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Testosterone replacement in men with age-related low testosterone: what did we learn from The Testosterone Trials?

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Abstract

The Testosterone (T) Trials were a coordinated set of seven double-blind, placebo-controlled trials to assess efficacy and safety of T versus placebo gel treatment for one year in 788 older men aged 65 years or older with hypogonadism who had self-reported and objective impairment of sexual and physical function and/or vitality and an average of two morning serum T concentrations <275 ng/dL. T dose was adjusted to the mid-normal range for young men. Compared to placebo, T treatment moderately improved sexual function and hemoglobin concentration and corrected anemia and slightly improved walking distance, vitality, mood and depressive symptoms, and bone density and strength but did not improve cognitive function. T treatment slightly increased noncalcified and total plaque volume; while concerning, the clinical significance of this finding is not clear. T treatment also increased prostate-specific antigen levels and referral for urological evaluation and caused erythrocytosis in some men. The T Trials provided definitive evidence for short-term clinically meaningful, albeit modest, benefits and risks of T treatment in older men with unequivocal age-related hypogonadism. Larger and long-term placebo-controlled clinical trials are needed to assess the long-term benefits and risks of T treatment on clinical outcomes such as frailty, depression, fractures, prostate cancer, and cardiovascular events.

Introduction

As men age, serum testosterone (T) concentrations decline progressively in association with conditions such as reduced sexual function, energy, muscle mass and function, cognitive function, bone mass with increased fracture risk, and anemia 1, 2, 3. These age-associated conditions also occur in men with organic hypogonadism because of diseases affecting the hypothalamic-pituitary-testicular axis. The decline in serum T levels with age contributes to an increasing prevalence of levels below the normal range for young men. However, the prevalence of clinical hypogonadism is much less 4, 5, 6. In the European Male Aging Study, only sexual symptoms (poor morning erections, low sexual desire, and erectile dysfunction) had a syndromic association with low serum T concentrations and the overall prevalence of age-related hypogonadism (termed late-onset hypogonadism) was 2.1% [6]. The etiology of hypogonadism as men age is complex and largely due to potentially reversible or treatable age-related comorbidities (e.g., obesity, chronic illness) or medication use (e.g. opioids, glucocorticoids) that suppress gonadotropins and T, that is functional causes of secondary hypogonadism. Less commonly, with advanced older age (e.g., older than 70 years), testis function declines substantially, resulting in organic primary hypogonadism 7, 8.

From clinical experience and older clinical trials, it is well established that T replacement therapy in men with severe organic hypogonadism improves sexual function, energy, muscle mass, bone mineral density (BMD), and anemia [9]. However, at the beginning of the 21st. century, it was unclear whether T treatment in old men with low T levels would be beneficial. Early trials investigated whether T treatment in older men yielded conflicting results because the populations of men studied were heterogeneous (including healthy men without symptoms of low T or who had low-normal T levels rather than unequivocally low T levels); T treatment resulted in either supraphysiological or subphysiological T levels; studies were underpowered for some outcomes; and the use of nonvalidated, insensitive, or nonclinically relevant surrogate outcome measures were used [10].

Because large long-term clinical outcome studies of T treatment in older men were lacking, in 2000, we proposed a 6-year randomized, double-blind, placebo-controlled trial (known as the Efficacy and Safety of Testosterone in Elderly Men, Department of Veterans Affairs Cooperative Studies Program No. 490) to determine the effect of T gel treatment on fractures (primary outcome), incident prostate cancer, cardiovascular (CV) events, sexual function, vitality, cognitive function, and invasive treatment of benign prostatic hyperplasia in 6000 men ≥ 65 years with serum low T concentrations. After a long and extensive reviews both by the Veterans Affairs Cooperative Studies Program and an National Institutes on Aging (NIA), the Efficacy and Safety of Testosterone in Elderly Men study was approved but not funded, largely because of concerns regarding the potential safety of long-term T treatment in older men, particularly the risk of prostate cancer [11].

In 2002, an Institute of Medicine (IOM) committee was convened to assess the state of clinical research on T therapy in older men. In 2003, the IOM committee concluded that there was insufficient evidence that T treatment in older men with low T levels was beneficial and recommended that the NIA support a coordinated set of short-term efficacy trials in older men with low T levels and at least one symptom that might be related to low T to investigate the efficacy of T therapy on sexual function, vitality/well-being/quality of life, muscle strength/frailty/disability, and cognitive function [12]. The committee further recommended that only if adequate short-term benefits were found, would a larger, long-term clinical efficacy and safety study be recommended. The NIA followed the IOM committee recommendations and supported The Testosterone Trials (T Trials.)

Section snippets

T Trials design

The design of the T Trials addressed the limitations of earlier trials of T therapy in older men and followed the recommendations of the IOM committee to assess the short-term benefits and risks of T treatment in older men [13]. The T Trials were a coordinated set of seven double-blind, placebo-controlled trials of T versus placebo gel treatment for one year in men aged 65 years or older who had an average of two morning serum T concentrations < 275 ng/dL and self-reported and objective

Recruitment and baseline characteristics

Fifty-one thousand eighty-five men recruited initially called study sites and underwent an initial telephone screening and subsequent two-stage, in-person screening visits. Of those who expressed interest in participating, only 1.5% of men were enrolled in the T Trials. The main reason of exclusion of men was insufficiently low serum T concentrations. Only 14.7% of men screened had sufficiently low serum T levels on two occasions to qualify. Recruitment for the T Trials confirmed that while

T concentrations

Seven hundred five of 788 (89%) men enrolled in the T Trials completed all 12 months of treatment and evaluations ••10, ••15. In the 394 men treated with T, serum T concentrations increased from levels unequivocally below the normal range to the mid-normal range for young men by month 3 and were maintained at that level for 12 months of treatment. However, to maintain serum T levels within the mid-normal range, 504 adjustments in the T dose were required in 301 of the 394 men treated with T.

What did we learn from the T Trials?

In older men over the age of 65 years with symptomatic, unequivocal hypogonadism for no apparent reason other than age, T treatment that increased and maintained T levels in the mid-normal range for young men for one year moderately improves sexual function and Hgb and corrects anemia and slightly improves walking distance, vitality, mood and depressive symptoms, and bone density and strength, but does not improve cognitive function. T treatment slightly increased noncalcified and total plaque

Conflict of interest

Dr. Matsumoto receives research support from AbbVie and GlaxoSmithKline and consulting fees from AbbVie and Aytu.

Acknowledgements

The Testosterone Trials were supported by the National Institute on Aging, National Institutes of Health (U01 AG30644), supplemented by funds from the National Heart, Lung, and Blood Institute, National Institute of Neurological Disorders and Stroke, National Institute of Child Health and Human Development and AbbVie that provided funding, and AndroGel and placebo gel. Dr. Matsumoto is supported by the Geriatric Research, Education and Clinical Center, V.A. Puget Sound Health Care System,

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