SeriesTestosterone treatment in older men: clinical implications and unresolved questions from the Testosterone Trials
Introduction
Testosterone replacement is routine for men with androgen deficiency due to underlying hypothalamic, pituitary, or testicular disease.1 Data from predominantly white populations show that the concentration of circulating testosterone in men decreases with age,2, 3, 4 even in the absence of hypothalamic-pituitary-testicular axis pathology, in parallel with an accumulation of age-related comorbidities. Geographical and racial variation might exist; in the USA, circulating testosterone concentrations are higher in African-American men than in white men, and Asian men living in Hong Kong and Japan have higher circulating testosterone concentrations than Asian men living in the USA. Longitudinal trajectories are less well characterised in men of other ethnic backgrounds.5, 6 Prescription of testosterone therapy to middle-aged and older men has increased markedly in recent decades,7, 8 especially in North America, probably in part because of direct consumer advertising.9 This trend occurred despite a relatively stable prevalence of pathological hypogonadism and despite the absence of definitive evidence from randomised controlled clinical trials. The Institute of Medicine has recommended short-term trials to determine testosterone efficacy in middle-aged and older men with low testosterone concentrations relative to the normal range for healthy young men and with androgen deficiency-like symptoms, with initiation of subsequent long-term trials dependent on initial findings from these short-term trials.10 The National Institutes of Health subsequently funded the Testosterone Trials (T-Trials) to address this need. The T-Trials11, 12 were a coordinated set of trials in 12 academic centres in the USA that involved 790 men aged 65 years or more who were randomly assigned to transdermal testosterone or placebo for 12 months. Eligible participants had a baseline testosterone concentration less than 9·54 nmol/L (<275 ng/dL, averaged from at least two measurements) and at least one symptom or sign consistent with hypogonadism (decreased libido, difficulty walking, or low vitality). The telephone screening-to-enrolment ratio was 65:1, equating to a recruitment yield of 1·5%.11 Dosing was adjusted to ensure that participants in the treatment group maintained a serum testosterone concentration within, but not in excess of, the normal range for healthy young men.12 Men with pathological hypogonadism were excluded. Most men enrolled into the T-Trials had cardiovascular risk factors such as obesity (63%) and hypertension (72%), and 15% of men had a history of myocardial infarction. Men could be included in one or more of seven trials depending on meeting specific eligibility criteria (table 1). In the European Male Ageing Study,17 sexual symptoms were most specific to the age-related decrease in testosterone concentrations. It is therefore noteworthy that the T-Trials results published in 201612 showed a modest improvement in sexual function with testosterone treatment, whereas the primary outcomes for vitality and physical function were not met (table 1). Here we review the background to and the results of the four remaining substudies, with outcomes related to cardiovascular disease,13 cognition,14 bone,15 and anaemia,16 and we discuss their clinical implications in the context of the existing evidence.
Section snippets
Testosterone and cardiovascular disease
Findings from epidemiological studies have shown that reduced endogenous androgens in middle-aged and older men are associated with adverse cardiovascular outcomes, including a higher incidence of cardiovascular events such as stroke18, 19, 20 and increased cardiovascular and all-cause mortality.21, 22, 23, 24 These associations have been confirmed in several large meta-analyses.25, 26, 27 However, observational studies do not prove causality, and in the case of menopausal hormone therapy in
T-Trials Cardiovascular Trial
170 of the men enrolled in the T-Trials had coronary artery plaque progression quantified by coronary CT angiography (CCTA) during the 12-month treatment period.13 66% of participants had hypertension, 30% diabetes, and 9% a prior myocardial infarction—a similar cardiovascular burden to the entire T-Trial population.12 51% of participants had a coronary artery calcification score greater than 300 Agatston units at baseline, suggesting severe atherosclerosis. 138 of the 170 men who were enrolled
Testosterone and cognition
