Testosterone replacement therapy and cardiovascular risk factors modification

Abstract

Hypogonadism in males is associated with increased atherosclerotic disease. Physiologically, testosterone appears to have both positive and negative effects on the cardiovascular system. Testosterone decreases angina and may improve the cardiac healing response after myocardial infarction. Testosterone enhances function in males with heart failure (HF). Testosterone causes water retention and oedema is common in older persons. Oedema should not be used to diagnose HF in older persons. Studies in older persons with HF and frailty have shown a non-statistically lower mortality rate compared to those receiving placebo.

Keywords:

• Hypogonadism
• testosterone replacement therapy
• cardiovascular risk factors
• heart failure

Introduction

As men age, their serum concentrations of testosterone and, to a greater extent, free testosterone, decrease [1–4 ]. As a result, men who are 80 years old have values that are one-half to one-third of those in men who are 20 years old. It is still a ‘mystery’ whether this fall represents a physiologic or pathologic phenomenon; and if it were pathologic should it be treated with testosterone administration? Changes in body function occur in aging men that are similar to the manifestations of hypogonadism due to a known disease, raising the possibility that the decline in testosterone production with aging may be a cause of these changes [5–7 ].

Anabolic deficits in aging men can induce: frailty, sarcopenia, poor muscle quality, muscle weakness, hypertrophy of adipose tissue, impaired memory and impaired neurotransmission [8–13 ].

Cardiovascular disease is the most prevalent non-communicable cause of death worldwide, although mortality from CAD is decreasing, morbidity is increasing, particularly in the older age group. Cumulative risk of atherosclerotic disease in men increases to 69% in a 90-year-old with greater than three risk factors [14]. Optimising the health standards in elderly population that is relatively healthy and independent with a good quality of life is important, and any intervention that can potentially help to accomplish that is worth investigation.

Testosterone deficiency and cardiovascular disease

Sex hormones, in particular testosterone, are well known to have cardiovascular effects [15,16]. In men, endogenous testosterone concentrations are inversely related to mortality due to cardiovascular disease and all causes [17]. Epidemiologic population-based studies reported in the past decade, indicate that low testosterone levels correlate with an increase in the risk for developing type 2 diabetes mellitus, metabolic syndrome and possibly a reduction in the overall survival, though this has not been found in all studies [4,18,19]. A recent prospective study found that bioavailable testosterone in middle-aged males with angiographically proven atherosclerosis, have a substantially higher cardiovascular mortality than men with normal values [20]. Total testosterone was much less predictive. Men with atherosclerotic heart disease have lower levels of testosterone than those with normal coronary angiograms [21]. Serum testosterone is inversely related to carotid intima thickness [22].

Recent animal-based and population-based studies have suggested that low testosterone levels have a poor prognosis and higher mortality in men with heart failure (HF) [23]. Male subjects with low testosterone levels are at higher risk of developing fatal arrhythmias, prolonged QT interval and poor exercise capacity [24]. Besides, testosterone administration might protect against myocardial ischaemia [25]. The effects of low testosterone are summarised in Table 1.

Table 1. Effects of testosterone deficiency on cardiovascular disease.

Increased mortality due to cardiovascular disease

Increased type 2 diabetes

Increased metabolic syndrome

Increased angiographic atherosclerosis

Increased carotid intima thickness

Poor heart failure outcomes

Increased arrythmias

Prolonged QT interval

Increased atrial fibrillation

Increased angina

Poor recovery from myocardial infarction

Restoring serum testosterone levels to the normal range results in benefits to the cardiovascular system, specifically in patients with documented HF. Successful management of testosterone replacement therapy requires appropriate evaluation and understanding of the benefits and risks of treatment.

Cardioprotective effects of testosterone

Modifiable risk factors for coronary artery disease (CAD) that are influenced by testosterone concentrations in men include plasma lipids, type-II diabetes, central adiposity, insulin concentrations and systemic blood pressure. Effects of testosterone can be either cardioprotective or pro-atherogenesis and these effects may be dose dependent (Table 2). Many of the components of the metabolic syndrome (obesity, hypertension, dyslipidemia-impaired glucose regulation and insulin resistance) are present in hypogonadal men. Over the last several years, the association of testosterone with metabolic and cardiovascular function has become a prominent focus of research and clinical attention.

Table 2. Physiological effects of testosterone on the cardiovascular system.

