Curr Atheroscler Rep (2016) 18:19 DOI 10.1007/s11883-016-0569-2
CORONARY HEART DISEASE (S. VIRANI AND S. NADERI, SECTION EDITORS)
Testosterone Replacement Therapy and the Cardiovascular System Sahar Naderi 1
# Springer Science+Business Media New York 2016
Abstract As testosterone replacement therapy (TRT) has emerged as a commonly prescribed therapy for symptomatic low testosterone, conflicting data have been reported in terms of both its efficacy and potential adverse outcomes. One of the most controversial associations has been that of TRT and cardiovascular morbidity and mortality. This review briefly provides background on the history of TRT, the indications for TRT, and the data behind TRT for symptomatic low testosterone. It then specifically delves into the rather limited data for cardiovascular outcomes of those with low endogenous testosterone and those who receive TRT. The available body of literature strongly suggests that more work, by way of clinical trials, needs to be done to better understand the impact of testosterone and TRT on the cardiovascular system. Keywords Testosterone . Cardiovascular disease . Male hormone therapy . Androgens
Introduction A focus on male sexual dysfunction in the last decade has resulted in a massive resurgence in testosterone replacement therapy (TRT). The USA has seen a fivefold increase in testosterone prescriptions between 2001 and 2011, and it is now a multi-billion dollar industry [1]. Because of its rapidly growing popularity, attention has turned to the appropriateness and This article is part of the Topical Collection on Coronary Heart Disease * Sahar Naderi [email protected]
1
Division of Cardiology, Stanford University Medical Center, 300 Pasteur Drive, H2155, Stanford, CA 94305, USA
safety of testosterone replacement therapy (TRT), particularly as it pertains to CV disease (CVD). Questions have arisen as to whether (a) low testosterone levels play a role in cardiovascular (CV) morbidity and mortality and (b) TRT is beneficial or detrimental to the CV system. In this review, we will lay the foundation for the use of TRT and discuss the available data regarding its effects on the CV system.
A Historical Perspective Androgens are hormones that control both the development and maintenance of male sex characteristics, with testosterone being the most important, necessary for both reproductive and sexual function. The effects of androgens have reportedly been known since the time of Aristotle, with historical documents suggesting the experimental castration of animals for purposes of domestication. In the 1840s, Arnold Berthold, a German physiologist, castrated roosters, resulting in regression of their comb and wattle. Returning their testicles to the abdominal cavity halted this process, suggesting that testicles secreted a substance that was integral to secondary sexual characteristics. Following these observations, Charles Edouard Brown-Sequard famously auto-injected extract from the testes of dogs and guinea pigs, reporting substantial increases in his physical and mental strength. He ultimately reported these effects in an 1889 paper in The Lancet. His advertisement of this BElixir of Life^ led to a public fervor that drove researchers to aggressively pursue a means by which to isolate androgens. By 1935, researchers Adolf Butenandt and Leopold Ruzicka had independently isolated what they recognized was a powerful androgen, later named testosterone, and ultimately won a Nobel Prize in Chemistry for this work. This led to the development of injectable forms of testosterone, and by
19
Curr Atheroscler Rep (2016) 18:19
Page 2 of 6
the 1940s, it had become a means of great financial gain for a number of pharmaceutical companies of the era. Despite reports in notable medical journals of substantial side effects as a result of indiscriminate use of testosterone [2], prescriptions continued to gain popularity, particularly among competitive athletes. Observations that Soviet-era Olympians were using testosterone as a means of enhancing performance led researchers at a Swiss pharmaceutical company to develop Dianabol, a synthetic form of testosterone. This so-called anabolic steroid contained mainly the component of testosterone responsible for muscle bulk and strength, making it more attractive than routine testosterone formulations. John Zeigler, the US Olympic team physician, began administering it to athletes to reportedly even the playing field with European Olympians. In the process, he observed that the drug was causing notable testicular atrophy and prostate enlargement. It was ultimately banned by the Food and Drug Administration (FDA), and by the 1990s, the use of anabolic steroids without a prescription was considered a felony [3]. As mentioned in the introduction, a focus largely on means of improving male libido and sexual function has led us into a new era of heightened interest in TRT, similar to that seen at the beginning and middle of the last century.
–
–
drop to baseline approximately 2–4 h after removal. This formulation also bypasses the effects of first-pass hepatic metabolism by being transported directly to the superior vena cava. The main concerns of this formulation are the transfer of testosterone to a partner via saliva and the accidental swallowing of the tablet, leading to subtherapeutic testosterone levels [6]. Topical patches and gels (the most expensive and most commonly used of the modalities) are applied to the skin daily. These formulations best mimic the body’s circadian release of testosterone, peaking in the morning and slowly declining over the course of the day. One notable issue is that the absorption of testosterone and thereby systemic testosterone levels can vary from person to person. The level of testosterone returns to normal 24 h after removal of the patch and 1–2 days after the last administration of the gel. Oral testosterone is generally not recommended due to reports of cholestasis, hepatotoxicity, and adverse lipid effects.
The Data Behind Testosterone Therapy Pharmacokinetics of Exogenous Testosterone Exogenous testosterone comes in a number of formulations: intramuscular, subcutaneous pellets, buccal, topical patches, and topical gels. –
–
–
Intramuscular injections are an earlier form of exogenous testosterone. While relatively cheap, the pharmacokinetics are unpredictable, with supraphysiologic levels in the first 2–3 days followed by a decline to subtherapeutic levels within 2–3 weeks. This requires injections every 3 weeks and can lead to psychological and sexual swings as a result of its non-physiologic mechanism of action [4]. Testosterone pellets are the earliest form of TRT and are implanted subcutaneously. They have a much more predictable pharmacokinetic profile, and while they produce supraphysiologic levels initially, the levels decline slowly over the course of 6 months, virtually eliminating any psychological or sexual swings. They have been noted to be painful, and there have been cases of extrusion. It is also a very long-acting formulation, making its effects difficult to reverse. Thus, it can be an unappealing mode of administration, particularly for elderly patients for which there may be concerns of particular side effects [5]. Transbuccal testosterone is administered by placing a small tablet on the gum tissue twice a day. The levels peak at 2 h and reach a steady state within 24 h. The levels
The Endocrine Society Clinical Practice Guidelines recommend TRT for patients with signs or symptoms of androgen deficiency and a testosterone level below 280–300 ng/dL with a goal testosterone level between 400 and 700 ng/dL (normal range considered to be between 280 and 800 ng/dL). There is an age-related decline in testosterone levels of approximately 1–2 % per year, and a substantial proportion of older men has testosterone levels below the lower limit of normal for young, healthy males [7•]. The signs and symptoms of androgen deficiency include more specific signs and symptoms of low libido, hot flashes, erectile dysfunction as well as less specific signs and symptoms of fatigue, loss of vigor, depressed mood, poor concentration, reduced physical performance, and sleep disturbance. These findings are the driver for consideration for TRT. Recommendations to support TRT in patients with low testosterone are largely as a result of signs and symptoms endorsed by participants in population-based surveys and cross-sectional studies [8, 9]. While these signs and symptoms could certainly be as a result of low testosterone levels, they could also be due to a number of other comorbidities that appear to coincide with low testosterone levels. Not only are the signs and symptoms of androgen deficiency somewhat vague, but testosterone levels can also vary greatly based on circadian variation. Almost 15 % of healthy males have testosterone levels below the lower limits of normal within a 24-h period [10]. Therefore, one low testosterone measurement is not adequate to diagnose androgen deficiency.
