Abstract: Testosterone replacement has been in the news today because of recent articles and news reports. The cardiovascular safety of testosterone replacement has been brought into question. Compounding the problem is the deluge of pharmaceutical ads promoting the virtues of testosterone replacement. There are many published animal and human studies demonstrating the adverse impact of low testosterone on the cardiovascular system and the benefits of replacement. Unfortunately large prospective studies are lacking. The studies that are currently in the news are retrospective and have yielded associations that are misinterpreted as causal by the media. Careful analysis of the data reveal serious design and interpretation flaws. It is important to remember that although testosterone replacement may seem to be a “quick fix” for the symptoms of low testosterone, as physicians we must not forget that lifestyle modifications such as weight loss, increased exercise, better sleep habits and diet, and stress reduction can be just as effective in alleviating the symptoms.
Testosterone replacement therapy for men has been in the news lately. It seems that every month a study appears in the news bringing into question the safety of testosterone replacement. How strong is the evidence? Is this merely “pushback” against the ever increasing pharmaceutical media blitz on “Low T”, or is it based on sound evidence?
Every day in my practice I see men, both young and old, who have recently been diagnosed with “Low T” or are asking me if they should have their testosterone checked. The presenting symptoms are those seen in the incessant media commercials that ask “Do you have lack of energy, changes in mood, low sex drive, erectile dysfunction and are you overweight? Ask your doctor if testosterone replacement is right for you.” In today’s high pressure society, what man doesn’t have at least one of these symptoms? When are these symptoms due a low testosterone and when are they just a consequence of aging and the epidemic of obesity and its consequences or dysfunctional lifestyle choices? To be sure, testosterone levels decrease significantly in patients with chronic illnesses such as end-stage renal disease, human immunodeficiency virus, chronic obstructive pulmonary disease, type 2 diabetes mellitus (T2DM), obesity, genetic conditions, trauma, castration, radiation, chemotherapy, acute illness, and pituitary tumors.
The testosterone replacement market has grown 133% in the past four years to 1.6 billion dollars and is expected to reach 5 billion by 2017. Unlike women, who have been “forced” to accept menopause and the total absence of estrogen by studies deeming the risks of replacement greater than the benefit, men whose testosterone decreases by 1% a year after age thirty (but never disappears) are told that they should have their testosterone replaced when it drops.
So what is the evidence in men that replacement is beneficial and safe? Therein lies the problem! The studies, both with animals and with humans, sometimes paint a confusing picture. Headline-grabbing epidemiologic studies associating treatment with favorable or adverse outcomes provide ammunition for both camps. Computerized databases allow clinicians and academicians to mine the data in any way that may suit their preconceived bias. In addition, the FDA, when considering their approval of a form of testosterone replacement, has only used “meeting the chemical benchmark blood level of 300ng/dl” without regard to resolution of the presenting symptoms or long term safety. Prospective randomized trials of clinical outcomes tend to be small, short term, and pharmaceutically-sponsored, designed to show efficacy. Long term randomized trials on safety are lacking.
Let’s look at the evidence.
Testosterone and Coronary Artery Disease (CAD): Existing evidence suggests that men with CAD have lower levels of testosterone. This finding is consistent with evidence that low testosterone levels are associated with risk factors for CAD, DM type 2, and obesity. It is not known whether low testosterone levels are a cause or a consequence of CAD, or if long term replacement is beneficial in CAD. Testosterone has been used in the past to treat angina in both men and women.1 In 1946, Lesser described improvement in angina symptoms in 91% of 100 treated patients. Contemporary studies show that in men with CAD, testosterone prolongs the time to exercise-induced ST-segment depression, as measured on treadmill stress testing. Men with lower testosterone benefitted the most. Experimental animal and human evidence suggests that testosterone increases angina threshold in men with CAD by causing vasodilation of coronary arteries independent of endothelial nitric oxide.2
Testosterone and Mortality: There are at least 8 studies linking increased cardiovascular and overall mortality with lower testosterone levels. The mechanism through which low testosterone increases mortality is not known. Testosterone may be acting directly on the cardiovascular system by a mechanism that is as yet undiscovered or it could be functioning as a marker for an underlying disease that increases the mortality risk. Long term studies on whether testosterone replacement changes that increased risk are not known.
