Among men with a deficiency in serum testosterone, re-establishing physiologic levels of testosterone has been shown to ameliorate many of the undesirable symptoms associated with testosterone deficiency (TD). Although the concept of testosterone replacement therapy (TRT) has been in place for several decades, the indications for treatment and defining the best candidates for therapy continue to evolve. Traditional indications for TRT were heavily skewed toward resolving sexual dissatisfaction related to a diminished sex drive, orgasmic problems, or erectile dysfunction. More contemporary evidence has highlighted the benefits of TRT as a modifier of important structural, metabolic, and cardiovascular (CV) outcomes among men with TD.
Concerns surrounding TRT have also evolved. Much of the apprehension surrounding TRT stems from a perceived risk to prostate health, the potential for testosterone abuse as an anabolic steroid or anti-aging elixir, parallels with the estrogen replacement in women saga, and, most recently, concerns with respect to cardiovascular disease (CVD). With the objective of defining the best candidates for TRT, this report will review the current indications for treatment, with a specific focus on the impact of TD and TRT on CV health.
Indications for TRT
Traditionally, the primary indication for TRT was to treat men with low serum testosterone levels with negative symptoms related to TD (Table 1). The etiology of the TD is generally attributed to be a consequence of a gradual decline (about 1%/year) in serum testosterone with age 1. A decline related both to diminished signaling of testosterone production from the hypothalamus and pituitary and diminished production of testosterone by the testes 2.
Recognizing that many of the signs and symptoms related to TD are ‘nonspecific’, a number of screening questionnaires have been validated to assist clinicians in identifying the best patients to biochemically screen for TD. The Androgen Deficiency in the Ageing Male (ADAM) questionnaire (Table 2) is the most commonly adopted validated screening tool for TD 3. The ADAM questionnaire was originally validated as a dichotomous (yes/no) screening tool and therefore did not offer useful quantitative scoring metrics and had limited utility in evaluating response to treatment. To address this limitation, the quantitative ADAM questionnaire was developed and validated to quantify and compare responses to treatment and progression 4.
Establishing a patient as TD generally requires documenting low morning serum testosterone on two separate occasions. Although there remains a debate on what fraction of testosterone to measure, total testosterone is generally accepted as a reasonable screening assay with the measurement of free testosterone or bioavailable testosterone at a reliable lab reserved for equivocal cases 5.
Most clinical societies are in general agreement over the indications for TRT, although there are subtle variations between guidelines. The primary indication for TRT across all guidelines is low levels of testosterone (irrespective of cause) with symptoms suggestive of TD. Additional indications include men with low testosterone and unique clinical scenarios: the presence of HIV infection with weight and muscle loss, long-term opioid and glucocorticoid use, and men with sarcopenia and/or anemia. The indications and contraindications to TRT published by various clinical practice guidelines are summarized in Table 3.
What about testosterone and prostate cancer and heart disease?
Concern in terms of TRT and prostate cancer began in the 1940s after Charles Huggins first reported that prostate cancer growth was androgen dependent. Huggins 8 showed that castration caused cancerous areas of the prostate to disappear in dogs. Following this research, bilateral orchiectomy became a standard treatment for advanced prostate cancer. By the 1980s, hormonal injections were developed for medical castration and largely eliminated the need for orchiectomy. Huggins received a Nobel prize for his practice-changing discovery in 1966. The discovery of the androgen dependency of prostate cancer led to many questions on the use of TRT and the risk of prostate cancer. Many physicians became hesitant to prescribe TRT altogether. Others required the absence of prostate cancer by biopsy before initiating TRT. In fact, it was initially believed that all men should have negative prostate biopsies before initiating TRT 9. Interestingly, data generated from those early prostate biopsy protocols showed a higher prevalence of prostate cancer among men with low testosterone 9. Multiple studies to date have shown that TRT has no clinically significant effect on prostate screening antigen (PSA) levels or the subsequent development or ‘unmasking’ of prostate cancer 10. Further, testosterone-deficient men successfully treated for prostate cancer, with no evidence of active disease, have been shown to be candidates for TRT without any apparent adverse effects on PSA levels or disease progression 11. Men with prostate cancer who may require androgen-deprivation therapy in the future represent a population that should not be offered TRT.