Curr Atheroscler Rep (2016) 18:19
Much of the data for the effects of low testosterone levels is based on signs and symptoms as a result of surgical orchiectomy or administration of gonadotropin-releasing hormone agonists or antagonists. Observational data of these patients show a marked loss of bone density, increase in fat mass, loss of muscle mass and strength, hot flashes, and a decrease in sexual function [7•]. However, the data showing the benefit of TRT in managing symptoms related to low testosterone are mixed. The only randomized control trial (RCT) of patients with erectile dysfunction and testosterone levels below 300 ng/dL showed no difference between 16 weeks of TRT and placebo on a standardized erectile dysfunction questionnaire [11]. These findings are supported by a systematic review of observational data [12]. A recent RCT of 274 patients receiving transdermal testosterone gel versus placebo did not show any difference in 4/5 muscle strength parameters, physical function tests, or psychological self-assessment. There was, however, a statistically significant difference in sexual and somatic self-assessment in the overall cohort as well as quality of life and physical function in a subgroup analysis of frail elderly participants [13]. Overall, there is a lack of largescale, long-term studies that clearly delineate who would benefit from TRT, and much of the current recommendations for TRT in symptomatic patients with low testosterone is based on observational data and expert consensus.
Cardiovascular Effects of Low Testosterone Given that testosterone levels do decrease with age and the average age of men at the time of MI is in the mid-60s, it was hypothesized that low testosterone levels were at least in part responsible. Unfortunately, most of the initial meta-analyses looking at this question were based on observational data. The first major one looked at 12 community-based studies of the association between low endogenous testosterone and allcause and CV mortality [14]. They found a statistically significant difference in all-cause mortality (relative risk (RR) 1.35, 95 % confidence interval (CI) 1.13–1.62) but no difference in CV mortality (RR 1.25, 95 % CI 0.97–1.60). Only 7 of the 12 studies reported CV mortality. Three of the 5 trials that trended towards an adverse association between low endogenous testosterone and CVD did not control for diabetes, an obviously crucial risk factor. There was also a lack of control for hyperlipidemia and hypertension in a number of the studies, and the testosterone levels were also measured at various times of the day. The authors rightfully concluded that while there was a trend towards increased CVD in those with low endogenous testosterone and a statistically significant association between low endogenous testosterone and all-cause mortality, there was too much between-study heterogeneity to make any solid conclusions from these data. Another meta-analysis looked at observational studies of endogenous testosterone levels in
Page 3 of 6 19
healthy men [15]. Overall, there was a weak protective effect of normal endogenous testosterone levels against the development of CVD (RR 0.89, 95% CI 0.83–0.96). This was largely driven by studies that included men over the age of 70 as there was no statistically significant difference in the studies of patients less than 70. Again, the conclusion was made that these observations may be due to comorbidities that are associated with low endogenous testosterone and not low endogenous testosterone itself. The authors went on to say that low endogenous testosterone may simply be a Bmarker of poor health^ and not the root cause of CV morbidity and mortality. While the meta-analyses of the observational data described above do not provide substantial evidence of a link between endogenous testosterone deficiency and CVD, data from patients with prostate cancer who have received androgen deprivation therapy (ADT) are more intriguing. Circulating androgens allow prostate cancer cells to grow, and lowering androgen levels can potentially eliminate these cancer cells. It is speculated that low circulating levels of androgens may lead to increased body weight, reduced insulin sensitivity, and dyslipidemia that predispose patients to CVD [16]. A number of population-based studies have shown a potential relationship. An assessment of over 70,000 Medicare patients showed that men treated with ADT had a statistically significantly higher risk of coronary heart disease versus those who were not treated with ADT (adjusted hazard ratio 1.16; p < .001), MI (adjusted HR 1.11; p = .03), and sudden cardiac death (adjusted HR 1.16; p = .004) [17]. Another population-based cohort of over 22,000 men showed a 20 % higher risk of serious CV morbidity within 12 months of treatment with ADT (HR 1.20, 95 % CI 1.15–1.26) [18]. A pooled analysis of three RCTs of 1372 men randomized to radiation therapy with or without ADT showed that those who received 6 months of ADT had an earlier onset of MI as compared to those who did not receive ADT (p = 0.017) [19]. Other studies have not corroborated these findings [20]. This prompted the American Heart Association, American Cancer Society, and American Urologic Association to come together to write a science advisory in 2010. They reported that Bwhether an association (or an actual cause-and-effect relationship) between ADT use and CV events and mortality exists remains controversial and continues to be studied… At this point, it is reasonable… to state that there may be a relationship between ADT and CV events and death [21].^ Shortly after the publication of this statement, a meta-analysis of 4141 patients in 8 randomized trials was published, which looked at prostate cancer patients in an ADT arm versus those who did not receive ADT. This analysis looked only at CV death but found no statistically significant different between those treated with ADT and those who were not (RR 0.93; 95 % CI 0.79–1.10, p = 0.41) [22]. Overall, it is safe to say there may be an association between low endogenous testosterone and CVD, but well-designed
19
Page 4 of 6
trials need to be performed in order to more fully answer this question.