Findings from epidemiological studies have associated reduced circulating testosterone concentration with poorer cognitive performance, but the data are not wholly consistent.62 In cross-sectional studies of middle-aged and older men, positive associations of testosterone with measures of general cognition have been reported,63, 64, 65, 66 as have neutral67 or inverse associations.68 In longitudinal studies, an increased ratio of testosterone to sex hormone-binding globulin was associated with
T-Trials Cognitive Function Trial
The Cognitive Function Trial reported by Resnick and colleagues14 included 493 men with age-associated memory impairment, defined as the presence of both subjective memory complaints and objective memory impairment (table 1). Baseline Mini Mental State Examination score was 28 (of a maximum score of 30). Testosterone and placebo groups were balanced in terms of baseline covariates and baseline cognitive function test scores. The trial result was clearly negative, and testosterone treatment did
Testosterone, bone structure, and fracture risk
Pathological hypogonadism due to hypothalamic, pituitary, or testicular disease is an important risk factor for osteoporosis in adult men.95 The prevalence of hypogonadism in older men with osteoporosis is not well described. In uncontrolled case series of men older than 60 years referred to metabolic bone clinics with previous minimal trauma fractures, 7–8% had evidence of hypogonadism.96, 97 Although randomised controlled trials have not been done, testosterone replacement therapy increases
T-Trials Bone Trial
The Bone Trial15 is the largest randomised controlled trial of the effects of testosterone treatment on BMD in older men (table 1). The study investigators determined the effect of testosterone on bone structure using quantitative CT. Nine of the 12 T-Trial sites in the USA participated and enrolled 211 men, meeting the enrolment target of 200 men. Men had normal BMD at baseline, as quantified by DXA, with T-scores ranging from −0·3 to 1·3 at baseline. After 12 months, compared with placebo,
Testosterone and anaemia
In community-dwelling men, the concentration of circulating testosterone correlates with haemoglobin concentrations.126, 127 Moreover, in multiple studies in both older and young men, testosterone treatment was found to increase haemoglobin concentration and haematocrit in a dose-dependent manner.128, 129, 130, 131 Recent findings by Bhasin and colleagues132, 133 suggested that testosterone induces erythropoiesis by decreasing expression of hepcidin, an important regulator of red blood cell
T-Trials Anaemia Trial
The Anaemia Trial16 was designed to specifically address whether treating older men with both low testosterone concentration and unexplained anaemia (haemoglobin concentration <12·7 g/dL) would increase haemoglobin concentrations. In so doing, this T-Trials substudy in part addressed the issue raised by the Institute of Medicine with respect to the need to demonstrate a benefit for testosterone therapy in several organ systems before conducting a larger randomised controlled trial powered to
Conclusions
Collectively, the T-Trials represent an important step forward and provide the most definitive and systematic evidence to date with respect to the multiorgan effects of testosterone treatment in carefully selected older men without overtly pathological hypogonadism. Testosterone treatment increased bone density and bone strength and improved haemoglobin concentrations, resolving anaemia irrespective of the aetiology in a substantial proportion of men. These results could be expected to
References (143)
- et al.
Association between exogenous testosterone and cardiovascular events: an overview of systematic reviews
Lancet Diabetes Endocrinol
(2016) - et al.
Impact of testosterone replacement therapy on myocardial infarction, stroke and death in men with low testosterone concentrations in an integrated health care system
Am J Cardiol
(2016) - et al.
Survival and cardiovascular events in men treated with testosterone replacement therapy: an intention-to-treat observational cohort study
Lancet Diabetes Endocrinol
(2016) - et al.
Prognostic value of cardiac computed tomography angiography
J Am Coll Cardiol
(2011) - et al.
Association of cardiac events with coronary artery disease detected by 64-slice or greater coronary CT angiography: a systematic review and meta-analysis
Int J Cardiol
(2013) - et al.
Genetic epidemiology and public health: hope, hype, and future prospects
Lancet
(2005) - et al.
Endogenous androgen exposures and ischemic heart disease, a separate sample Mendelian randomization study
Int J Cardiol
(2016) - et al.
Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study
Lancet
(2012) Hormonal changes and their impact on cognition and mental health of ageing men
Maturitas
(2014)- et al.
