Androgens and cardiovascular disease: Gender-related differences

Introduction

In recent years, there has been growing interest and increasing recognition of the influence of gender-related differences in cardiovascular (CV) function and treatment.^1,2 Both estrogens and androgens are implicated in the development of CV disease and hypertension. Indeed, female and male sex hormones directly affect cardiac function, endothelial function and vascular tone through both genomic and non-genomic effects that are mainly receptor-dependent. ³ However, while estrogens are considered to play a positive role on CV health, it has been long debated whether androgens play a detrimental or, conversely, a protective role on CV function. ⁴ Moreover, a definitive answer as to whether testosterone affects risk for CV disease in a gender-dimorphic way is yet to be provided.

In this review, we will discuss the existing studies regarding the link between androgens and CV disease, with a focus on sex-related differences. The terms “sex”, which is genetically determined, and “gender”, which is related to social factors, will be here used as synonyms.

Androgens and cardiovascular function: risk or benefit?

Androgens in general, and testosterone in particular, have been assumed to play a pivotal role in determining the risk of CV disease. ⁴ The effects of testosterone on CV disease have been investigated since early 1940s, resulting in a proliferation of cross-sectional and prospective studies on this topic for decades. Briefly, speculations on the relationship between testosterone and CV risk can be summarised as follows. On the one hand, it has been argued that high testosterone levels increase the risk for CV disease, although a clear causal link has never been proven. ⁵ Observations supporting this hypothesis are that men have a greater incidence of coronary artery disease (CAD) than women at the same age, that android fat distribution is associated with a greater incidence of CAD and that synthetic androgens exert an unfavourable effect upon plasma lipids. ⁵ Thus, these findings seem to indicate that a hyper-androgenic state plays an adverse role on the CV system.

On the other hand, clinical studies have shown that testosterone has rather a protective effect on the CV function, as recently reviewed. ⁶ Such a protection may be linked to its favourable effect on endothelial function and vasomotor tone, throughout metabolic and direct mechanisms of action on human vasculature. ⁵ Observations supporting this hypothesis are that a hypo-androgenic state is associated with atherosclerosis and CAD in both aged men and women^7,8 and that testosterone replacement led to improvement of CV functions ⁹ (see next paragraphs).

Taken together, all these data are not contradictory as both hyper- and hypo-testosterone conditions are therefore associated with CV dysfunction and CV risk, whereas testosterone levels within the physiological range seem to exert a protective CV effect.

Interestingly, the imbalance of testosterone and estrogen (i.e. T/E2 ratio) in male affected by CAD, rather than the absolute levels of androgens, has been recently found as a crucial parameter in modulating the effect of androgens on cardiac function in males. ¹⁰

Ultimately, testosterone plays a multifaceted role on the CV system, with both direct and indirect influences, ⁹ also depending upon the concurrent circulating levels of estrogens.

Direct effects of testosterone on cardiovascular system according to gender

There is evidence that physiological testosterone levels improve endothelial function, peripheral vascular resistance and vasomotor tone, therefore acting directly on the vessel wall. ¹¹ This influence appears to be sex-dimorphic as differences in androgen receptor expression in human vasculature have been reported, with higher levels in men than women. ¹² Indeed, androgens show sex-specific endothelial responses, with testosterone inducing proliferation of male, but not female, rat lung endothelial cells. ¹³

Studies on transsexual people have helped clarify the gender-specific effect of testosterone on CV function. Genetic females (female-to-male transsexuals) who underwent long-term administration of testosterone to maintain its plasma levels within the physiologic range found in men showed larger brachial artery diameter and reduced nitrate-induced response, but had similar endothelial function to that of age-matched female control subjects. ¹⁴ Accordingly, an improvement in flow-mediated vasodilation was observed in estrogen-treated post-menopausal women who were also receiving parenteral testosterone. ¹⁵ Thus, the sex-dimorphic effect of testosterone in women may be explained by the concurrent level of estrogenization.