Cardiovascular Effects of Testosterone Replacement Just as the effects of endogenous testosterone on the CV system are unclear, the studies looking at the effects of exogenous testosterone and its impact on the CV system have also been mixed. A meta-analysis of randomized placebo-controlled trials of long-term (greater than 12 weeks duration) testosterone use looked at reported adverse CV events [23]. The primary outcome was a composite of broadly defined CV events. Twenty-seven trials of 2994 patients were included; 13 trials were supported by the pharmaceutical industry. Two of the included trials were stopped, 1 due to adverse events and 1 due to no foreseeable benefit. TRT in this analysis increased the risk of CV events (OR 1.54, 95 % CI 1.09–2.18). There was a marginally statistically significant difference in predefined so-called serious CV events (OR 1.61, 95 % CI 1.01–2.56). The authors noted that adverse events varied by source of funding based on meta-regression analysis of risk (p value of interaction 0.03), with trials not funded by the pharmaceutical industry more likely to show risk. There was no such interaction noted for baseline testosterone (p value of 0.7). Those that favored TRT were also all substantially smaller studies. The authors did note that they had to exclude trials that did not report CVevents by arm, which may have affected their results. They concluded that while endogenous testosterone may be protective, exogenous testosterone and its metabolites may increase adverse CV events [23]. A double-blinded RCT of TRT in relatively healthy men 60 years and older looked at the rate of change in carotid artery intima media thickness (IMT) and coronary artery calcium as a surrogate for progression or development of atherosclerosis over the course of 3 years. Patients in the treatment arm were specifically treated to normal levels of testosterone. The rate of change in IMT was not statistically significantly different between groups: 0.010 mm/year in the placebo group and 0.012 mm/year in the testosterone group (mean difference 0.002 mm/year, 95 % CI −0.003–0.003, p = 0.89). End of treatment IMT also did not differ significantly between groups. In terms of coronary calcium score, the Agatston score for the placebo group was 41.4 vs. 3.14 for the intervention group, which was not statistically significantly different (mean difference −10.8, 95 % CI −45.7–24.2, p = 0.54). Therefore, there appears to be no adverse effect of testosterone on these two surrogate markers for atherosclerosis. Caution should be given to interpretation of these results as IMT and coronary artery calcification are surrogate markers and do not supplant studies looking at hard CV outcomes [24]. A very controversial paper by Vigen et al. [25] looked at the association of TRT with mortality, MI, and stroke in men with
Curr Atheroscler Rep (2016) 18:19
low testosterone. This was a retrospective cohort study of 8709 male veterans with a testosterone level less than 300 ng/dL who underwent coronary angiography between 2005 and 2011. Fourteen percent of the patients in the study initiated TRT after heart catheterization. These men were noted to be younger, with fewer comorbidities. Patients were assumed to be taking TRT if they had filled a prescription at the VA pharmacy. Patients enrolled filled 17.6 % of prescriptions, and only 60 % of participants in the study had a followup testosterone level checked. Patients were also assumed to be taking the prescription until an adverse outcome occurred or until the follow-up period was complete. The primary outcome was a composite end-point of mortality, MI, and stroke. They found that those receiving TRT had an increased risk of the primary outcome (HR 1.29, 95 % CI 1.05–1.58, p = 0.02). This finding persisted when controlling for presence of coronary artery disease. The authors concluded Bthe use of testosterone therapy was associated with increased risk of adverse outcomes.^ The publication of this paper led to a number of criticisms [26]. These ranged from inaccuracies in statistical analysis to inclusion/exclusion criteria in the study. The most striking argument was that the data were likely skewed as a result of inadequate treatment of the testosterone group. The mean testosterone level of the men post-treatment was noted to be 332.2 ng/dL, significantly lower than the 400–700 ng/dL recommended cutoff, and 63 % of men being treated with the testosterone patch were on a subtherapeutic dose. Despite the flaws in the Vigen et al. trial, the results built upon an already growing body of literature suggesting TRT increase CV events. These include a RCT of 209 men over the age of 65 with low testosterone levels who received TRT for limited mobility [27]. The study was stopped prematurely at 6 months due to increased adverse events. It should be emphasized that adverse events ranged from serious outcomes to more minor events such as ectopy on EKG, hypertension, and peripheral edema. There was also a cohort study by Finkle et al. of 55,953 Medicare enrollees who received TRT for low testosterone levels [28]. They compared the incidence of MI 90 days after TRT to the incidence 1 year prior to initiation of therapy. They found an overall increased risk of MI in the group after treatment with testosterone (rate ratio 1.36, 95 % CI 1.03–1.81), with the burden of risk among those over the age of 65 (RR 2.19, 95 % CI 1.27–3.77). The risk increased with age; the risk being particularly high in those over the age of 75. There was an increased risk in those under the age of 65 with a history of prior CV disease (RR 2.90, 95 % CI 1.49– 5.62). There have also been a number of studies to suggest increased thrombotic risk in patients receiving TRT [29, 30]. Based on these results, the FDA released a safety communication on March 3, 2015 stating Bthere is a possible increased CV risk associated with testosterone use,^ and therefore, they are Brequiring labeling changes for all prescription
Curr Atheroscler Rep (2016) 18:19
testosterone products to reflect the possible increased risk of heart attacks and strokes associated with testosterone use.^ They also called for a clinical trial to better elucidate the CV risk of TRT. The most robust data to date may in fact come from a recent retrospective analysis of 91,012 veterans without CVD receiving care within the Veterans Health Administration from 1999 to 2014 [31••]. The study included 21,380 individuals not treated with exogenous testosterone and 69,632 treated with exogenous testosterone. They then divided those treated with testosterone into those with persistent low levels (n = 25,701) and those with normalized levels based on current guidelines (n = 43,931). Normal levels were defined individually based on the normal reference range reported, given heterogeneity of defined normal levels between reference labs. As compared to the untreated group, the treated group whose levels normalized was younger and had less comorbidities whereas the treated group with persistent low levels was older and had more comorbidities. The authors found that those treated to normal had lower all-cause mortality (HR 0.40, 95 % CI 0.39– 0.43, p < 0.001), myocardial infarction (MI) (HR 0.70, 95 % CI 0.59–0.83, p < 0.001), and stroke (HR 0.57, 95 % CI 0.40– 0.82, p < 0.001) as compared to the untreated group. The nonnormalized group showed an all-cause mortality benefit of TRT (HR 0.83, 95 % CI 0.79–0.87, p < 0.001) but no benefit in terms of reduction in MI (HR 0.95, 95 % CI 0.79–1.15, p = 0.599) or CVA (HR 0.90, 95 % CI 0.61–1.34, p = 0.610). These data were consistent with those of a previous study of veterans, although that one, like many others mentioned, did not follow post-treatment testosterone levels [32]. The authors suggested that previous studies may have been confounded by inadequate TRT (i.e., patients continued to have persistently low testosterone levels despite therapy) and that this may have falsely led to the conclusion that TRT increases CV risk. There was also mention of evidence that about 25 % of patients are initiated on TRT without initial confirmation of low testosterone levels and approximately 21 % of patients do not have levels checked after initiation of therapy. This can greatly confound the analysis of available data and also potentially places those with baseline normal testosterone levels at increased risk of CVand other adverse outcomes. If normalizing testosterone levels does in fact decrease CV morbidity and mortality, it is still unclear by what mechanism it does so. Additional studies will be needed to further investigate these findings.
