Historically, high androgen levels have been linked with an increased risk for coronary artery disease (CAD). However, more recent data suggest that low androgen levels are associated with adverse cardiovascular risk factors, including an atherogenic lipid profile, obesity and insulin resistance. The aim of the present study was to evaluate the relationship between plasma sex hormone levels and presence and degree of CAD in patients undergoing coronary angiography and in matched controls. We evaluated 129 consecutive male patients (mean age 58±4 years, range 43–72 years) referred for diagnostic coronary angiography because of symptoms suggestive of CAD, but without acute coronary syndromes or prior diagnosis of hypogonadism. Patients were matched with healthy volunteers. Out of 129 patients, 119 had proven CAD; in particular, 32 of them had one, 63 had two and 24 had three vessel disease, respectively. Patients had significantly lower levels of testosterone than controls (9.8±6.5 and 13.5±5.4 nmol/l, P<0.01) and higher levels of gonadotrophin (12.0±1.5 vs 6.6±1.9 IU/l and 7.9±2.1 vs 4.4±1.4, P<0.01 for follicle-stimulating hormone and luteinizing hormone, respectively). Also, both bioavailable testosterone and plasma oestradiol levels were lower in patients as compared to controls (0.84±0.45 vs 1.19±0.74 nmol/l, P<0.01 and 10.7±1.4 vs 13.3±3.5 pg/ml, P<0.05). Hormone levels were compared in cases with one, two or three vessel disease showing significant differences associated with increasing severity of coronary disease. An inverse relationship between the degree of CAD and plasma testosterone levels was found (r=−0.52, P<0.01). In conclusion, patients with CAD have lower testosterone and oestradiol levels than healthy controls. These changes are inversely correlated to the degree of CAD, suggesting that low plasma testosterone may be involved with the increased risk of CAD in men.
Historically, the link between plasma testosterone levels and increased risk of coronary artery disease (CAD) has been attributed, at least in part, to the unfavourable effect of the hormone on lipid metabolism and fibrinolysis.1, 2, 3, 4 The evidence that men have a greater incidence of CAD and myocardial infarction than women of similar age, together with the evidence that android fat distribution is associated with a greater incidence of CAD compared with gynoid distribution, helped to reinforce the belief that high plasma testosterone levels are associated with an increased risk of CAD.5, 6, 7, 8, 9 This belief contrasts with the physiological effects of androgens on the cardiovascular system. In fact, it has been shown that in men testosterone correlates positively with the major stimulator of fibrinolysis, that is, tissue plasminogen activator activity, and inversely with plasminogen activator inhibitor activity and fibrinogen,3 and that replacement of natural androgens inhibits atheroma formation in castrate male animals.9 There is also evidence to suggest that low levels of androgens are associated with adverse cardiovascular risk factors, including an atherogenic lipid profile, obesity, insulin resistance and raised fibrinogen in humans.10, 11, 12 In the past decade, it has been shown that testosterone has vasoactive properties improving both systemic and coronary blood flow.13, 14 Despite these evidences between low levels of androgens, risk factors for coronary heart disease and changes in coronary blood flow, a number of prospective epidemiological studies have failed to show a relationship between baseline testosterone levels and the subsequent development of clinically apparent CAD.15, 16, 17, 18 More recently, English et al.15 have reported that men with proven CAD have lower androgen levels than patients with normal coronary arteriograms. The question rises as to whether patients with different degrees of CAD may have different sex hormone milieu than normal subjects.
The aim of the present study was to evaluate the relationship between plasma sex hormone levels and presence and degree of CAD in patients undergoing coronary angiography and in matched controls.
The study population included 138 consecutive male patients referred for diagnostic coronary angiography because of symptoms suggestive of CAD.
