After recent scientific and press reports relating to the increased perceived cardiovascular risk associated with testosterone replacement therapy in the ageing male, the US FDA released a final report in 2015 (FDA Drug Safety Communication: 2015). The 2015 report cautioned that prescribing testosterone products should only be reserved for men who have low testosterone levels due to primary or secondary hypogonadism as a consequence of malfunctions with the testes, pituitary or hypothalamus. The FDA’s position was that there was not enough evidence on the benefits and safety with regards to prescribing testosterone in the ageing male. This essay will seek to investigate the effects that testosterone has upon cardiovascular risk in men. The reader will then be able to determine whether the stance of the FDA used sound evidence-based medicine or not.
Coronary heart disease is the most significant cause of death in both the Western and the developing world. One of the more salient epidemiological features that emerged from the studies is the consistent difference between men and women. Twice as many men as women are affected with coronary heart disease across all ages (Jousilahti P, et al, 1999). This difference was attributed to testosterone in men; hence it would be natural than to make the assertion that TRT increases cardiovascular risk. Before attempting to look at studies to confirm whether this is the case it would be interesting to conduct a thought experiment. If excess testosterone causes increased cardiovascular risk then the reverse should be true, namely low testosterone should result in a decrease of cardiovascular risk. A good place to start would be to look at men who are hypogonadic and who would therefore have low testosterone levels and analyse whether this impacted upon their cardiovascular risk. Hypogonadism is a clinical condition, which is manifested by signs, and symptoms associated with low testosterone levels. When this occurs in older males it has been called the andropause or androgen deficiency in the ageing male or late-onset hypogonadism (LOH) (Nieschlag E, et al 2005). Studies have demonstrated that an inverse relationship exists between the concentration of endogenous testosterone and mortality due to cardiovascular disease. In fact, it has been postulated that low testosterone could be a predictive marker for those individuals at high risk for cardiovascular disease (Khaw KT et al 2007). A common clinical scenario can be used to observe the effect of the relationship between low testosterone levels and cardiovascular risk. In men suffering from prostate cancer, androgen deprivation therapy (ADT) is commonly used creating a hypogonadal state. This has allowed a number of researchers to evaluate the relationship between this induced hypogonadal state and cardiovascular risk. In a study of over 22,000 men with prostate cancer, those who received ADT had a 20% increased risk of cardiovascular morbidity in the first year of treatment (Saigal et al.2007). From these observations, it can be appreciated that the relationship between cardiovascular risk and testosterone levels is subtler than initially thought.
Testosterone levels decrease in a gradual, age-related process with a greater decline in free bioavailable testosterone levels compared to total testosterone levels (Harman SM et al 2001, Feldman HA et al 2002, Liu PY et al, 2007) particularly in men aged over the of 65 (Yeap BB et al, 2007). This excessive reduction of free bioavailable testosterone is caused by an increase in Sexual Hormone Binding Globulin (SHBG) (Mitchell Harman et al, 2001). This low testosterone level in the ageing male is thought to be caused by reduced responses from the testes to gonadotrophin stimuli coupled with incomplete hypothalamo–pituitary compensation for the fall in total and free testosterone levels. (Veldhuis JD, 2008). By addressing this fall in testosterone with exogenous supplies the health benefits associated with testosterone could be maintained.
When determining whether or not a cardiovascular risk is associated with testosterone replacement therapy (TRT), it is important to restrict the research to TRT that returns levels within the physiological and not supraphysiological. Numerous studies have found that supraphysiological testosterone levels can induce an increase in LDL-C, followed with a decrease of HDL-C (Zmuda JM et al, 1993) increasing the risk of cardiovascular disease significantly.
A Meta-analyses by Whitsel EA, et al 2001) found that physiologic dose of androgens would not cause a drastic change in lipids. It was observed in an RCT by Emmelot-Vonk MH et al 2008) that testosterone supplementation induced a decrease in high-density lipoprotein cholesterol. Another randomized 24-week parallel-group study with multi-centre observed by Dobs et al, 1999 observed that administration of transdermal and intramuscular administration of androgens in 58 men did not cause a significant change in HDL levels or in the ratio of total cholesterol to HDL in either group. Zmuda JM et al 1997 found in a follow-up study that testosterone replacement decreases lipoprotein A. It is believed that the reduction in lipids is caused by the action that testosterone, has on abdominal visceral fat (Mårin P, et al, 1993) by inhibiting lipoprotein lipase activity thus, increasing lipolysis (Xu XF, 1991). Triglycerides are also mobilised from abdominal fat (Mårin Pet al, 1995). The action on the visceral fat explains the inverse relationship between testosterone levels and the severity of coronary artery disease (Phillips GB et al, 1994) who suggested that “not only that a low testosterone level may be prospective for MI but also that it may lead to atherosclerosis and that testosterone, rather than being a causative factor, may protect against atherosclerosis in men.” (Phillips GB et al, 1994). An RCT by English KM et al 2000 discovered that low-dose transdermal testosterone therapy improves angina threshold in men with chronic stable angina. Kabakci G et al 1999 noted that there was no consistent relationship between the levels of free or total testosterone and coronary atherosclerosis in men, undergoing coronary angiography.
An early retrospective study by Hajjar RR et al, 1997 found that testosterone-replacement therapy does not increase the incidence of cardiovascular disease or events such as myocardial infarction, stroke, or angina.