Page 5 of 6 19
on gathering these data in order to better inform the millions of patients who are currently seeking or receiving TRT. We should make it a priority to determine, via large RCTs, if low testosterone is the cause of symptoms and whether TRT is effective in reducing these symptoms. While these studies are being conducted, the CV community needs to better determine what the impact of low testosterone and TRT is on CV outcomes. This is vital in better informing our recommendations regarding the CV pros and cons of TRT. Compliance with Ethical Standards Conflict of Interest Sahar Naderi declares no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.
2. 3. 4. 5. 6.
7.•
8.
Conclusion 9.
In 2004, the Institutes of Medicine charged the medical community with the task of obtaining critical scientific data demonstrating the benefits and risks of TRT. This was followed by a similar recent call by the FDA. Today, we are still working
10.
Baillargeon J, Urban RJ, Ottenbacher KJ, Pierson KS, Goodwin JS. Trends in androgen prescribing in the United States, 2001 to 2011. JAMA Internal Medicine. 2013;173:1465–6. Morales A. The long and tortuous history of the discovery of testosterone and its clinical application. J Sex Med. 2013;10:1178–83. Dotson JL, Brown RT. The history of the development of anabolicandrogenic steroids. Pediatr Clin North Am. 2007;54:761–9. xi. Edelstein D, Dobs A, Basaria S. Emerging drugs for hypogonadism. Expert Opin Emerg Drugs. 2006;11:685–707. Zitzmann M, Nieschlag E. Hormone substitution in male hypogonadism. Mol Cell Endocrinol. 2000;161:73–88. Ross RJ, Jabbar A, Jones TH, Roberts B, Dunkley K, Hall J, et al. Pharmacokinetics and tolerability of a bioadhesive buccal testosterone tablet in hypogonadal men. Eur J Endocrinol. 2004;150:57–63. Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95:2536–59. This article outlines the current guidelines for testosterone therapy from the Endocrine Society. Wu FC, 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: 2737–45. Hall SA, Esche GR, Araujo AB, Travison TG, Clark RV, Williams RE, et al. Correlates of low testosterone and symptomatic androgen deficiency in a population-based sample. J Clin Endocrinol Metab. 2008;93:3870–7. Brambilla DJ, O’Donnell AB, Matsumoto AM, McKinlay JB. Intraindividual variation in levels of serum testosterone and other
19
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
Curr Atheroscler Rep (2016) 18:19
Page 6 of 6 reproductive and adrenal hormones in men. Clin Endocrinol (Oxf). 2007;67:853–62. Paduch DA, Polzer PK, Ni X, Basaria S. Testosterone replacement in androgen-deficient men with ejaculatory dysfunction: a randomized controlled trial. J Clin Endocrinol Metab. 2015;100:2956–62. Bolona ER, Uraga MV, Haddad RM, Tracz MJ, Sideras K, Kennedy CC, et al. Testosterone use in men with sexual dysfunction: a systematic review and meta-analysis of randomized placebocontrolled trials. Mayo Clin Proc. 2007;82:20–8. Srinivas-Shankar U, Roberts SA, Connolly MJ, O’Connell MD, Adams JE, Oldham JA, et al. Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, doubleblind, placebo-controlled study. J Clin Endocrinol Metab. 2010;95: 639–50. Araujo AB, Dixon JM, Suarez EA, Murad MH, Guey LT, Wittert GA. Clinical review: endogenous testosterone and mortality in men: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2011;96:3007–19. Ruige JB, Mahmoud AM, De Bacquer D, Kaufman JM. Endogenous testosterone and cardiovascular disease in healthy men: a meta-analysis. Heart. 2011;97:870–5. Levine GN, D’Amico AV, Berger P, Clark PE, Eckel RH, Keating NL, et al. Androgen-deprivation therapy in prostate cancer and CV risk: a science advisory from the American Heart Association, American Cancer Society, and American Urological Association: Endorsed by the American Society for Radiation Oncology. CA Cancer J Clin. 2010;60:194–201. Keating NL, O’Malley A, Freedland SJ, Smith MR. Diabetes and CV disease during androgen deprivation therapy: observational study of veterans with prostate cancer. J Natl Cancer Inst. 2012;104:1518–23. Saigal CS, Gore JL, Krupski TL, Hanley J, Schonlau M, Litwin MS, et al. Androgen deprivation therapy increases CV morbidity in men with prostate cancer. Cancer. 2007;110:1493–500. D’Amico AV, Denham JW, Crook J, Chen MH, Goldhaber SZ, Lamb DS, et al. Influence of androgen suppression therapy for prostate cancer on the frequency and timing of fatal myocardial infarctions. J Clin Oncol. 2007;25:2420–5. Efstathiou JA, Bae K, Shipley WU, Hanks GE, Pilepich MV, Sandler HM, et al. CV mortality after androgen deprivation therapy for locally advanced prostate cancer: Rtog 85-31. J Clin Oncol. 2009;27:92–9. Levine GN, D’Amico AV, Berger P, Clark PE, Eckel RH, Keating NL, et al. Androgen-deprivation therapy in prostate cancer and CV risk: a science advisory from the American Heart Association,
22.
23.
24.
25.
26. 27.
28.
29.
30.
31.••
32.
American Cancer Society, and American Urological Association: Endorsed by the American Society for Radiation Oncology. Circulation. 2010;121:833–40. Nguyen PL, Je Y, Schutz FA, Hoffman KE, Hu JC, Parekh A, et al. Association of androgen deprivation therapy with cardiovascular death in patients with prostate cancer: a meta-analysis of randomized trials. JAMA. 2011;306:2359–66. 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. Basaria S, Harman SM, Travison TG, Hodis H, Tsitouras P, Budoff M, et al. Effects of testosterone administration for 3 years on subclinical atherosclerosis progression in older men with low or lownormal testosterone levels: a randomized clinical trial. JAMA. 2015;314:570–81. Vigen R, O’Donnell CI, Baron 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;310:1829–36. Jones TH, Channer KS. Deaths and cardiovascular events in men receiving testosterone. JAMA. 2014;311:962–3. 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;363:109–22. 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. Glueck CJ, Friedman J, Hafeez A, Hassan A, Wang P. Testosterone, thrombophilia, thrombosis. Blood Coagul Fibrinolysis. 2014;25: 683–7. Glueck CJ, Goldenberg N, Budhani S, Lotner D, Abuchaibe C, Gowda M, et al. Thrombotic events after starting exogenous testosterone in men with previously undiagnosed familial thrombophilia. Transl Res. 2011;158:225–34. Sharma R, Oni OA, Gupta K, Chen G, Sharma M, Dawn B, et al. Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. Eur Heart J. 2015;36:2706–15. This is the most robust data to date on the association between testosterone therapy and myocardial infarction and mortality. Shores MM, Smith NL, Forsberg CW, Anawalt BD, Matsumoto AM. Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab. 2012;97:2050–8.