Testosterone and Diabetes Mellitus: The association between low T and Type 2 DM has been established in well over 20 studies. Longitudinal Scandinavian studies have shown that men with the lowest quartile of testosterone were more likely to develop Type 2 DM. Men on androgen deprivation for prostate cancer were at increased risk of developing Type 2 DM. A meta-analysis demonstrated that testosterone replacement therapy significantly improves hemoglobin A1c in addition to fasting plasma glucose.3 The association between testosterone and Type 2 DM is most likely bidirectional and involves visceral adiposity and hypothalamic regulation.
Testosterone and Obesity : The link between low testosterone and increased BMI has been firmly established in the literature. 4 In the Hypogonadism in Males study, the mean BMI for hypogonadal men was found to be 31.5 compared with 28.5 for men with normal testosterones. Replacement therapy seems to be beneficial. In a placebo controlled study testosterone replacement resulted in a decrease in BMI by 1.3 at 30 weeks.5
Testosterone and Dyslipidemia: Because of the differences in cardiovascular disease and dyslipidemia between the sexes, investigators have hypothesized that the difference was related to the different levels of circulating sex hormones. Unfortunately, large, prospective population-based studies that investigate the association between testosterone levels and lipid subfractions are not currently available. The evidence regarding the association between baseline testosterone levels and different lipid subfractions is conflicting as is the effect of testosterone replacement on levels of lipid subfractions. None of the studies reported an increase in triglycerides.
Testosterone and the QTc interval: Growing evidence suggests that testosterone may play an important role in the regulation of ventricular repolarization. Heart-rate-corrected QT (QTc) interval has long been accepted as an accurate measure of ventricular repolarization, and prolongation of the QTc interval is associated with increased incidence of ventricular arrhythmias. Moreover, sex- and age-related differences in ventricular repolarization have also been well established. There is no difference in ventricular repolarization patterns between the 2 sexes prior to the onset of puberty. Men experience a gradual shortening of their QTc interval from approximately age 9 until around age 50, when their androgen levels are highest. Afterwards, the male QTc interval starts to prolong gradually, until approximately age 60, at which point it becomes quite similar to the QTc interval of women of the same age. In addition, castrated men have been shown to have QTc intervals that are longer than the QTc interval in non-castrated men. Hypogonadal obese have been shown to have longer QTc intervals than obese men. Testosterone replacement therapy has been found to significantly reduce the QTc interval in as few as 2 days of treatment. In summary, existing evidence strongly suggests that testosterone plays an important role in the regulation of ventricular repolarization by shortening the length of the QTc interval.
Testosterone and Atherosclerosis: Intima-media thickness (IMT) of the carotid artery is considered a marker for preclinical atherosclerosis. Increasing carotid IMT has been associated with generalized atherosclerosis and increased incidence of myocardial infarction and stroke and is generally considered a poor prognostic factor for future adverse cardiovascular events.2 Lowered testosterone has been associated with increased carotid and thoracic aorta IMT on progression of atherosclerosis of the abdominal aorta after adjustment for age, smoking, physical activity, blood pressure, and lipid levels. There are no studies in humans demonstrating improvement in the intimal thickness with replacement therapy.
Testosterone and Congestive Heart Failure (CHF): A key pathologic feature of (CHF) is a metabolic shift, which results from the activation of neuroendocrine and inflammatory pathways which, in turn, causes progressively worsening exercise intolerance, as well as cardiac weakening.2 Emerging evidence indicates that there might be a significant association between testosterone deficiency, CHF, and exercise capacity. Jankowska6 has shown that men with CHF have significantly reduced levels of testosterone, and with increasing severity of CHF, there was a significant stepwise decrease in the levels of testosterone. Four authors have investigated the effects of testosterone replacement therapy on exercise capacity in men with CHF. Toma 7 et al performed a meta-analysis of these studies. The meta- analysis revealed that patients treated with testosterone replacement therapy experienced an increase of 16.7% (equivalent to 54 m) in the 6-minute walk test, an increase of 15.9% in the isometric walk test, and finally an increase of 22.7% in peak VO2. In addition, major adverse cardiovascular events were evenly distributed among the 2 treatment and placebo groups, with the testosterone replacement group experiencing 7% of the total major adverse cardiovascular events compared with 6% for the placebo group. In summary, testosterone replacement therapy has been shown to significantly improve exercise capacity, without affecting LVEF.