Patients with prior diagnosis of hypogonadism or hypopituitarism or taking drugs that might have affected sex hormone levels as those with high C-reactive protein levels (>5) suggestive of acute infection and/or inflammation were excluded from the study. One hundred and twenty-nine patients (mean age 58±4 years, range 43–72 years), with proven stable CAD and no acute coronary syndromes, were included in the study. Patients were matched with healthy volunteers, recruited from the Hospital medical and non-medical staff, as control group. Patients and controls were excluded if they had major illness within the preceding 3 months or if they had any past history of hypogonadism. Subjects were excluded if they had either a previous cardiovascular event or a diagnosis of coronary or peripheral atherosclerosis and if they had symptoms suggestive of cardiac origin or cardiovascular risk >20% in 10 years as assessed by the risk charts of the European Society of Cardiology.19 Patients and controls gave written informed consent to participate in this study that was approved by the local ethics committee.
Baseline data including age, personal and family history of risk factors for CAD were recorded. Blood samples (10 ml of whole blood) were obtained at admission in patients and at recruitment in controls after an overnight fasting at 0800 hours (±60 min), the day before cardiac catheterization in patients and on the day following a non-working day in controls. Whole blood was spun at 3500 r.p.m. for 9 min. The serum obtained was then stored at −80°C for a maximum length of time of 4 weeks. Body mass index (BMI) was calculated by the formula: weight (kg)/height (m).
All samples obtained from the same subject were measured in the same assay. All determinations were performed in duplicate. Serum concentrations of total testosterone were measured by radioimmunoassay (RIA) using a commercial kit (Diagnostic System Laboratories, Webster, TX, USA). The intra- and inter-assay coefficients of the total testosterone assay were 7.5 and 11%, respectively, at the normal adult male range, which in our laboratory was 300–1000 ng/dl. Serum-free testosterone was measured by RIA of the dialysate after an overnight equilibrium dialysis using the same RIA reagents as in the total testosterone assay. The coefficient of variation for free testosterone recovery for increasing doses of total testosterone in the adult male ranged from 10 to 18%. The intra- and inter-assay precisions of free testosterone were 14 and 17%, respectively, at the normal adult male range, which in our laboratory was 200–700 pmol/l. Oestradiol was measured with chemiluminescence (provided by Architect Systems, Abbotts diagnostics, Germany), with a normal adult male range of 0–30 pg/ml; sex hormone-binding globulin levels were measured by immunoradiometric assay (Radim SpA, Pomezia, Italy) with an intra- and inter-assay CV below 6% at the normal adult range, which in our laboratory was 9–55 nmol/l; luteinizing hormone and follicle-stimulating hormone were measured by direct chemiluminescence (ADVIA Centaur, Bayer Co., Germany) with an intra- and inter-assay CV between 6 and 3% at the normal adult range, which in our laboratory was 1.5–9 and 2–11 IU/l, respectively.
All patients underwent cardiac catheterization and coronary angiography using the Judkins technique. The presence of CAD was assessed by the investigator performing the diagnostic procedure, whereas the degree of coronary artery stenosis was evaluated using the in-built quantitative coronary angiography software (Philips Integris 5000, Philips Medical Systems, Nederland BV). Significant coronary atherosclerosis was defined by the presence of a stenosis >50% in the left main or in the principal coronary arteries. Coronary artery score was obtained by multiplying the degree of coronary artery obstruction by the number of stenosis as reported elsewhere.19
Data are expressed as mean±s.d. or percentage where appropriate. Statistical analysis was performed using the GBStat statistical package. The unpaired t-test or the χ2 test was used to test statistical differences in continuous and categorial variables between groups. Comparisons between patients with one-, two- and three-vessel disease were made using one-way analysis of variance. Spearman's correlation test was performed to evaluate statistical correlation between plasma testosterone level and coronary artery score. Statistical significance was accepted when P⩽0.05.
Out of 129 patients who were eligible for the study and performed coronary angiography, nine patients were found to have completely normal coronary arteries, one patient had a myocardial bridge on the medial left anterior descending artery and 119 had proven CAD. In particular, 32 of them had one, 63 had two and 24 had three vessel disease, respectively. Baseline characteristics of the patients and controls are shown in Table 1. Patients had a greater incidence of coronary risk factors for CAD than controls but similar BMI. Mean differences in hormones levels in patients vs controls are summarized in Table 2. Patients and controls had similar plasma levels of total cholesterol.