CORONARY HEART DISEASE (S. VIRANI AND S. NADERI, SECTION EDITORS)
Testosterone Replacement Therapy and the Cardiovascular System Sahar Naderi 1
# Springer Science+Business Media New York 2016
Abstract As testosterone replacement therapy (TRT) has emerged as a commonly prescribed therapy for symptomatic low testosterone, conflicting data have been reported in terms of both its efficacy and potential adverse outcomes. One of the most controversial associations has been that of TRT and cardiovascular morbidity and mortality. This review briefly provides background on the history of TRT, the indications for TRT, and the data behind TRT for symptomatic low testosterone. It then specifically delves into the rather limited data for cardiovascular outcomes of those with low endogenous testosterone and those who receive TRT. The available body of literature strongly suggests that more work, by way of clinical trials, needs to be done to better understand the impact of testosterone and TRT on the cardiovascular system. Keywords Testosterone . Cardiovascular disease . Male hormone therapy . Androgens
Introduction A focus on male sexual dysfunction in the last decade has resulted in a massive resurgence in testosterone replacement therapy (TRT). The USA has seen a fivefold increase in testosterone prescriptions between 2001 and 2011, and it is now a multi-billion dollar industry [1]. Because of its rapidly growing popularity, attention has turned to the appropriateness and This article is part of the Topical Collection on Coronary Heart Disease * Sahar Naderi [email protected]
1
Division of Cardiology, Stanford University Medical Center, 300 Pasteur Drive, H2155, Stanford, CA 94305, USA
safety of testosterone replacement therapy (TRT), particularly as it pertains to CV disease (CVD). Questions have arisen as to whether (a) low testosterone levels play a role in cardiovascular (CV) morbidity and mortality and (b) TRT is beneficial or detrimental to the CV system. In this review, we will lay the foundation for the use of TRT and discuss the available data regarding its effects on the CV system.
A Historical Perspective Androgens are hormones that control both the development and maintenance of male sex characteristics, with testosterone being the most important, necessary for both reproductive and sexual function. The effects of androgens have reportedly been known since the time of Aristotle, with historical documents suggesting the experimental castration of animals for purposes of domestication. In the 1840s, Arnold Berthold, a German physiologist, castrated roosters, resulting in regression of their comb and wattle. Returning their testicles to the abdominal cavity halted this process, suggesting that testicles secreted a substance that was integral to secondary sexual characteristics. Following these observations, Charles Edouard Brown-Sequard famously auto-injected extract from the testes of dogs and guinea pigs, reporting substantial increases in his physical and mental strength. He ultimately reported these effects in an 1889 paper in The Lancet. His advertisement of this BElixir of Life^ led to a public fervor that drove researchers to aggressively pursue a means by which to isolate androgens. By 1935, researchers Adolf Butenandt and Leopold Ruzicka had independently isolated what they recognized was a powerful androgen, later named testosterone, and ultimately won a Nobel Prize in Chemistry for this work. This led to the development of injectable forms of testosterone, and by
19
Curr Atheroscler Rep (2016) 18:19
Page 2 of 6
the 1940s, it had become a means of great financial gain for a number of pharmaceutical companies of the era. Despite reports in notable medical journals of substantial side effects as a result of indiscriminate use of testosterone [2], prescriptions continued to gain popularity, particularly among competitive athletes. Observations that Soviet-era Olympians were using testosterone as a means of enhancing performance led researchers at a Swiss pharmaceutical company to develop Dianabol, a synthetic form of testosterone. This so-called anabolic steroid contained mainly the component of testosterone responsible for muscle bulk and strength, making it more attractive than routine testosterone formulations. John Zeigler, the US Olympic team physician, began administering it to athletes to reportedly even the playing field with European Olympians. In the process, he observed that the drug was causing notable testicular atrophy and prostate enlargement. It was ultimately banned by the Food and Drug Administration (FDA), and by the 1990s, the use of anabolic steroids without a prescription was considered a felony [3]. As mentioned in the introduction, a focus largely on means of improving male libido and sexual function has led us into a new era of heightened interest in TRT, similar to that seen at the beginning and middle of the last century.
–
–
drop to baseline approximately 2–4 h after removal. This formulation also bypasses the effects of first-pass hepatic metabolism by being transported directly to the superior vena cava. The main concerns of this formulation are the transfer of testosterone to a partner via saliva and the accidental swallowing of the tablet, leading to subtherapeutic testosterone levels [6]. Topical patches and gels (the most expensive and most commonly used of the modalities) are applied to the skin daily. These formulations best mimic the body’s circadian release of testosterone, peaking in the morning and slowly declining over the course of the day. One notable issue is that the absorption of testosterone and thereby systemic testosterone levels can vary from person to person. The level of testosterone returns to normal 24 h after removal of the patch and 1–2 days after the last administration of the gel. Oral testosterone is generally not recommended due to reports of cholestasis, hepatotoxicity, and adverse lipid effects.
The Data Behind Testosterone Therapy Pharmacokinetics of Exogenous Testosterone Exogenous testosterone comes in a number of formulations: intramuscular, subcutaneous pellets, buccal, topical patches, and topical gels. –
–
–
Intramuscular injections are an earlier form of exogenous testosterone. While relatively cheap, the pharmacokinetics are unpredictable, with supraphysiologic levels in the first 2–3 days followed by a decline to subtherapeutic levels within 2–3 weeks. This requires injections every 3 weeks and can lead to psychological and sexual swings as a result of its non-physiologic mechanism of action [4]. Testosterone pellets are the earliest form of TRT and are implanted subcutaneously. They have a much more predictable pharmacokinetic profile, and while they produce supraphysiologic levels initially, the levels decline slowly over the course of 6 months, virtually eliminating any psychological or sexual swings. They have been noted to be painful, and there have been cases of extrusion. It is also a very long-acting formulation, making its effects difficult to reverse. Thus, it can be an unappealing mode of administration, particularly for elderly patients for which there may be concerns of particular side effects [5]. Transbuccal testosterone is administered by placing a small tablet on the gum tissue twice a day. The levels peak at 2 h and reach a steady state within 24 h. The levels
The Endocrine Society Clinical Practice Guidelines recommend TRT for patients with signs or symptoms of androgen deficiency and a testosterone level below 280–300 ng/dL with a goal testosterone level between 400 and 700 ng/dL (normal range considered to be between 280 and 800 ng/dL). There is an age-related decline in testosterone levels of approximately 1–2 % per year, and a substantial proportion of older men has testosterone levels below the lower limit of normal for young, healthy males [7•]. The signs and symptoms of androgen deficiency include more specific signs and symptoms of low libido, hot flashes, erectile dysfunction as well as less specific signs and symptoms of fatigue, loss of vigor, depressed mood, poor concentration, reduced physical performance, and sleep disturbance. These findings are the driver for consideration for TRT. Recommendations to support TRT in patients with low testosterone are largely as a result of signs and symptoms endorsed by participants in population-based surveys and cross-sectional studies [8, 9]. While these signs and symptoms could certainly be as a result of low testosterone levels, they could also be due to a number of other comorbidities that appear to coincide with low testosterone levels. Not only are the signs and symptoms of androgen deficiency somewhat vague, but testosterone levels can also vary greatly based on circadian variation. Almost 15 % of healthy males have testosterone levels below the lower limits of normal within a 24-h period [10]. Therefore, one low testosterone measurement is not adequate to diagnose androgen deficiency.