Adipose tissue and cholesterol:

Activates hormone sensitive lipase

Decreases adipose tissue and visceral adipose mass

Increases free fatty acids

Stimulates very low density lipoprotein production

Enhanced insulin sensitivity

Normalises hypertriglyceridemia

Decreased leptin levels

Decreased HDL-C

Lowered Lp(a)

Hemostasis:

Suppressed PAI-1 production

Decrease of fibrinogen

Decrease cyclo-oxygenase activity

Increased platelet aggregability

Vascular function:

Physiological testosterone restricts vasodilation

Pharmacological doses produce non-genomic vasodilation through inhibition of calcium reflux

Improved coronary artery blood flow

Macrophages:

Favours lipid accumulation and lipid secretion

Suppression of proinflammatory cytokines (TNF, IL-1, IL-6) and potentiates expression of anti-inflammatory cytokine IL-10

Arterial smooth muscle:

Stabilizes plaque growth and stabilizes plaques through conversion to estradiol

Myocardium:

Reduces injury response to ischemia-reperfusion

Reduces cell death in an isolated ventricular myocyte preparation

Induces cardiac hypertrophy

Attenuates calcium overload during ischemia reperfusion

Enhanced activation of alpha-1 adrenoreceptors

Activates mitochondrial Katp channel blockade

Activates insulin growth factor-1 in myocardium which is cardioprotective

Emerging data indicate that androgens play an important and favourable role in lipid metabolism. Androgen deficiency contributes to increased triglycerides, total cholesterol, LDL-cholesterol and reduced HDL-cholesterol while androgen treatment results in a favourable lipid profile, suggesting that androgens may provide a protective effect against the development and/or progression of atherosclerosis [26]. The effect of testosterone treatment on the lipid profile depends on the route of administration and the resultant plasma concentrations of testosterone. A recent study showed that intramuscular administration of testosterone in hypogonadal men with type-II diabetes decreases total cholesterol levels but had no effects on lipoproteins [27]. In contrast, high doses of testosterone or anabolic steroids dramatically derange the lipid profile [28].

Testosterone has immune-modulating properties, and current in vitro evidence suggests that testosterone may suppress the expression of the proinflammatory cytokines TNF, IL-1 and IL-6 and potentiate the expression of the anti-inflammatory cytokine IL-10. Testosterone replacement shifts the cytokine balance to a state of reduced inflammation and lowers total cholesterol [29].

There is evidence to suggest that an inverse relationship exists between serum testosterone levels and the degree of obesity in men [30,31]. Data suggest a bi-directional relationship exists between testosterone and obesity in men, with lower total testosterone and sex hormone binding globulin (SHBG) levels than their non-obese peers.

Central adiposity, is associated with insulin resistance, hyperinsulinaemia, type-II diabetes and the metabolic syndrome, and these are all linked to reduced testosterone concentrations in men [32,33].

There is a close relationship between obesity and low serum testosterone levels in healthy men [34]. Twenty per cent to 64% of older obese men have a low serum total or free testosterone level [35]. Visceral obesity is more strongly inversely related to total and free testosterone levels than other forms of obesity [36,37]. The relationship between reduced testosterone and obesity in men can be explained by increased aromatisation of testosterone to estradiol in white fat. Estradiol, in turn, reduces luteinizing hormone, thus inducing an acquired state of hypogonadotropic hypogonadism. Central obesity and low testosterone levels are both linked to insulin resistance and type-II diabetes, and men with diabetes have lower endogenous testosterone levels than non-diabetic men [32]. Kapoor et al. showed that intramuscular testosterone replacement in hypogonadal men with diabetes reduced insulin resistance, waist circumference and waist/hip ratio, along with an improvement in glycaemic control [27]. Obese men with confirmed androgen deficiency should be offered treatment.

The effect of testosterone replacement in hypertensive male subjects is not definite to date. Independent of age and body mass index (BMI), low testosterone levels are associated with elevated blood pressure [38,39]. Testosterone treatment in hypogonadal men has no effect on blood pressure [40–42 ]. In an animal model, removal of androgens by castration failed to provide any protective effect against the hypertension programmed by maternal protein restriction. The lifelong presence of normal levels of testicular hormones does not play a major role either in maintaining baseline blood pressure higher in males than in females, or in promoting further elevations in blood pressure in males [43].

In spontaneously hypertensive rats, testosterone treatment exacerbated hypertension by reducing pressure naturesis. In males, salt-sensitive rats fed a high-salt diet, testosterone contributed to the development of hypertension and renal injury, by up-regulating the renin–angiotensin system [43,44]. Testosterone supplementation trials should be encouraged to assess the definite effect of androgens on hypertensive male subjects who are hypogonadal.