So far it seems the evidence in favour of testosterone replacement therapy or at the very least testosterone within physiological levels is fairly compelling. What then has raised concerns over its safety with regards to cardiovascular risk factors? Liverman et al, 2004 expressed concern that TRT was being increasingly prescribed based on evidence from trials that generally had not been designed or adequately powered to detect effects on clinically significant cardiovascular events. Although an association with low testosterone and increased risk of cardiovascular disease has already been observed further long-term studies are required to establish conclusively the safety of TRT in relation to cardiovascular risk. Liverman et al 2004 were correct in his paper when he mentioned the dearth of good quality research that investigated the relationship between TRT and cardiovascular risk factors as the primary endpoint. Vast numbers of the data come from trials, which illustrate that this was not the primary endpoint. Results are only available from six small, short-term studies, which were combined in a meta-analysis by Corona G, et al, 2011, who subsequently found that TRT was positively associated with a significant increase in treadmill test duration (168 seconds) and time to ST-segment depression (57 seconds). Studies involving TRT and heart failure are also few in number and involve a short follow-up duration, but all available studies have reported significant improvements in exercise capacity after 12 to 52 week period of TRT. A meta-analysis of four such RCTs carried out by Toma M, et al 2012 who observed from their results an increase in exercise capacity of almost 54 meters using the six-minute walk test.
Concerns regarding the cardiovascular risks associated with TRT have come from studies that were designed for other purposes. In a series of meta-analysis assessing the occurrence of adverse CV events in men treated with testosterone or placebo in RCTs designed for other purposes, four of the five (Calof OM, 2005, Haddad RM et al, 2007, Fernández-Balsells MM et al, 2010, Corona G, et al, 2014) did not find either a protective or harmful effect of TRT on CV events. However one meta-analysis by. Xu L et al, 2013 suggested a possible increased cardiovascular risk associated with testosterone treatment. However, when this meta-analysis is subjected a careful analysis a number of potential flaws can be observed. For instance, the authors selected studies lasting 12 weeks or more, which reported a rather broad definition of CV endpoints from peripheral oedema to self-reported syncope all CV-related events. Thus, this leads to an over-reporting of CV effects, which would produce results which would be misleading. Rather, the assessment of the CV safety of any therapy should be based on the incidence of major adverse cardiac events (MACE), which are easier to detect as well as less controversial to diagnose. A significant weighted study in the Xy et al meta-analysis came from the study by Basaria et al 2010 in his famous study published by the prestigious New England Journal of Medicine. A study designed to investigate the safety of TRT, which had to be stopped early due to safety issues regarding TRT. Pretty damning, that is until a closer analysis of the Basaria et al study is undertaken. The RCT’s study’s authors randomized men aged 65 years and above (mean age, 74±5 years) with limitations in mobility and total T levels between 3.5 and 12.1 nmol/L or free T <173 pmol/L to placebo or a supraphysiological dose of T gel (100 mg daily) for six months, in order to assess the effect of TRT on exercise tolerance. The cohort consisted of elderly community-dwelling men with limited mobility who had a high prevalence of hypertension, obesity, diabetes, dyslipidemia, and known cardiovascular disease. The study found that the supraphysiological doses of TRT produced significant improvement in physical function, however, the trial was ended early due to imbalances in respiratory, dermatological and, most importantly, cardiovascular events between the two arms. However, the clinical value of the study is impaired again by the lack of a structured classification of the cardiovascular events and by the fact that supraphysiological doses in a transdermal preparation were used. The method of administration could not be relied upon to provide consistent absorption across all men tested as absorption could vary significantly when compared to intramuscular injections. Furthermore, the study was made up of frail men who were given supraphysiological doses, it is interesting to note that the majority of adverse cardiovascular events (CV) were reported in men with extremely high testosterone blood levels above 34.6 moll/L; a supraphysiological dose. One could argue that the increased vitality and vigour felt by the frail men due to the TRT could have contributed to the CV events by allowing them to engage in more strenuous activity. This despite its flaws has shed light on important aspects of TRT dosing with regards to older more frail men.
A quick review of the other four meta-analyses reveals that the first by Calof et al 2005 reviewed adverse events in 19 studies performed between 1966 and 2004 reported 18 CV events in the 651 testosterone-treated men and 16 events in the 433 placebo-treated men. Haddad et al, 2007 included 30 placebo-controlled studies conducted between 1966 and 2004 for possible testosterone-induced adverse effects and meta-analysed six studies that recognised CV events. Fourteen events were observed among the 161 men treated with testosterone while seven events, which were observed among the 147 men in the placebo arm. Finally, Fernández-Balsells et al 2010 in their work studied 51 placebo-controlled studies conducted from 2003 to 2008, with follow-up ranging from three months to three years. Their work failed to find any significant differences in the rates of death, MI, revascularization procedures, or cardiac arrhythmias between the testosterone and the placebo groups.
From the above discussion, it seems that some meta-analyses and RCTs have been given more weight compared with others. The flaws of these studies have been mentioned despite the fact that they have provided valuable evidence with regards to the safe dosing of TRT. The evidence so far seems to suggest that so long as normal physiological levels are maintained testosterone replacement therapy will not cause any serious cardiovascular effects.
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