Curr Atheroscler Rep (2016) 18:19
Much of the data for the effects of low testosterone levels is based on signs and symptoms as a result of surgical orchiectomy or administration of gonadotropin-releasing hormone agonists or antagonists. Observational data of these patients show a marked loss of bone density, increase in fat mass, loss of muscle mass and strength, hot flashes, and a decrease in sexual function [7•]. However, the data showing the benefit of TRT in managing symptoms related to low testosterone are mixed. The only randomized control trial (RCT) of patients with erectile dysfunction and testosterone levels below 300 ng/dL showed no difference between 16 weeks of TRT and placebo on a standardized erectile dysfunction questionnaire [11]. These findings are supported by a systematic review of observational data [12]. A recent RCT of 274 patients receiving transdermal testosterone gel versus placebo did not show any difference in 4/5 muscle strength parameters, physical function tests, or psychological self-assessment. There was, however, a statistically significant difference in sexual and somatic self-assessment in the overall cohort as well as quality of life and physical function in a subgroup analysis of frail elderly participants [13]. Overall, there is a lack of largescale, long-term studies that clearly delineate who would benefit from TRT, and much of the current recommendations for TRT in symptomatic patients with low testosterone is based on observational data and expert consensus.
Cardiovascular Effects of Low Testosterone Given that testosterone levels do decrease with age and the average age of men at the time of MI is in the mid-60s, it was hypothesized that low testosterone levels were at least in part responsible. Unfortunately, most of the initial meta-analyses looking at this question were based on observational data. The first major one looked at 12 community-based studies of the association between low endogenous testosterone and allcause and CV mortality [14]. They found a statistically significant difference in all-cause mortality (relative risk (RR) 1.35, 95 % confidence interval (CI) 1.13–1.62) but no difference in CV mortality (RR 1.25, 95 % CI 0.97–1.60). Only 7 of the 12 studies reported CV mortality. Three of the 5 trials that trended towards an adverse association between low endogenous testosterone and CVD did not control for diabetes, an obviously crucial risk factor. There was also a lack of control for hyperlipidemia and hypertension in a number of the studies, and the testosterone levels were also measured at various times of the day. The authors rightfully concluded that while there was a trend towards increased CVD in those with low endogenous testosterone and a statistically significant association between low endogenous testosterone and all-cause mortality, there was too much between-study heterogeneity to make any solid conclusions from these data. Another meta-analysis looked at observational studies of endogenous testosterone levels in
Page 3 of 6 19
healthy men [15]. Overall, there was a weak protective effect of normal endogenous testosterone levels against the development of CVD (RR 0.89, 95% CI 0.83–0.96). This was largely driven by studies that included men over the age of 70 as there was no statistically significant difference in the studies of patients less than 70. Again, the conclusion was made that these observations may be due to comorbidities that are associated with low endogenous testosterone and not low endogenous testosterone itself. The authors went on to say that low endogenous testosterone may simply be a Bmarker of poor health^ and not the root cause of CV morbidity and mortality. While the meta-analyses of the observational data described above do not provide substantial evidence of a link between endogenous testosterone deficiency and CVD, data from patients with prostate cancer who have received androgen deprivation therapy (ADT) are more intriguing. Circulating androgens allow prostate cancer cells to grow, and lowering androgen levels can potentially eliminate these cancer cells. It is speculated that low circulating levels of androgens may lead to increased body weight, reduced insulin sensitivity, and dyslipidemia that predispose patients to CVD [16]. A number of population-based studies have shown a potential relationship. An assessment of over 70,000 Medicare patients showed that men treated with ADT had a statistically significantly higher risk of coronary heart disease versus those who were not treated with ADT (adjusted hazard ratio 1.16; p < .001), MI (adjusted HR 1.11; p = .03), and sudden cardiac death (adjusted HR 1.16; p = .004) [17]. Another population-based cohort of over 22,000 men showed a 20 % higher risk of serious CV morbidity within 12 months of treatment with ADT (HR 1.20, 95 % CI 1.15–1.26) [18]. A pooled analysis of three RCTs of 1372 men randomized to radiation therapy with or without ADT showed that those who received 6 months of ADT had an earlier onset of MI as compared to those who did not receive ADT (p = 0.017) [19]. Other studies have not corroborated these findings [20]. This prompted the American Heart Association, American Cancer Society, and American Urologic Association to come together to write a science advisory in 2010. They reported that Bwhether an association (or an actual cause-and-effect relationship) between ADT use and CV events and mortality exists remains controversial and continues to be studied… At this point, it is reasonable… to state that there may be a relationship between ADT and CV events and death [21].^ Shortly after the publication of this statement, a meta-analysis of 4141 patients in 8 randomized trials was published, which looked at prostate cancer patients in an ADT arm versus those who did not receive ADT. This analysis looked only at CV death but found no statistically significant different between those treated with ADT and those who were not (RR 0.93; 95 % CI 0.79–1.10, p = 0.41) [22]. Overall, it is safe to say there may be an association between low endogenous testosterone and CVD, but well-designed
19
Page 4 of 6
trials need to be performed in order to more fully answer this question.