Metabolic syndrome, according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATPIII), is defined by the presence of at least three of the following criteria: central obesity, elevated triglycerides (or receiving treatment), reduced HDL-cholesterol (or receiving treatment), arterial blood pressure ≥130/85 mmHg (or receiving treatment), fasting plasma glucose ≥100 mg/dl or type-II diabetes. Early studies suggest that TRT in men with low testosterone levels may improve metabolic status by: lowering blood sugar and HbA1C in men with type-2 diabetes, reducing abdominal girth, ameliorating features of the metabolic syndrome, all of which may be protective of the cardiovascular system. It has been known for several years that decreased testosterone levels are associated with increased glucose and insulin concentrations [43], but it has only been in recent years that this association has been studied more seriously, taking into consideration the clinical implications of these findings and the possible benefits of treatment with testosterone. Results from the first UK prospective study recommend screening for metabolic syndrome and testosterone deficiency in male subjects with erectile dysfunction. The Massachusetts Male Aging study showed a marked association between lower testosterone concentrations and the metabolic syndrome but only in men with a body mass index <25 kg/m², indicating that central adiposity rather than overall adiposity together with decreased testosterone concentrations are associated with increased risk of developing the metabolic syndrome.

In summary, endogenous testosterone concentrations are generally inversely related to cardiovascular risk factors in men, low testosterone may be a predictive marker for those at high risk. The evidence is not conclusive regarding a generalised positive or negative treatment effect. New studies are still emerging in the area of the effect of testosterone replacement therapy on the adverse consequences of the metabolic and cardiovascular sequelae of hypogonadism. It is clear that a low testosterone level is associated with negative metabolic and cardiovascular outcome. On the other hand, it is still ambiguous if testosterone might reverse some of those adverse outcomes, although the emerging literature appears to be suggesting that this may be the case.

Testosterone and angina pectoris

A number of studies in the late 1940s and early 1950s found that testosterone could reduce angina [45–49 ]. Wu et al. [50] conducted a randomised placebo crossover trial in 62 men with angina. Angina was relieved in 77.4% of patients and electrocardiogram and Holder recordings showed less ischaemia in 68.8% and 75% of subjects.

In 1977, Jaffe [51] studied 50 men who had ST depression of 0.1 mV or more after a two-step exercise test. Half received testosterone cypionate and half placebo. There was no change in the placebo treated group and 51% had a decrease in ST depression after 12 weeks. English et al. [52] found that a low-dose transdermal testosterone significantly increased time to 1 mm ST depression during treadmill exercise. Pain perception also decreased. Similar results were reported by Malkin et al. [53] in a 4-week protocol. Dihydrotestosterone also significantly increased time to onset of angina and time to 1 mm ST depression [54]. A 12-week study showed that compared to placebo, testosterone decreased the number o angina attacks and silent ischaemic episodes [55]. In a small study of 13 men receiving testosterone and 6 receiving placebo who were followed for a year, testosterone increased time to ischaemia [56].

An animal study suggested that testosterone produced coronary vasodilation by inhibiting calcium-induced vascular constriction [57]. In a patch-clamp study using human L-type calcium channel cells, testosterone inhibited current flow [58]. A point mutation which abolished nifedipine action also abolished the effect of testosterone. These findings suggest that testosterone plays a calcium channel antagonist, explaining its antianginal effect.

Testosterone and heart failure

HF is a common and frequently life-limiting illness with increasing prevalence, particularly among the growing population of elderly persons. Some 300,000 persons in the United States die with HF annually and as many as one in three HF patients die within 1-year of hospitalisation for HF [59]. The average life-expectancy after diagnosis of HF is under 6 years. However, the course of HF is variable, and some persons live 10 years or more with a good response to treatment. Congestive chronic heart failure (CHF) is a progressive disorder in which a complex interaction of hemodynamic, neurohormonal and metabolic disturbances leads to subsequent immune activation [60]. Anorexia, weight loss and cachexia are common features of advanced HF and are related to the associated neurohormonal and cytokine abnormalities [60–62 ]. The greatest attention has been given to the concept that the progression of HF is due to neurohormonal abnormalities.