To date, all clinical practice guidelines recommend a baseline digital rectal exam and PSA level before starting TRT. Urologic consultation before the initiation of TRT is recommended in men suspected to be at high risk for prostate cancer on the basis of family history, digital rectal exam, and PSA results. Once initiated on TRT, prostate health should be evaluated initially at 3–6-month intervals following treatment and then annually on the basis of established prostate cancer screening guidelines.
In summary, despite almost a century of concern, there is no consistent evidence that restoring testosterone to normal physiologic levels significantly influences PSA nor increases the risk of developing prostate cancer. Men treated for prostate cancer with no evidence of active disease are candidates for TRT.
Low testosterone and cardiovascular disease
Background – lessons from prostate cancer patients
There is a rich history of research examining the impact of TD on CV risk factors as well as the impact of TRT on CV health among hypogonadal men. There are reports as early as 1946 showing the benefits of using TRT for angina pectoris 12. Studies exploring the benefits of TRT in peripheral vascular disease appear as early as 1939 13.
Following the discovery of the androgen dependency of prostate cancer, men with advanced prostate disease were treated with surgical or medical castration. Eliminating or suppressing testosterone was shown to improve prostate cancer survival; however, this came at a significant metabolic and CV cost. These men with low or absent androgen levels showed significantly higher rates of CVD and CV mortality 14,15.
Subsequently, several studies have shown that low testosterone is strongly associated with significant CV risk factors including obesity, metabolic syndrome, type 2 diabetes, hypertension, and hypercholesterolemia 16–18.
Several studies have investigated the impact of TD and TRT on overall mortality. Consistently, mortality has been shown to be inversely related to endogenous testosterone levels. A large VA study reported that low testosterone is associated with a higher risk of all-cause mortality 19. A population-based study from Finland reported that higher endogenous levels of testosterone were associated with improved overall survival in elderly men 20. Recently, a 2011 study from Sweden reported TD to be associated independently with CV mortality and all-cause mortality in end stage renal disease patients 21.
Cardiovascular and metabolic benefits of TRT
TD is strongly linked to important CV risk factors and metabolic diseases. Emerging evidence suggests that TRT can positively modify CV risk 22. A 2001 study reported a small but significant reduction of total cholesterol, LDL, and HDL in men on TRT 23. More recently, a large meta-analysis from 2011 reported a decrease in HbA1C, fasting glucose, and triglyceride levels in men on various forms of TRT 24. In men with congestive heart failure, it has been shown that TRT leads to a significant improvement in exercise tolerance, glucose metabolism, and muscle strength 25. Consistent evidence shows that TRT increases muscle mass and strength while reducing body fat and waist circumference 26. Studies have reported that low levels of testosterone are associated with an increased severity of coronary artery disease and carotid plaques thickness 27. A large meta-analysis from 2014 reported that CV risk is not elevated in men on TRT 28. Similarly, a large Medicare study from 2014 reported no increased myocardial infarction (MI) risk associated with intramuscular TRT 29. Further, a large-scale meta-analysis from 2007 that included 1642 men over 30 trials found no increased risk of CVD in men on TRT 30.
Controversy over increased cardiovascular risk with TRT
Despite the association of TD with important CV risk factors and the reported benefits of TRT on CV health, testosterone therapy remains controversial as it relates to heart disease and stroke. Four studies, published beginning in 2010, have purportedly reported an association between TRT and CV events (Table 4). These studies have led to significant controversy among physicians, patients, and the media. The first study 31 was published in 2010 in New England Journal of Medicine and was a prospective randomized trial investigating whether TRT improved the functional status of frail, older men. The study was terminated early because there were 23 cardiac ‘events’ in the TRT group compared with five in the placebo group. It is important to note that CV outcomes were not a specified outcome in the study design. Furthermore, and perhaps more importantly, the definition of an ‘event’ in this study included subjective symptoms that were not necessarily indicative of clinically significant CV endpoints. Of the 23 events in the TRT group, only four were major cardiac events and the rate of major cardiac events did not differ significantly between the testosterone-treated men and the men receiving placebo.
