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Defining the best candidates for testosterone replacement?

Krakowsky, Yonah; Grober, Ethan D.

Cardiovascular Endocrinology & Metabolism: September 2015 - Volume 4 - Issue 3 - p 77–82
doi: 10.1097/XCE.0000000000000059
Review articles
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It is widely known that re-establishing physiologic levels of testosterone in symptomatic men with testosterone deficiency (TD) improves the undesirable symptoms associated with low testosterone. The indications for testosterone replacement therapy (TRT) have been evolving as research continues to find out who are the best candidates for therapy. Recently, concerns on the association of TRT and cardiovascular disease have received considerable attention. Before this, considerable attention had focused on the potential dangers of TRT and the risk of prostate cancer. The vast majority of contemporary evidence suggests that men with treated prostate cancer and no evidence of active disease are appropriate candidates for TRT in the context of symptomatic TD. Further, current evidence does not support denying TRT to symptomatic men with TD based on stable cardiac disease.

Division of Urology, University of Toronto, Ontario, Canada

Correspondence to Ethan D. Grober MD, MEd, Murray Koffler Urologic Wellness Centre, Mt. Sinai Hospital, Joseph and Wolf Lebovic Building, 60 Murray St, 6th Floor, Box 19, Toronto Otario M5T 3L9, Canada E-mail: grober@mtsinai.on.ca

Received March 19, 2015

Accepted June 24, 2015

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Introduction

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.

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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.

Table 1

Table 1

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.

Table 2

Table 2

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.

Table 3

Table 3

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What about testosterone and prostate cancer and heart disease?

Prostate health

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.

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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.

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Mortality

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.

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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.

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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.

Table 4

Table 4

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.

Table 5

Table 5

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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.

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Acknowledgements

Conflicts of interest

Ethan D. Grober has affiliations with Lilly and Paladin. Yonah Krakowsky declares no conflicts of interest.

