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Testosterone treatment in older men: clinical implications and unresolved questions from the Testosterone Trials

https://doi.org/10.1016/S2213-8587(17)30416-3Get rights and content

Summary

A decrease in the concentration of circulating testosterone in many older men is a biomarker and possibly a rectifiable contributing factor to ill health. Low circulating testosterone concentration has been associated with cardiovascular disease, reduced cognition, fracture risk, and anaemia. However, randomised placebo-controlled trials are essential to clarify the benefits and possible risks of testosterone treatment in men without hypothalamic, pituitary, or testicular disease. The Testosterone Trials (T-Trials) were a coordinated set of trials that, following a screening-to-enrolment ratio of 65:1, randomly assigned 790 men aged 65 years or older who had a baseline testosterone concentration of less than 9·54 nmol/L and symptoms consistent with hypogonadism, but no recognisable hypothalamic–pituitary–testicular axis pathology, to daily transdermal testosterone or placebo for 12 months. In the main trial, testosterone treatment resulted in a modest benefit for sexual function, whereas the other primary outcomes of vitality and physical function were not met. Data from concomitant substudies raised a possible concern over changes in coronary plaque volume, showed a neutral effect on memory and other cognitive functions, and revealed improvements in volumetric bone mineral density and anaemia. Although insufficient to alter the existing clinical equipoise, the T-Trials provided substantial new data on organ-specific outcomes for testosterone treatment in older men. Further clinical trials are necessary to determine whether testosterone treatment will translate into patient-valued health outcomes and to clarify effects on the cardiovascular system.

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

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