With advancing age and the development of chronic diseases such as HF, the secretion of testosterone and other anabolic hormones decreases [63]. It has been hypothesised that the relative anabolic deficiency may not simply mirror catabolism accompanying HF, but may also aggravate HF symptoms and possibly accelerate disease progression. Deficiency of anabolic sex steroids is common in HF. The pathophysiological implications of this phenomenon, however, have not been fully elucidated. DHEAS and free testosterone, but not total testosterone, were inversely associated with NYHA class [63]. Another observational study demonstrated that in patients with HF, high levels of SHBG correlate with other measurements of severity of the disease and are associated with an increased risk of cardiac death in the follow-up period in the long term. These findings suggest a possible role of SHBG in the pathophysiology of the anabolic deterioration which appears during HF progression, although it is not possible to establish causal relationships because this is an observational study. Implementation of new studies, which clarify the possible role of SHBG in HF is needed [60]. A recent double-blind randomised study assessed the effects of a long-acting testosterone treatment, given together with optimal medical therapy, on functional capacity and ventilatory efficiency in elderly male patients with moderate-to-severe HF [65]. Medically stable patients with NYHA class II and III were enrolled in this study. The data showed that testosterone supplementation given in addition to optimal medical therapy improves functional capacity, large-muscle strength, and glucose metabolism in elderly patients with CHF. The increase in functional capacity and muscular strength is related to the increase in plasma levels of testosterone and not related to changes in left ventricular function. The mechanism through which testosterone affects cardiorespiratory indexes is unclear, but may be due to improved muscle performance. A significant increase in both static and dynamic strength in addition to a reduced fatigue index and improved work output was observed in the testosterone-treated group. These effects would depend on the action of testosterone at the muscular (peripheral) level as there were no effects of testosterone on left ventricular function [64]. In men with CHF, low circulating testosterone independently relates to exercise intolerance. The greater the reduction of serum testosterone in the course of disease, the more severe is the progression of exercise intolerance [65]. In conclusion, androgens are important determinants of anabolic function and muscle strength. Low plasma levels of testosterone have been reported in patients with CHF, and it has been hypothesised that a relative hypotestosteronemia could be involved in the impairment of skeletal muscle function and exercise tolerance that occur in the HF syndrome [66]. Anabolic hormone depletion has been reported to be relatively common in CHF and to carry a negative prognosis [60]. Hence, improving the anabolic status of patients with CHF could represent an additional therapeutic target.

The animal model

Studies conducted on rats have confirmed the cardioprotective effects of testosterone supplementation in hypogonadal male rats. In one study conducted on orchiectomised male rats they had impaired cardiac recovery following global ischaemia, while pretreatment with either physiological or supraphysiological testosterone improves cardiac recovery [67]. In this study it was concluded that testosterone may confer ischaemic resistance through both direct and indirect tissue level interactions. Moreover, the recent discovery that the beneficial effects of testosterone are observed with both short and longer term administration of testosterone at both physiological and supraphysiologic doses suggests that like other forms of preconditioning (e.g. exercise and ischaemic preconditioning), the stimulus threshold for testosterone-mediated protection may be fairly low at physiologic levels and may occur rapidly at supraphysiologic levels. The main finding of this study is that treatment of hypogonadal male rats for 21 days with a supraphysiological dose of testosterone produced cardioprotection. Specifically, hearts from testosterone-supplemented animals exhibited improved post-ischaemic recovery of aortic flow, cardiac output, cardiac work, LVDP and contractility. In addition, untreated hypogonadal subjects produced an unexpected increase in lactic dehydrogenase (LDH) during pre-ischaemia and a marked elevation of LDH into the coronary effluent during post-ischaemic reperfusion; both of which were prevented by testosterone administration. In a subsequent animal study, it was concluded that testosterone therapy improves cardiac function of male rats with right heart failure (RHF) [68]. The level of serum testosterone was gradually decreased, while that of TNF-α obviously increased in male rats with RHF. After testosterone treatment, the testosterone group showed a remarkable improvement of cardiac performance and a significant decrease in the level of serum TNF-α as compared with the RHF group. Physiological supplementation of testosterone can improve the cardiac function of RHF male rats, probably through its inhibition of TNF-α [68]. In addition, in animals testosterone enhances recovery from stroke [69].