Indirect effects of testosterone on cardiovascular system according to gender

Testosterone has also an indirect effect on the CV system, i.e. by influencing vascular risk factors.

One of the main risk factors for CV disease is obesity, which is strongly associated with metabolic syndrome and is thought to have hormonal underpinnings. In men, obesity and metabolic syndrome are often associated with reductions in testosterone levels, which are, in turn, linked to increased inflammation. ⁹ Indeed, serum testosterone concentrations have been found to be lower in obese than control male subjects^16,17 and physiological testosterone supplements may improve the lipid profile. Thus, inflammation may be reversed by androgen replacement in men. Testosterone-associated effects on weight gain and insulin resistance have been further confirmed by the 13-year longitudinal sub-study ¹⁸ from the Multiple Risk Factor Intervention Trial (MRFIT) that was conducted on middle-aged men. The study found that the decrease in endogenous testosterone observed with age was associated with an increase in triglycerides and a decrease in high-density lipoprotein cholesterol, also showing a relation with increased low-density lipoprotein cholesterol. This study also indicated that the gradual decline in total testosterone levels observed in older men was related to lifestyle and psychosocial factors and with potentially unfavourable changes in triglycerides and high-density lipoprotein cholesterol.

On the other hand, in women, obesity and metabolic syndrome are associated with an increase in androgen levels, which are linked to inflammation; therefore, it is necessary to reduce androgens to lower inflammation. ¹⁹ Accordingly, testosterone at supra-physiological doses may promote atherogenicity in women. In a study evaluating the effect of testosterone replacement on lipid profile in female-to-male transsexuals, ²⁰ a group of “androgenized” women, i.e. genetic females treated with testosterone esters after sex re-assignment, was compared to a control group of female transsexuals prior to starting androgen therapy and to a group of post-operative female transsexuals while on and after stopping the androgen therapy. Interestingly, the study showed that higher androgen levels due to long-term androgen therapy had adverse effects on lipid and lipoprotein profiles, suggesting that chronic exposure to increased levels of testosterone may promote atherogenicity in genetic females.

Consistently, another CV risk factor is atherosclerosis, which is one of the mechanisms underlying the association between low testosterone and CAD. It has been shown that endogenous testosterone has a protective role against the development and progression of atherosclerosis and its clinical complications. ²¹ It has been consistently found that low androgen levels are associated with a more unhealthy artery wall in both sexes. ²² However, gender differences in the development of atherosclerosis are evident in both humans and animal models of the disease. In several animal models of diet-induced atherosclerosis, males develop atherosclerotic plaques earlier and more broadly than females, independent of lipid levels.^23–25 Sex-specific differences in the development of atherosclerosis and CAD can not only simply be ascribed to a direct antiatherogenic effect of sex hormones but also to both direct effects within the vessel wall and to their influence on CV risk factors. ²¹ Consistently, natural androgens inhibit atherosclerosis in male animal models of atherosclerosis.^25,26

Finally, low testosterone levels are associated with high blood pressure in middle-aged men.^9,27 However, acute and chronic testosterone administration do not significantly affect blood pressure ²⁸ and changes in blood pressure are indistinguishable from those induced by ageing. ²⁹ Thus, the biological underpinnings for why this occurs are still unknown. A possible mechanism may be related to a greater conversion of testosterone into estradiol in older men. ⁹

Androgens and CAD in women and men

Several studies have examined the relationship between testosterone and CAD in post-menopausal women^30–32 given the greater incidence of CAD after the menopause. The Rancho Bernardo Study, ³⁰ a population-based prospective study, has investigated testosterone levels of 651 post-menopausal women who did not take estrogen replacement therapy, showing that testosterone levels did not correlate with incidence of cardiac events. However, it is well known that women with hyper-androgenic conditions (e.g. polycystic ovary syndrome) may be associated with an unfavourable progression of atherosclerosis.5 It is therefore possible that the increased incidence of CAD observed in women after the menopause is linked to ovarian hormone deficiency and that androgen deprivation associated with ageing has the same effect in men. Although androgens may influence vasomotor tone, it is more likely that their effect upon the progression of atherosclerosis is related to the combination of their effect within the vessel wall and to their metabolic effects. ⁵