The second study, a 2013 meta-analysis 32 published in BMC Medicine, reported a higher rate of CV events among men on TRT when compared with men on placebo. This meta-analysis only included studies that reported at least one CV event, therefore excluding any study without a CV event that would have otherwise lowered the event rate. A total of 27 studies were included in this meta-analysis; however, two studies contributed toward 35% of all the CV events. This is the only study from a number of meta-analyses to date that suggests increased CV risk with TRT.
Two more recent publications have received widespread media attention for associating TRT with increased CV risks in men with TD. Vigen et al.33, published in Journal of the American Medical Association in 2013, presented a retrospective review of men within the VA system who underwent coronary angiography. The study reported a higher rate of MI, stroke, and death in men with low testosterone who filled a prescription for TRT compared with men who did not fill a testosterone prescription. Subsequent to publication, there has been a whirlwind of media attention, critique, and uncertainty related to this Journal of the American Medical Association study.
The actual event rates offered by the unadjusted data showed fewer CV events in the TRT group. Only following a complex statistical adjustment of the data on the basis of over 50 variables did the authors conclude that CV events were higher among men prescribed testosterone. After publication, two official corrections were made to the study to address concerns in the study design and analysis including the acknowledgement that the data set that included women. Twenty-nine medical societies have petitioned Journal of the American Medical Association to retract the article.
The second publication to receive such widespread attention was published in PLoS One in 2014 by Finkle et al. 34. This study was a retrospective analysis of a health insurance database and reported the rate of MI in the period up to 90 days after TRT prescription. The rate of MI after the date of the prescription was then compared with that 12 months ago. The MI rate in the TRT group was compared with a group of men who received a phosphodiesterase 5 inhibitor (PDE5I) prescription. The study reported a higher rate of MI after TRT prescription compared with the period before the prescription. In the comparison group, those receiving PDE5Is, there was no significant increase in MI rates. Significant limitations in this study were the absence of information on known MI risk factors, the lack of an equivalent comparison group to determine the baseline MI rate during the same time period, and a lack of any actual testosterone values in either group.
Despite the amount of attention that these reports have received, the majority of well-designed studies and meta-analyses have not shown any increase in CV events in testosterone-deficient men on TRT 28.
Fueled by the growing uncertainty and debate on TRT and CV risk, several national regulating bodies initiated independent investigations focusing specifically on the issue of CV risk with testosterone products. The conclusions of the Health Canada, FDA, and European Medicines Society are summarized in Table 5.
Conclusion – who are the ideal candidates for TRT?
The ideal candidate for TRT has evolved over the past 60 years and will continue to evolve as research sheds more light on the benefits and potential risks associated with TRT.
Traditional indications for TRT that were largely directed toward improving a man’s sex life and overall well-being have been broadened as we consider using TRT as a modifier of important structural, metabolic, and CV outcomes among men with TD.
The ideal candidates for TRT remain symptomatic men with documented TD. The biochemical definition of TD has some variability across guidelines, with a consensus that a total testosterone below 230 ng/dl represents true TD 38. Testosterone levels between 230 and 350 ng/dl may require further characterization with additional testing 38. The evidence and guidelines available to date suggest that symptomatic men with low testosterone should not be denied a trial of TRT on the basis of prostate health concerns or CV risks. There are currently no CV risk factors that absolutely preclude the use of TRT. Contemporary evidence suggests that TRT does not increase the risk of prostate cancer. Testosterone-deficient men treated previously for prostate cancer with no evidence of active disease remain candidates for TRT.
The recent highly publicized studies that suggest an increased CV risk with TRT are at odds with decades of research suggesting that TD increases CV risk and mortality and that TRT improves vascular integrity and cardiac function without increasing the risk of CV events. Symptomatic men with TD and stable CVD remain candidates for TRT.
Conflicts of interest
Ethan D. Grober has affiliations with Lilly and Paladin. Yonah Krakowsky declares no conflicts of interest.
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