Cardiovascular Effects of Testosterone Replacement Just as the effects of endogenous testosterone on the CV system are unclear, the studies looking at the effects of exogenous testosterone and its impact on the CV system have also been mixed. A meta-analysis of randomized placebo-controlled trials of long-term (greater than 12 weeks duration) testosterone use looked at reported adverse CV events [23]. The primary outcome was a composite of broadly defined CV events. Twenty-seven trials of 2994 patients were included; 13 trials were supported by the pharmaceutical industry. Two of the included trials were stopped, 1 due to adverse events and 1 due to no foreseeable benefit. TRT in this analysis increased the risk of CV events (OR 1.54, 95 % CI 1.09–2.18). There was a marginally statistically significant difference in predefined so-called serious CV events (OR 1.61, 95 % CI 1.01–2.56). The authors noted that adverse events varied by source of funding based on meta-regression analysis of risk (p value of interaction 0.03), with trials not funded by the pharmaceutical industry more likely to show risk. There was no such interaction noted for baseline testosterone (p value of 0.7). Those that favored TRT were also all substantially smaller studies. The authors did note that they had to exclude trials that did not report CVevents by arm, which may have affected their results. They concluded that while endogenous testosterone may be protective, exogenous testosterone and its metabolites may increase adverse CV events [23]. A double-blinded RCT of TRT in relatively healthy men 60 years and older looked at the rate of change in carotid artery intima media thickness (IMT) and coronary artery calcium as a surrogate for progression or development of atherosclerosis over the course of 3 years. Patients in the treatment arm were specifically treated to normal levels of testosterone. The rate of change in IMT was not statistically significantly different between groups: 0.010 mm/year in the placebo group and 0.012 mm/year in the testosterone group (mean difference 0.002 mm/year, 95 % CI −0.003–0.003, p = 0.89). End of treatment IMT also did not differ significantly between groups. In terms of coronary calcium score, the Agatston score for the placebo group was 41.4 vs. 3.14 for the intervention group, which was not statistically significantly different (mean difference −10.8, 95 % CI −45.7–24.2, p = 0.54). Therefore, there appears to be no adverse effect of testosterone on these two surrogate markers for atherosclerosis. Caution should be given to interpretation of these results as IMT and coronary artery calcification are surrogate markers and do not supplant studies looking at hard CV outcomes [24]. A very controversial paper by Vigen et al. [25] looked at the association of TRT with mortality, MI, and stroke in men with
Curr Atheroscler Rep (2016) 18:19
low testosterone. This was a retrospective cohort study of 8709 male veterans with a testosterone level less than 300 ng/dL who underwent coronary angiography between 2005 and 2011. Fourteen percent of the patients in the study initiated TRT after heart catheterization. These men were noted to be younger, with fewer comorbidities. Patients were assumed to be taking TRT if they had filled a prescription at the VA pharmacy. Patients enrolled filled 17.6 % of prescriptions, and only 60 % of participants in the study had a followup testosterone level checked. Patients were also assumed to be taking the prescription until an adverse outcome occurred or until the follow-up period was complete. The primary outcome was a composite end-point of mortality, MI, and stroke. They found that those receiving TRT had an increased risk of the primary outcome (HR 1.29, 95 % CI 1.05–1.58, p = 0.02). This finding persisted when controlling for presence of coronary artery disease. The authors concluded Bthe use of testosterone therapy was associated with increased risk of adverse outcomes.^ The publication of this paper led to a number of criticisms [26]. These ranged from inaccuracies in statistical analysis to inclusion/exclusion criteria in the study. The most striking argument was that the data were likely skewed as a result of inadequate treatment of the testosterone group. The mean testosterone level of the men post-treatment was noted to be 332.2 ng/dL, significantly lower than the 400–700 ng/dL recommended cutoff, and 63 % of men being treated with the testosterone patch were on a subtherapeutic dose. Despite the flaws in the Vigen et al. trial, the results built upon an already growing body of literature suggesting TRT increase CV events. These include a RCT of 209 men over the age of 65 with low testosterone levels who received TRT for limited mobility [27]. The study was stopped prematurely at 6 months due to increased adverse events. It should be emphasized that adverse events ranged from serious outcomes to more minor events such as ectopy on EKG, hypertension, and peripheral edema. There was also a cohort study by Finkle et al. of 55,953 Medicare enrollees who received TRT for low testosterone levels [28]. They compared the incidence of MI 90 days after TRT to the incidence 1 year prior to initiation of therapy. They found an overall increased risk of MI in the group after treatment with testosterone (rate ratio 1.36, 95 % CI 1.03–1.81), with the burden of risk among those over the age of 65 (RR 2.19, 95 % CI 1.27–3.77). The risk increased with age; the risk being particularly high in those over the age of 75. There was an increased risk in those under the age of 65 with a history of prior CV disease (RR 2.90, 95 % CI 1.49– 5.62). There have also been a number of studies to suggest increased thrombotic risk in patients receiving TRT [29, 30]. Based on these results, the FDA released a safety communication on March 3, 2015 stating Bthere is a possible increased CV risk associated with testosterone use,^ and therefore, they are Brequiring labeling changes for all prescription
Curr Atheroscler Rep (2016) 18:19
testosterone products to reflect the possible increased risk of heart attacks and strokes associated with testosterone use.^ They also called for a clinical trial to better elucidate the CV risk of TRT. The most robust data to date may in fact come from a recent retrospective analysis of 91,012 veterans without CVD receiving care within the Veterans Health Administration from 1999 to 2014 [31••]. The study included 21,380 individuals not treated with exogenous testosterone and 69,632 treated with exogenous testosterone. They then divided those treated with testosterone into those with persistent low levels (n = 25,701) and those with normalized levels based on current guidelines (n = 43,931). Normal levels were defined individually based on the normal reference range reported, given heterogeneity of defined normal levels between reference labs. As compared to the untreated group, the treated group whose levels normalized was younger and had less comorbidities whereas the treated group with persistent low levels was older and had more comorbidities. The authors found that those treated to normal had lower all-cause mortality (HR 0.40, 95 % CI 0.39– 0.43, p < 0.001), myocardial infarction (MI) (HR 0.70, 95 % CI 0.59–0.83, p < 0.001), and stroke (HR 0.57, 95 % CI 0.40– 0.82, p < 0.001) as compared to the untreated group. The nonnormalized group showed an all-cause mortality benefit of TRT (HR 0.83, 95 % CI 0.79–0.87, p < 0.001) but no benefit in terms of reduction in MI (HR 0.95, 95 % CI 0.79–1.15, p = 0.599) or CVA (HR 0.90, 95 % CI 0.61–1.34, p = 0.610). These data were consistent with those of a previous study of veterans, although that one, like many others mentioned, did not follow post-treatment testosterone levels [32]. The authors suggested that previous studies may have been confounded by inadequate TRT (i.e., patients continued to have persistently low testosterone levels despite therapy) and that this may have falsely led to the conclusion that TRT increases CV risk. There was also mention of evidence that about 25 % of patients are initiated on TRT without initial confirmation of low testosterone levels and approximately 21 % of patients do not have levels checked after initiation of therapy. This can greatly confound the analysis of available data and also potentially places those with baseline normal testosterone levels at increased risk of CVand other adverse outcomes. If normalizing testosterone levels does in fact decrease CV morbidity and mortality, it is still unclear by what mechanism it does so. Additional studies will be needed to further investigate these findings.
Page 5 of 6 19
on gathering these data in order to better inform the millions of patients who are currently seeking or receiving TRT. We should make it a priority to determine, via large RCTs, if low testosterone is the cause of symptoms and whether TRT is effective in reducing these symptoms. While these studies are being conducted, the CV community needs to better determine what the impact of low testosterone and TRT is on CV outcomes. This is vital in better informing our recommendations regarding the CV pros and cons of TRT. Compliance with Ethical Standards Conflict of Interest Sahar Naderi declares no conflict of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
References Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance 1.
