Abstract Testosterone products are recommended by some prescribers in response to a diagnosis or presumption of “low testosterone” (low-T) for cardiovascular health, sexual function, muscle weakness or wasting, mood and behavior, and cognition. We performed a systematic review of 156 eligible randomized controlled trials in which testosterone was compared to placebo for one or more of these conditions. We included studies in bibliographic databases between January 1, 1950 and April 9, 2016, and excluded studies involving bodybuilding, contraceptive effectiveness, or treatment of any condition in women or children. Studies with multiple relevant endpoints were included in all relevant tables. Testosterone supplementation did not show consistent benefit for cardiovascular risk, sexual function, mood and behavior, or cognition. Studies that examined clinical cardiovascular endpoints have not favored testosterone therapy over placebo. Testosterone is ineffective in treating erectile dysfunction and controlled trials did not show a consistent effect on libido. Testosterone supplementation consistently increased muscle strength but did not have beneficial effects on physical function. Most studies on mood-related endpoints found no beneficial effect of testosterone treatment on personality, psychological well-being, or mood. The prescription of testosterone supplementation for low-T for cardiovascular health, sexual function, physical function, mood, or cognitive function is without support from randomized clinical trials.

Citation: Huo S, Scialli AR, McGarvey S, Hill E, Tügertimur B, Hogenmiller A, et al. (2016) Treatment of Men for “Low Testosterone”: A Systematic Review. PLoS ONE 11(9): e0162480. https://doi.org/10.1371/journal.pone.0162480 Editor: Johnson Rajasingh, University of Kansas Medical Center, UNITED STATES Received: February 21, 2016; Accepted: August 23, 2016; Published: September 21, 2016 Copyright: © 2016 Huo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability: This is a systematic review. Studies we reference are available in the public domain. Funding: There were no funding sources for this study. Dr. Scialli is the sole participant in Scialli Consulting LLC. Scialli Consulting LLC has no employees and did not support this study with either salary or any other funding. Scialli Consulting LLC did not have any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific role of this author is articulated in the ‘author contributions’ section. Competing interests: Adriane Fugh-Berman is an expert witness at the request of plaintiffs in litigation regarding pharmaceutical marketing practices (Adriane Fugh-Berman was briefly engaged as an expert in testosterone litigation last year but has no relevant conflicts now). Adriane Fugh-Berman also directs PharmedOut, a Georgetown University Medical Center project that advances evidence-based prescribing and educates healthcare professionals about pharmaceutical marketing practices, and provides educational content for the Washington DC Department of Health-funded DC Center for Rational Prescribing through a contract with the George Washington University Milken School of Public Health. Alessandra Hirsch is a former project manager of PharmedOut and Alycia Hogenmiller is the current project manager of PharmedOut; their salaries are provided by Georgetown University Medical Center. Dr. Scialli is the sole participant in Scialli Consulting LLC. He is a reproductive toxicologist who consults for industry, government, and educational institutions. He has consulted for manufacturers of testosterone products, but never about testosterone. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

1. Introduction Testosterone and methyltestosterone are marketed in the United States for men with congenital or acquired hypogonadism. Some practitioners have used testosterone preparations to treat a variety of symptoms identified as those of “low testosterone” (low-T), a term that has not been uniformly defined. We present a systematic review of randomized controlled trials (RCTs) that evaluated the use of testosterone therapy against placebo or inactive comparator in adult men for cardiovascular health, sexual function, muscle weakness/wasting, mood and behavior, or cognition. We did not include studies of testosterone in men with missing or damaged testicles, or who had Klinefelter syndrome or other genetic anomalies. We did not include studies on the use of testosterone for any indication in women or in children, the use of androgens in contraception, or the use of androgens for bodybuilding or athletic performance.

