tsitouras P, Li Z, Hally KA, Asthana S, Storer TW, Basaria S. Effects of long-term testosterone administration on cognition in older men with low or low-to-normal testosterone concentrations: a prespecified secondary analysis of data from the randomised, double-blind, placebo-controlled TEAAM trial. Lancet Diabetes Endocrinol. 2016 Aug;4(8):657-665. doi: 10.1016/S2213-8587(16)30102-4. Epub 2016 Jul 1.
citation: Basaria S, Harman SM, Travison TG, Hodis H, Tsitouras P, Budoff M, Pencina KM, Vita J, Dzekov C, Mazer NA, Coviello AD, Knapp PE, Hally K, Pinjic E, Yan M, Storer TW, Bhasin S. Effects of Testosterone Administration for 3 Years on Subclinical Atherosclerosis Progression in Older Men With Low or Low-Normal Testosterone Levels: A Randomized Clinical Trial. JAMA. 2015 Aug 11;314(6):570-81. doi: 10.1001/jama.2015.8881.