2. 3. 4. 5. 6.
7.•
8.
Conclusion 9.
In 2004, the Institutes of Medicine charged the medical community with the task of obtaining critical scientific data demonstrating the benefits and risks of TRT. This was followed by a similar recent call by the FDA. Today, we are still working
10.
Baillargeon J, Urban RJ, Ottenbacher KJ, Pierson KS, Goodwin JS. Trends in androgen prescribing in the United States, 2001 to 2011. JAMA Internal Medicine. 2013;173:1465–6. Morales A. The long and tortuous history of the discovery of testosterone and its clinical application. J Sex Med. 2013;10:1178–83. Dotson JL, Brown RT. The history of the development of anabolicandrogenic steroids. Pediatr Clin North Am. 2007;54:761–9. xi. Edelstein D, Dobs A, Basaria S. Emerging drugs for hypogonadism. Expert Opin Emerg Drugs. 2006;11:685–707. Zitzmann M, Nieschlag E. Hormone substitution in male hypogonadism. Mol Cell Endocrinol. 2000;161:73–88. Ross RJ, Jabbar A, Jones TH, Roberts B, Dunkley K, Hall J, et al. Pharmacokinetics and tolerability of a bioadhesive buccal testosterone tablet in hypogonadal men. Eur J Endocrinol. 2004;150:57–63. Bhasin S, Cunningham GR, Hayes FJ, Matsumoto AM, Snyder PJ, Swerdloff RS, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95:2536–59. This article outlines the current guidelines for testosterone therapy from the Endocrine Society. Wu FC, 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: 2737–45. Hall SA, Esche GR, Araujo AB, Travison TG, Clark RV, Williams RE, et al. Correlates of low testosterone and symptomatic androgen deficiency in a population-based sample. J Clin Endocrinol Metab. 2008;93:3870–7. Brambilla DJ, O’Donnell AB, Matsumoto AM, McKinlay JB. Intraindividual variation in levels of serum testosterone and other
19
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
Curr Atheroscler Rep (2016) 18:19
Page 6 of 6 reproductive and adrenal hormones in men. Clin Endocrinol (Oxf). 2007;67:853–62. Paduch DA, Polzer PK, Ni X, Basaria S. Testosterone replacement in androgen-deficient men with ejaculatory dysfunction: a randomized controlled trial. J Clin Endocrinol Metab. 2015;100:2956–62. Bolona ER, Uraga MV, Haddad RM, Tracz MJ, Sideras K, Kennedy CC, et al. Testosterone use in men with sexual dysfunction: a systematic review and meta-analysis of randomized placebocontrolled trials. Mayo Clin Proc. 2007;82:20–8. Srinivas-Shankar U, Roberts SA, Connolly MJ, O’Connell MD, Adams JE, Oldham JA, et al. Effects of testosterone on muscle strength, physical function, body composition, and quality of life in intermediate-frail and frail elderly men: a randomized, doubleblind, placebo-controlled study. J Clin Endocrinol Metab. 2010;95: 639–50. Araujo AB, Dixon JM, Suarez EA, Murad MH, Guey LT, Wittert GA. Clinical review: endogenous testosterone and mortality in men: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2011;96:3007–19. Ruige JB, Mahmoud AM, De Bacquer D, Kaufman JM. Endogenous testosterone and cardiovascular disease in healthy men: a meta-analysis. Heart. 2011;97:870–5. Levine GN, D’Amico AV, Berger P, Clark PE, Eckel RH, Keating NL, et al. Androgen-deprivation therapy in prostate cancer and CV risk: a science advisory from the American Heart Association, American Cancer Society, and American Urological Association: Endorsed by the American Society for Radiation Oncology. CA Cancer J Clin. 2010;60:194–201. Keating NL, O’Malley A, Freedland SJ, Smith MR. Diabetes and CV disease during androgen deprivation therapy: observational study of veterans with prostate cancer. J Natl Cancer Inst. 2012;104:1518–23. Saigal CS, Gore JL, Krupski TL, Hanley J, Schonlau M, Litwin MS, et al. Androgen deprivation therapy increases CV morbidity in men with prostate cancer. Cancer. 2007;110:1493–500. D’Amico AV, Denham JW, Crook J, Chen MH, Goldhaber SZ, Lamb DS, et al. Influence of androgen suppression therapy for prostate cancer on the frequency and timing of fatal myocardial infarctions. J Clin Oncol. 2007;25:2420–5. Efstathiou JA, Bae K, Shipley WU, Hanks GE, Pilepich MV, Sandler HM, et al. CV mortality after androgen deprivation therapy for locally advanced prostate cancer: Rtog 85-31. J Clin Oncol. 2009;27:92–9. Levine GN, D’Amico AV, Berger P, Clark PE, Eckel RH, Keating NL, et al. Androgen-deprivation therapy in prostate cancer and CV risk: a science advisory from the American Heart Association,
22.
23.
24.
25.
26. 27.
28.
29.
30.
31.••
32.
American Cancer Society, and American Urological Association: Endorsed by the American Society for Radiation Oncology. Circulation. 2010;121:833–40. Nguyen PL, Je Y, Schutz FA, Hoffman KE, Hu JC, Parekh A, et al. Association of androgen deprivation therapy with cardiovascular death in patients with prostate cancer: a meta-analysis of randomized trials. JAMA. 2011;306:2359–66. 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. Basaria S, Harman SM, Travison TG, Hodis H, Tsitouras P, Budoff M, et al. Effects of testosterone administration for 3 years on subclinical atherosclerosis progression in older men with low or lownormal testosterone levels: a randomized clinical trial. JAMA. 2015;314:570–81. Vigen R, O’Donnell CI, Baron 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;310:1829–36. Jones TH, Channer KS. Deaths and cardiovascular events in men receiving testosterone. JAMA. 2014;311:962–3. 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;363:109–22. 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. Glueck CJ, Friedman J, Hafeez A, Hassan A, Wang P. Testosterone, thrombophilia, thrombosis. Blood Coagul Fibrinolysis. 2014;25: 683–7. Glueck CJ, Goldenberg N, Budhani S, Lotner D, Abuchaibe C, Gowda M, et al. Thrombotic events after starting exogenous testosterone in men with previously undiagnosed familial thrombophilia. Transl Res. 2011;158:225–34. Sharma R, Oni OA, Gupta K, Chen G, Sharma M, Dawn B, et al. Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. Eur Heart J. 2015;36:2706–15. This is the most robust data to date on the association between testosterone therapy and myocardial infarction and mortality. Shores MM, Smith NL, Forsberg CW, Anawalt BD, Matsumoto AM. Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab. 2012;97:2050–8.