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References

1. Wu FCW, Tajar A, Pye SR, Silman AJ, Finn JD, O’Neill TW, et al.. Hypothalamic-pituitary-testicular axis disruptions in older men are differentially linked to age and modifiable risk factors: the European Male Aging Study. J Clin Endocrinol Metab 2008; 93:2737–2745.
2. Morley JE, Kaiser FE, Perry HM 3rd, Patrick P, Morley PM, Stauber PM, et al.. Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men. Metabolism 1997; 46:410–413.
3. Morley JE, Charlton E, Patrick P, Kaiser FE, Cadeau P, McCready D, Perry HM 3rd. Validation of a screening questionnaire for androgen deficiency in aging males. Metabolism 2000; 49:1239–1242.
4. Mohamed O, Freundlich RE, Dakik HK, Grober ED, Najari B, Lipshultz LI, Khera M. The quantitative ADAM questionnaire: a new tool in quantifying the severity of hypogonadism. Int J Impot Res 2010; 22:20–24.
5. Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, Montori VM. Task Force, Endocrine Society. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 2010; 95:2536–2559.
6. Buvat J. International Society for Sexual Medicine, 2009. Available at: http://www.issm.info/news/review-reports/who-would-benefit-from-testosterone-therapy/. [Accessed 18 March 2015].
    7. Dohle GR, Arver S, Bettocchi C, Kliesch S. Guidelines on male hypogonadism. Association of urology 2012. Available at http://www.guideline.gov/content.aspx?id=37626, as part of the National Guideline Clearinghouse.
      8. Huggins C. Effect of orchiectomy and irradiation on cancer of the prostate. Ann Surg 1942; 115:1192–1200.
      9. Morgentaler A, Bruning CO 3rd, DeWolf WC. Occult prostate cancer in men with low serum testosterone levels. JAMA 1996; 276:1904–1906.
      10. Calof OM, Singh AB, Lee ML, Kenny AM, Urban RJ, Tenover JL, Bhasin S. Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. J Gerontol A Biol Sci Med Sci 2005; 60:1451–1457.
      11. Kaufman JM, Graydon RJ. Androgen replacement after curative radical prostatectomy for prostate cancer in hypogonadal men. J Urol 2004; 172:920–922.
      12. Levine EB, Sellers AL. Testosterone in angina pectoris. Am J Med Sci 1946; 1:7–11.
      13. Clausen FW, Freudenberger CB. A comparison of the effects of male and female sex hormones on immature female rats. Endocrinology 1939; 25:585–592.
      14. Keating NL, O’Malley AJ, Smith MR. Diabetes and cardiovascular disease during androgen deprivation therapy for prostate cancer. J Clin Oncol 2006; 24:4448–4456.
      15. Tsai HK, D’Amico AV, Sadetsky N, Chen MH, Carroll PR. Androgen deprivation therapy for localized prostate cancer and the risk of cardiovascular mortality. J Natl Cancer Inst 2007; 99:1516–1524.
      16. Khaw KT, Dowsett M, Folkerd E, Bingham S, Wareham N, Luben R, et al.. Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European prospective investigation into cancer in Norfolk (EPIC-Norfolk) Prospective Population Study. Circulation 2007; 116:2694–2701.
      17. Laaksonen DE, Niskanen L, Punnonen K, Nyyssönen K, Tuomainen TP, Valkonen VP, et al.. Testosterone and sex hormone-binding globulin predict the metabolic syndrome and diabetes in middle-aged men. Diabetes Care 2004; 27:1036–1041.
      18. Mulligan T, Frick MF, Zuraw QC, Stemhagen A, McWhirter C. Prevalence of hypogonadism in males aged at least 45 years: the HIM study. Int J Clin Pract 2006; 60:762–769.
      19. Shores MM, Matsumoto AM, Sloan KL, Kivlahan DR. Low serum testosterone and mortality in male veterans. Arch Intern Med 2006; 166:1660–1665.
      20. Lehtonen A, Huupponen R, Tuomilehto J, Lavonius S, Arve S, Isoaho H, et al.. Serum testosterone but not leptin predicts mortality in elderly men. Age Ageing 2008; 37:461–464.
      21. Carrero JJ, Qureshi AR, Parini P, Arver S, Lindholm B, Bárány P, et al.. Low serum testosterone increases mortality risk among male dialysis patients. J Am Soc Nephrol 2009; 20:613–620.
      22. Isidori AM, Giannetta E, Greco EA, Gianfrilli D, Bonifacio V, Isidori A, et al.. Effects of testosterone on body composition, bone metabolism and serum lipid profile in middle-aged men: a meta-analysis. Clin Endocrinol (Oxf) 2005; 63:280–293.
      23. Whitsel EA, Boyko EJ, Matsumoto AM, Anawalt BD, Siscovick DS. Intramuscular testosterone esters and plasma lipids in hypogonadal men: a meta-analysis. Am J Med 2001; 111:261–269.
      24. Corona G, Monami M, Rastrelli G, Aversa A, Sforza A, Lenzi A, et al.. Type 2 diabetes mellitus and testosterone: a meta-analysis study. Int J Androl 2011; 34 (Pt 1):528–540.
      25. Caminiti G, Volterrani M, Iellamo F, Marazzi G, Massaro R, Miceli M, et al.. Effect of long-acting testosterone treatment on functional exercise capacity, skeletal muscle performance, insulin resistance, and baroreflex sensitivity in elderly patients with chronic heart failure: a double-blind, placebo-controlled, randomized study. J Am Coll Cardiol 2009; 54:919–927.
      26. Srinivas-Shankar U, Roberts SA, Connolly MJ, O’Connell MD, Adams JE, Oldham JA, Wu FC. Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab 2010; 95:639–650.
      27. De Pergola G, Pannacciulli N, Ciccone M, Tartagni M, Rizzon P, Giorgino R. Free testosterone plasma levels are negatively associated with the intima-media thickness of the common carotid artery in overweight and obese glucose-tolerant young adult men. Int J Obes Relat Metab Disord 2003; 27:803–807.
      28. Corona G, Maseroli E, Rastrelli G, Isidori AM, Sforza A, Mannucci E, Maggi M. Cardiovascular risk associated with testosterone-boosting medications: a systematic review and meta-analysis. Expert Opin Drug Saf 2014; 13:1327–1351.
      29. Baillargeon J, Urban RJ, Kuo YF, Ottenbacher KJ, Raji MA, Du F, et al.. Risk of myocardial infarction in older men receiving testosterone therapy. Ann Pharmacother 2014; 48:1138–1144.
      30. Haddad RM, Kennedy CC, Caples SM, Tracz MJ, Boloña ER, Sideras K, et al.. Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc 2007; 82:29–39.
      31. Basaria S, Coviello AD, Travison TG, Storer TW, Farwell WR, Jette AM, et al.. Adverse events associated with testosterone administration. N Engl J Med 2010; 363:109–122.
      32. Xu L, Freeman G, Cowling BJ, Schooling CM. Testosterone therapy and cardiovascular events among men: a systematic review and meta-analysis of placebo-controlled randomized trials. BMC Med 2013; 11:108.
      33. Vigen R, O’Donnell CI, Barón AE, Grunwald GK, Maddox TM, Bradley SM, et al.. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA 2013; 310:1829–1836.
      34. Finkle WD, Greenland S, Ridgeway GK, Adams JL, Frasco MA, Cook MB, et al.. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PLoS One 2014; 9:e85805.
      35. Health Canada. Summary safety review – testosterone replacement products – cardiovascular risks. Available at: http://www.hc-sc.gc.ca/dhp-mps/medeff/reviews-examens/testosterone-eng.php. [Accessed 18 March 2015].
        36. Food and Drug Administration. Joint meeting of the bone, reproductive and urologic drugs advisory committee and the drug safety and risk management advisory committee meeting announcement. Available at: http://www.fda.gov/AdvisoryCommittees/ucm404905.htm. [Accessed 18 March 2015].
          38. Wang C, Nieschlag E, Swerdloff R, Behre HM, Hellstrom WJ, Gooren LJ, et al.. Investigation, treatment and monitoring of late-onset hypogonadism in males. Int J Androl 2009; 32:1–10.
          Keywords:

          testosterone deficiency; testosterone replacement therapy; cardiovascular risk

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