Patients had mean lower levels of both testosterone and bioavailable testosterone levels than controls (Table 2). Plasma oestradiol levels were also significantly lower in the cases than in controls (10.7±1.4 and 13.3±3.5 pg/ml; P<0.05) (mean±s.d.) without any difference in the oestradiol:testosterone ratio. Patients had significantly higher plasma gonadotropin levels than control group (Figure 1). Compared with patients with normal coronary arteriograms, patients with coronary atherosclerosis had significantly lower plasma testosterone and bioavailable testosterone levels (9.8±6.5 vs 12.4+2.3 nmol/l, P<0.05 and 0.84±0.45 vs 1.2±0.52 nmol/l, P<0.05, respectively) and a similar oestradiol/testosterone ratio (3.9±0.5 vs 3.8±0.9; P=NS).
In a multivariate analysis, hormone levels were compared in cases with one (no. 32), two (no. 63) or three (no. 24) vessel disease, showing significant differences associated with increasing severity of coronary disease (Figure 2). An inverse relationship was found between plasma testosterone levels and coronary artery score (r=−0.52, P<0.01). Following correction for age and BMI, levels of total, bioavailable and free testosterone, and free androgen index remained significantly lower in patients than in controls (data not shown).
Our study shows that men with proven CAD have significantly lower serum levels of androgens compared to normal controls, and that these lower androgen levels are likely to be related to testicular dysregulation. Our findings are confirmatory in that the beneficial effects of testosterone on myocardial ischaemia have been already shown.20, 21, 22, 23 We have also found that among patients with CAD, those with lower androgen levels have a greater amount of coronary atherosclerosis, thereby suggesting a possible pathogenetic role of low testosterone levels in the development of CAD. Whether this effect is related to a direct effect of androgens on the progression of atherosclerosis or whether it is dependent on the effect of androgens on surrogate markers of atherosclerosis is still a matter of speculation. Previous data from observational studies lack to show a positive relationship between testosterone and CAD to demonstrate that high levels of this androgen may be a risk factor, but seem to suggest that patients with CAD may have lower testosterone levels.10 On the other hand, clinical studies investigating the effect of testosterone administration exclude a possible causal relationship between testosterone exposure and development of CAD, and suggest a potential beneficial effects on myocardial ischemia.10 Our group has shown that acute intravenous administration of testosterone, in patients with proven CAD, improves exercise-induced myocardial ischaemia.4 In that study, although the effect seemed to be more evident in those patients with lower plasma level of the hormone, testosterone had an anti-ischaemic effect also in patients with normal plasma testosterone levels. Pugh et al.24 have evaluated the effect of acute testosterone administration and have found that testosterone increases cardiac output acutely, apparently via reduction of left ventricular after-load.
The concept that chronic testosterone supplementation adversely affects the plasma lipoprotein profile and increase the risk of atherosclerotic heart disease is not supported by data gathered in patients in whom a physiological supplementation of testosterone was obtained.25, 26 Studies using supraphysiological doses of testosterone and non-aromatizable androgens in athletes or in female to male transexuals showed a decrease in plasma high-density lipoprotein (HDL)-c levels,27, 28, 29, 30, 31 and physiological testosterone replacement in older men has been associated with no decrease in plasma HDL-c.32, 33, 34, 35 On the other hand, a recent study on transsexual, healthy, non-obese, young subjects does not show unequivocally that high-dose testosterone administration increases cardiovascular risk, as testosterone had a neutral effects on blood pressure and insulin sensitivity.36 Furthermore, cross-sectional studies of middle-aged men have found a direct relationship between serum testosterone levels and plasma HDL-c concentrations and an inverse correlation between serum testosterone levels and visceral fat volume.37 These data suggest that testosterone levels in the range that is mid-normal is related to an optimal cardiovascular risk profile at any age, and that testosterone concentration either above or below the physiological normal range may increase the risk of atherosclerotic heart disease.37