2. Methods 2.1 Data Search, Synthesis and Analysis Computerized literature searches were conducted in PubMed, Embase, and APA PsycNET. Searches were limited to human males but were not restricted by language or date. The PubMed search was conducted using the MeSH term “testosterone” and the modifiers “administration and dosage,” “adverse effects,” “deficiency,” “standards,” “therapeutic use,” or “therapy.” The original PubMed search was conducted for studies published between January 1, 1950 and November 26, 2013. The Embase search was conducted using the Emtree key term “testosterone,” modified by “adverse drug reaction,” “androgen deficiency,” “therapy,” “drug dose,” or “clinical trial.” The original Embase search was conducted for studies published between January 1, 1974 and November 26, 2013. The PsycNET search was conducted using the term “testosterone” modified by “addiction,” “drug dependency,” “therapy,” “treatment,” or “deficiency.” The original PsycNET search was conducted for studies published between January 1, 1806 and November 26, 2013. All searches were repeated on April 9, 2016 to identify clinical trials that had been published since the initial search, so the final search included more than four decades of trials from all databases. 2.2 Study Selection Search results were combined using EndNote and duplicates were deleted. These results were filtered using the key term “clinical trial.” Titles and abstracts were reviewed to identify RCTs and eliminate irrelevant studies. Relevant studies were retrieved. 2.3 Data Extraction Data were extracted into tables by 4 independent reviewers according to the presence of information on cardiovascular health, sexual function, muscle weakness/wasting, mood and behavior, or cognition. Studies with multiple relevant endpoints were included in all relevant tables. Review articles were identified and retrieved, and their reference lists were searched for primary publications of RCTs. Some studies that included randomized controlled designs also included open-label continuation phases. We evaluated and summarized the randomized controlled portions of these studies. Although our primary interest was the use of testosterone for the treatment of hypogonadism, however defined by study authors, we included trials of testosterone in eugonadal men. In some studies, eugonadal subjects were randomized to receive testosterone or a comparator (usually placebo), and hypogonadal subjects were treated with testosterone only. We evaluated and summarized only the randomized portions of these studies. 2.4 Quality Assessment We assessed quality of studies by a 5-point Jadad score. In order to be as inclusive as possible, we included all studies identified regardless of Jadad score. For clinical endpoints only (angina/ischemia, congestive heart failure, and erectile dysfunction) we also included an analysis of studies restricted to Jadad scores of 4 or 5. We accepted whatever criteria were used by individual study authors to define low testosterone.