Given the data presented above, much of which is quite positive for testosterone replacement, why is there such concern? There have been several studies recently performed that have received a great deal of press.
- Calof et al performed a meta-analysis of 19 randomized placebo-controlled trials that included 651 men who received testosterone replacement therapy and 433 men who received placebo8. The testosterone replacement group was shown to have a greater combined incidence of all prostate-related adverse events compared with that in the placebo group. It should be noted, however, that none of the individual prostate-related adverse events significantly differed from those in the placebo group. This included cases of prostate cancer, which showed no significant difference between the testosterone group and the placebo group. Calof et al did not find a significant difference in the rate of cardiovascular events between the testosterone replacement group and the placebo group. Specifically, no statistically significant differences between the 2 groups in the rates of atrial fibrillation, atrial arrhythmia, myocardial infarction, chest pain or ischemia, coronary procedures including coronary artery bypass grafting, vascular events, and cerebrovascular events.
- Haddad9 performed a meta-analysis of 30 placebo controlled randomized trials, which included 808 men in the testosterone replacement group and 834 men in the placebo group. Haddad et al defined adverse cardiovascular events as cardiovascular death, fatal and nonfatal myocardial infarction, angina, arrhythmia, revascularization procedures, and stroke. The difference in adverse cardiovascular events between the testosterone and placebo groups was not statistically significant.
- Fernandez-Balsells et al performed a This meta-analysis that included 51 studies. 10 They did not find any statistically significant difference between the testosterone and placebo groups for rate of death, myocardial infarction, coronary revascularization procedures, or arrhythmias, rates of prostate cancer, the need for prostate biopsy, international prostate symptom score, increase in PSA, or total number of prostate-related adverse events.
- Shores et al analyzed clinical data from 1031 male veterans in a retrospective observational study. The mortality rate in the testosterone-treated group was found to be 10.3% compared with 20.7% in the untreated group. After multivariable adjustment, including obesity, the hazard ratio for all-cause mortality in men who were treated with testosterone was 0.6. 11
- In a recent retrospective review of VA men with CAD a 5.8% absolute risk increase for the composite of all-cause mortality, MI and ischemic stroke in male veterans who were treated with exogenous testosterone12. The authors correctly point out the weaknesses of their study which include retrospective study design and lack of randomization, small sample size at extremes of follow-up, lack of outcome validation by chart review and poor generalizability of the results.
Where does leave us? Is testosterone replacement safe? The answer is that in selected patients it is. Patients should be chemically hypogonadal and be symptomatic. With proper monitoring ,normalization of testosterone can improve the symptoms of hypogonadism and is safe. It important to keep in mind, modification of lifestyle, compliance with all medications, stress reduction, improved sleep health and diet is as important as the treatment of low T. Unlike what some of the promotional ads might imply, testosterone normalization is not the solution to all of life’s problems.
In future articles I will report on the various forms of treatment for low T and some of the pitfalls associated with treatment.
Issues regarding hormone replacement will also be discussed at my upcoming CME course, Reproductive and Sexual Health Update for Primary Care Providers, on Saturday, June 7th, 2014. For more information, visit our website: www.uroinstitute.org .
Be sure to keep reading our blog for further info and more urological news & opinions.
Written by Andrew McCullough, M.D.
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9. Haddad RM, Kennedy CC, Caples SM, et al. Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc. Jan 2007;82(1):29-39.
10. Fernandez-Balsells MM, Murad MH, Lane M, et al. Clinical review 1: Adverse effects of testosterone therapy in adult men: a systematic review and meta-analysis. J Clin Endocrinol Metab. Jun 2010;95(6):2560-2575.
11. Shores MM, Smith NL, Forsberg CW, Anawalt BD, Matsumoto AM. Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab. Jun 2012;97(6):2050-2058.
12. Vigen R, O’Donnell CI, Baron AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. Nov 6 2013;310(17):1829-1836.