Testosterone and arrhythmia

Recently, it was suggested that testosterone replacement might reduce the incidence of fatal cardiac arrhythmia. A pilot study demonstrated that the prevalence of prolonged QT interval in males was higher in hypogonadal subjects. Prolonged QT interval was observed in hypogonadal men who may therefore be at increased risk for cardiac arrhythmias. This observation reveals an additional feature of male hypogonadism, which may benefit from testosterone replacement therapy. Therefore, male hypogonadism is associated with an increased prevalence of prolonged QT interval and risk for fatal ventricular arrhythmias. QT interval measurement should be included in the evaluation of hypogonadal men and may provide an additional rationale for testosterone replacement therapy [70,71]. In another study, it was concluded that low testosterone in elderly rats was associated with increased prevalence of atrial fibrillation (AF) [72]. To date, the mechanisms of aging-induced AF have not been fully elucidated. It is possible that an age-related decline in testosterone may play a role.

As discussed previously, age related decline in testosterone levels in males leads to an increased risk of cardiovascular disease including coronary artery disease and HF which are well-known predisposing factors for the development of AF. In this study, gonadectomy increased the atrial arrhythmogenecity without any alterations in the electrophysiological parameters in male rats, and administration of testosterone attenuated this increased vulnerability. Interestingly, it was also observed that gonadectomy could cause less binding of FK506-binding protein to ryanodine receptor type 2, which induces calcium leak from the sarcoplasmic reticulum and may contribute to the initiation or maintenance of AF [73].

Effects of testosterone on persons with heart failure and frailty

Much evidence has suggested that testosterone replacement therapy may be beneficial for older persons with heart disease. However, a recent article in the New England Journal of Medicine suggested that testosterone therapy was harmful for frail older persons [74]. This article failed to put its results into context with multiple other studies, which had shown no major negative effects of testosterone on the heart. The authors also used oedema as a sign of HF, apparently being unaware of the common causes of oedema in older, frail persons. These include low albumin and low red cells, varicose veins, decreased muscle strength and decreased activity [75,76]. Testosterone also acts as a calcium channel antagonist which results in peripheral oedema [57]. Testosterone clearly causes water retention, which would aggravate peripheral oedema. Finally, it should be recognised that frail old persons are very likely to have a variety of events, unrelated to therapeutic interventions [77–79 ].

A meta-analysis was conducted of 19 testosterone replacement studies, in which 651 persons received testosterone and 433 placebo [80]. There were 18 cardiovascular events in the testosterone group and 16 (3.7%) in the placebo group. Arrythmias were slightly more common in the testosterone treated group, but this was not statistically significant. HF was not a problem in the testosterone treated group. In a retrospective study, Hajjar et al. [81] found a decrease in cardiovascular disease in males treated with testosterone.

A total of 11 placebo-controlled studies have examined the effects of testosterone in males with either cardiovascular disease or frailty (Table 3) [53,56,64,82–85 ]. In these studies, the mortality was higher in the placebo treated group. While HF was slightly more common in the testosterone-treated group, this appeared to be predominantly defined by the presence of ankle oedema. In the study by Caminiti et al. [64], HF did occur but was easily treatable with slight increases in the furosemide dose. In addition, Chapman et al. [86] found a decrease in hospitalisations in frail males and females receiving low dose testosterone.

Table 3. Side effects of testosterone in persons with cardiovascular disease and/or frailty.

			Death		MI		CHF		Oedema
Study (Ref. No.)	n	Duration (weeks)	Placebo	T	Placebo	T	Placebo	T	Placebo	T
Jaffe [52]	50	8	0	0	0		0	0	0	9
Wu & Weng [51]	62	10	0	0	0	0	0	0	0	1
English et al. [53]	46	12	0	0	0	1	0	0	0	0
Pugh et al. [83]	20	12	0	0	0	0	0	1	0	0
Malkin et al. [54]	10	12	0	0	0	0	0	0	0	0
Malkin et al. [84]	76	52	1	0	0	0	2	2	0	0
Mathur et al. 2009 [57]	19	52	0	0	0	0	0	0	0	0
Caminiti et al. [65]	70	12	0	0	0	0	1	2	0	0
Srinivas-Shankar et al. [85]	262	26	1	0	1	0	0	1	0	0
Kenny et al. [86]	131	52	7	3	?	?	?	?	?	?
Basaria et al. [75]	209	26	0	1	0	2	0	1	0	5

T, testosterone; MI, myocardial infarction; CHF, congestive heart failure; ?, unknown.

Summary

Overall, the available data support the use of testosterone in frail persons [88–90 ] and those with HF. It would appear that the benefits outweigh any as yet not proven side effects. There is a need for a large (1000 or more subjects) trial of testosterone replacement therapy in males with HF. It is possible that this would be coupled with a protein supplement [90–91 ].

Declaration of interest:

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the article.