4. Discussion This systematic review examined published RCTs of testosterone supplementation for cardiovascular disease or surrogates of cardiovascular disease, sexual function, muscle strength, mood, and cognition. The review was limited to published studies in English and to trials indexed before April 9, 2016. The evidence supporting the use of testosterone for preventing or treating cardiovascular disease is inconsistent and, on balance, unconvincing. Some evidence supported an acute and chronic effect of testosterone therapy on increasing time to ST-segment depression, and there is evidence of improvement in some measures of congestive heart failure. Most studies showed no effect of testosterone therapy on inflammatory markers, and the effects on lipids were inconsistent. Studies that examined clinical effects have not favored testosterone therapy over placebo. Two of 3 studies that assessed angina showed no effect. Three studies from the same group found a benefit for symptoms associated with CHF. One study was stopped early for cardiovascular adverse effects. Testosterone supplementation did not demonstrate consistent effectiveness for improving sexual function or satisfaction. Testosterone is ineffective in treating ED. Controlled trials were mixed on libido, with more positive than negative studies. Substantial evidence supports a favorable effect of testosterone treatment on muscle mass in both healthy men and men with HIV, and a majority of studies showed a decrease in fat mass. Testosterone did not affect most measures of muscle strength. While decreasing frailty and increasing strength in older men might be beneficial, testosterone supplementation does not improve physical function in older men. Most studies on mood-related endpoints found no beneficial effect of testosterone treatment on personality, psychological well-being, or mood. Although 2 studies showed decreased anxiety, treatment of depression showed mixed and inconsistent results. Even if testosterone did benefit mood, social adverse events might ensue; 5 studies noted treatment-related increases in anger, aggression, or hostility. Testosterone did not benefit cognitive impairment or Alzheimer disease; neither did it benefit verbal fluency, memory, or other cognitive endpoints in normal men. In summary, evidence from RCTs does not support treatment of so-called low-T for improving physical function, sexual function, mood, or cognition. Testosterone increases muscle mass, but not strength, and while some improvement is seen in some surrogate markers of cardiovascular risk, there is little evidence of clinical benefit. There is conflicting evidence on the association between testosterone supplementation and cardiovascular events. RCTs have reported increased cardiovascular risk with testosterone therapy. One such trial that specifically examined cardiovascular disease and mortality endpoints was stopped early because of an increased risk of cardiovascular events.[17] A meta-analysis of 2994 men in 27 randomized controlled trials through 2012 found that testosterone therapy increased the risk of cardiovascular events (OR, 1.54; 95% CI, 1.09–2.18).[141] Observational studies examining the effect of testosterone treatment have shown conflicting results on risk. A Veterans Administration study evaluated men who had undergone coronary angiography and had a total testosterone concentration (presumably plasma) less than 300 ng/dL (10.4 nM).[142] Men who were treated with testosterone had an increased risk of all-cause mortality, MI, and stroke compared to men who did not use testosterone (HR, 1.29; 95% CI, 1.05–1.58), based on a mean of 27.5 months of follow-up. Another retrospective cohort study using Veterans Administration data showed a lower rate of all-cause mortality, myocardial infarction, and stroke among testosterone-treated men whose testosterone concentrations “normalized” after treatment.[143] Another observational study of men in a large, integrated health care organization found that death rates were reduced over 3 years, but there was no effect on myocardial infarction or stroke.[144] A Medicare-based study identified testosterone exposures and MI outcomes using claims data and matched testosterone-treated with untreated subjects using an empirically derived propensity score and found no increased risk.[145] The adjusted HR for testosterone therapy and MI was 0.84 (95% CI 0.69–1.02). Analysis of subjects in the highest quartile propensity score range suggested a protective effect of testosterone treatment, with a HR of 0.69 (95% CI 0.53–0.92). An observational study in men with low testosterone found that treatment was associated with reduced mortality;[146] another in diabetics[147] reported benefit on all-cause mortality but excluded men who had received testosterone for less than one year and excluded deaths occurring before six months. A large cohort study found that myocardial infarction rates were significantly increased within three months of testosterone treatment initiation; testosterone-treated men over 65 experienced double the rate of myocardial infarctions compared to men who did not received testosterone.[148] Testosterone treatment has been considered for disease prevention because men who are obese, diabetic, hypertensive, or chronically ill have lower plasma concentrations of testosterone.[149] However, the direction of causality is unclear; it is possible that obesity or lack of exercise and chronic disease lower testosterone rather than low testosterone concentrations causing disease. It is also possible that another mechanism both lowers testosterone concentrations and increases the risk of some diseases. Observational studies attributing positive health effects to testosterone may be affected by an increased likelihood of healthier men being prescribed testosterone rather than testosterone improving health. There are parallels between the recommendation of testosterone and of menopausal hormone therapy in women. Physicians prescribed estrogen and estrogen-progestin preparations to menopausal women to prevent cardiovascular disease because observational studies showed that women who took menopausal hormones had less heart disease than women who did not. RCTs, however, showed that menopausal hormone therapy increased the risk of heart attacks and stroke.[150–153] It is likely that healthier women chose to take menopausal hormone therapy, but menopausal hormone administration did not improve health. In 2012, sales for testosterone therapies exceeded $2 billion, and sales continue to grow in dozens of countries.[154] To the extent that this increase in use of testosterone supplementation is based on anticipated improvements in cardiovascular health, sexual function, physical functioning, mood, or cognition, we suggest that it might represent therapy without adequate clinical trial support. We identified no population of normal men for whom the benefits of testosterone use outweigh its risk. Given the known risks of testosterone therapy and the lack of evidence for clinical benefits in normal men, we do not think further trials of testosterone are necessary.

Acknowledgments We thank Matthew Puretz, Anastassia Reznik, and Nicole Dubowitz for their research assistance in the preparation of this paper.

Author Contributions Conceived and designed the experiments: AS AFB. Performed the experiments: SH SM EH BT AFB AS. Analyzed the data: SH SM EH BT AFB AS AH AIH. Wrote the paper: SH SM EH BT AFB AS AH AIH.