Conversely, in women within the reproductive age, the role of endogenous androgens in the development of CAD is less clear. An ancillary study to the Coronary Artery Risk Development in Young Adults (CARDIA) study, a population-based multicenter cohort study with 20 years of follow-up, examined the prospective association of serum androgens and Sex Hormone Binding Globulin (SHBG) with subclinical coronary and carotid disease among young to middle-aged women. The study failed to find any associations for total or free testosterone with either coronary artery calcification or intima-media thickness, whereas SHBG levels were inversely associated with subclinical CV disease. On the contrary, the Dallas Heart Study, ³³ conducted in young women without known cardiac disease, showed that circulating free testosterone levels were independently and inversely associated with BNP and NT-proBNP, suggesting that testosterone, and not estradiol, mediates gender differences in natriuretic peptides. In addition, the study revealed an association between higher BMI and lean body mass with natriuretic peptides that could be mediated by testosterone.

Finally, several observations support the hypothesis that low levels of testosterone may contribute to CAD development in men. Male survivors of myocardial infarction have lower testosterone levels than controls^5,34,35 and most cross-sectional studies have repetitively found an association between hypo-testosteronemia and CV morbidity^18,36–38 and coronary events.^39,40 However, prospective studies showed the lack of a clear relationship between circulating testosterone and CAD, ⁴¹ possibly due to the low event rate typical of such studies. ⁵

Testosterone supplementation in women and men

It is well known that female androgen insufficiency not only leads to the typical signs of reduced androgen exposure such as decreased muscle mass, reduced bone density, but also to an impairment in sexual drive, depressed mood and a decreased sense of well-being. ⁴² Thus, androgen supplementation within physiological levels is of particular importance in metabolic, psychological and sexual functions in women.

A testosterone transdermal patch has been developed for the treatment of post-menopausal women with hypoactive sexual desire disorder, showing its utility. ¹⁵ CV effects and safety of transdermal testosterone have been also assessed, showing that testosterone replacement is safe and associated with a favourable change of CV risk profile in post-menopausal women. ⁴³

In men and women with heart failure, testosterone supplementation has been shown to be effective. Indeed, lower testosterone levels are associated with heart failure severity, and when replaced, they may exert a beneficial metabolic effect on insulin resistance. ⁴⁴ In women with heart failure, testosterone deficiency is associated with reduced functional capacity and transdermal testosterone supplementation has been found to improve functional capacity, insulin resistance and muscle strength. ⁴³ Similarly, intramuscular injections of testosterone added to optimal medical therapy in elderly men with chronic heart failure have been found to improve exercise capacity, muscle strength and glucose metabolism. ⁴⁵

In men with CAD, testosterone administration favours peripheral blood flow, myocardial perfusion, and acute and chronic ischemia, and increases coronary vascular flow and vessel diameter at physiological concentrations. ¹⁴

Thus, testosterone supplementation seems to be an effective and safe therapy for men and women with CV disease. On the other hand, in clinical trials where testosterone was used in patients with other preexisting CV conditions, its effects was either neutral or beneficial, as recently reviewed. ⁴⁶ In these trials, testosterone treatment efficacy was limited to an increase in hematocrit and a decrease in high-density lipoprotein cholesterol.

Conclusions

Endogenous testosterone and its replacement within physiological levels display a favourable impact, throughout direct and indirect mechanisms, on CV function, both in men and women. Post-menopausal women and aged men seem to particularly benefit from testosterone supplementation therapy. However, future studies are strongly needed in order to deepen our understanding on this topic. In particular, upcoming research should investigate both differing doses and routes of administration of testosterone, e.g. the optimal degree-physiologic or supraphysiologic of androgen replacement, including much larger patient populations of both sexes, also exploring other clinical correlates. ⁴⁷ Prospective data from large, well-designed, long-term trials are particularly required to verify the CV efficacy/safety of testosterone treatment in both sexes.