The association between endogenous free testosterone and cognitive performance: a population-based study in 35 to 90 year-old men and women
Psychoneuroendocrinology
(2006)
Negative association of testosterone on spatial visualisation in 35-80 year old men
Cortex
Effect of testosterone undecanoate on visuospatial cognition, mood and quality of life in elderly men with low-normal gonadal status
Maturitas
Characterization of verbal and spatial memory changes from moderate to supraphysiological increases in serum testosterone in healthy older men
Psychoneuroendocrinology
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 TEAMM trial
Lancet Diabetes Endocrinol
Risk factors for spinal osteoporosis in men
Am J Med
Endocrine Society of Australia position statement on male hypogonadism (part 1): assessment and indications for testosterone therapy
Med J Aust
Longitudinal effects of aging on serum total and free testosterone levels in healthy men
J Clin Endocrinol Metab
Age trends in the level of serum testosterone and other hormones in middle-aged men: longitudinal results from the Massachusetts Male Aging Study
J Clin Endocrinol Metab
Reference ranges and determinants of testosterone, dihydrotestosterone and estradiol levels measured using liquid chromatography-tandem mass spectrometry in a population-based cohort of older men
J Clin Endocrinol Metab
Trends in sex hormone concentrations in US males: 1988–1991 to 1999–2004
Int J Androl
Evidence for geographical and racial variation in serum sex steroid levels in older men
J Clin Endocrinol Metab
Global trends in testosterone prescribing, 2000–2011: expanding the spectrum of prescription drug misuse
Med J Aust
Testosterone lab testing and initiation in the United Kingdom and the United States 2000–2011
J Clin Endocrinol Metab
Association between direct-to-consumer advertising and testosterone testing and initiation in the United States, 2009–2013
JAMA
Recruitment and screening for the Testosterone Trials
J Gerontol A Biol Sci Med Sci
Effects of testosterone treatment in older men
N Engl J Med
Testosterone treatment and coronary artery plaque volume in older men with low testosterone
JAMA
Testosterone treatment and cognitive function in older men with low testosterone and age-associated memory impairment
JAMA
Effect of testosterone treatment on volumetric bone density and strength in older men with low testosterone: a controlled clinical trial
JAMA Intern Med
Association of testosterone levels with anemia in older men: a controlled clinical trial
JAMA Intern Med
Identification of late-onset hypogonadism in middle-aged and elderly men
N Engl J Med
Lower testosterone levels predict incident stroke and transient ischemic attack in older men
J Clin Endocrinol Metab
In older men, higher plasma testosterone or dihydrotestosterone is an independent predictor for reduced incidence of stroke but not myocardial infarction
J Clin Endocrinol Metab
Testosterone and dihydrotestosterone and incident ischaemic stroke in men in the Cardiovascular Health Study
Clin Endocrinol
Low serum testosterone and mortality in older men
J Clin Endocrinol Metab
Low serum testosterone levels are associated with increased risk of mortality in a population-based cohort of men aged 20–79
Eur Heart J
In older men an optimal plasma testosterone is associated with reduced all-cause mortality, and higher dihydrotestosterone with reduced ischaemic heart disease mortality, while estradiol levels do not predict mortality
J Clin Endocrinol Metab
Testosterone, dihydrotestosterone, and incident cardiovascular disease and mortality in the cardiovascular health study
J Clin Endocrinol Metab
Endogenous testosterone and cardiovascular disease in healthy men: a meta-analysis
Heart
Hypogonadism as a risk factor for cardiovascular mortality in men: a meta-analytic study
Eur J Endocrinol
Clinical review: endogenous testosterone and mortality in men: a systematic review and meta-analysis
J Clin Endocrinol Metab
Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial
JAMA
Longitudinal changes in testosterone over five years in community-dwelling men
J Clin Endocrinol Metab
Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels
JAMA
Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men
PLoS One
Risk of myocardial infarction in older men receiving testosterone therapy
Ann Pharmacother
Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men
Eur Heart J
Association of testosterone replacement with cardiovascular outcomes among men with androgen deficiency
JAMA Intern Med
Testosterone treatment and mortality in men with low testosterone levels
J Clin Endocrinol Metab
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