The inverse relationship between testosterone levels and coronary atherosclerosis found in our study suggests a possible protective role of the hormone on the progression of atherosclerosis. The data described here do not explain any testicular dysregulation but just an association with reduced testosterone levels if compared with the control group. Previous studies have investigated the effect of androgens on the development and progression of experimentally induced atherosclerosis in different animal models with diet- or injury-induced atherosclerosis.38, 39, 40, 41, 42, 43, 44, 45, 46, 47 Larsen et al.44 investigated the effect of intramuscular testosterone enhantate in castrated male rabbits and found no difference in the cholesterol content of abdominal aorta lesion after 17 weeks. Alexandersen et al.40 found in the same animal model that androgen replacement reduces total cholesterol and prevents the development of atherosclerosis, suggesting that testosterone might be atheroprotective, acting independently on both plasma lipid profile and cell proliferation. Adams et al.,45 who evaluated the effect of testosterone administration in female ovariectomized monkeys, found that the experimentally induced male plasma androgen pattern results in an exacerbation of diet-induced progression of atherosclerosis.45 These conflicting results from animal studies reflect the existence of many different mechanisms in the pathophysiology of atherosclerosis that could be influenced by androgens, the sexually dimorphic response to atherogenic triggers, as well as the gender-specific response to sex steroid.10 Although it is difficult to translate from animals studies the potential effect of sex hormones in humans, the animal data suggest that low testosterone levels may favour the development of coronary atherosclerosis in men, whereas in women this latter is consistent with a state of relative hyperandrogenism.47 On the other hand, it can be postulated that endothelial dysfunction of testicular vessels can be another, maybe early, manifestation of atherosclerosis. In such case, this ubiquitous manifestation of CAD may be responsible for testicular dysfunction and androgen deficiency rather than being the result of them.
Levels of testosterone decline with age in healthy subjects, but data in coronary patients are limited. It is known that late-onset hypogonadism (LOH)48 is associated with endothelial and erectile dysfunction (ED) and with several cardiovascular risk factors, including dyslipidaemia, adverse clotting profiles, obesity and insulin resistance, probably because hypogonadal men have a higher visceral fat mass than age-matched eugonadal control, all of them are often reversed by testosterone administration.49, 50, 51 The occurrence of hypogonadism in our patients is consistent with the presence of LOH, associated with higher gonadotrophin levels. We could not search for a direct relationship between the use of lipid-lowering drugs, that is, statins, and the observed reduction of sex hormone levels, but it has been recently reported in a meta-analysis that testosterone replacement therapy may delay time to ischaemia and is associated with potentially beneficial reductions of total cholesterol, fat mass and fat-free mass.52 It is therefore plausible to evaluate the potential benefits of androgen replacement therapy also in patients with CAD and lower testosterone levels.
A possible limitation of our study may be related to the selection of the control group. Subjects selected as controls in our study have several differences in baseline risk factors compared to patients with CAD. However, these are the differences that do exist between patients with CAD and the general population. Furthermore, our control group did not undergo cardiac catheterization for the exclusion of possible CAD, causing a possible grey zone of potential unknown CAD. The reason why we choose to use consecutive subjects without clinical evidence of cardiovascular disease instead of patients with normal coronary arteriograms as a control group is related to the fact that patients with normal coronary arteriograms undergoing coronary angiography often have a higher degree of cardiovascular risk than the general population, whereas the aim of our study was to address whether sex hormones are different in normal subjects and in patients with coronary atherosclerosis. Previous studies have shown, however, that patients with proven CAD have lower plasma testosterone levels compared to patients with symptoms suggestive of a possible cardiac origin but with normal coronary arteriograms.15 Although limited in the sample size, similar findings were observed in our patients with normal coronary arteriograms that showed significantly lower plasma testosterone levels than patients with proven coronary atherosclerosis. Another possible limitation of the study is represented by the lack of data on the prevalence of ED in our cardiac patients. However, it is known that risk factors for ED (hypertension, diabetes, smoking and lipid abnormality) are also risk factors for CAD. Recent studies reported that ED is extremely common in men with chronic CAD (affecting approximately 75%), yet most cardiologists do not ask about it.53 Based on how common ED is in patients with chronic stable CAD, we could speculate that most of patients included in our study might be considered as potentially affected by some degree of endothelial dysfunction of cavernous arteries hence affecting their overall sexual capacity.
In conclusion, our data confirm that a significant relationship exists between testosterone plasma level and the severity of coronary atherosclerosis, suggesting that low testosterone levels may be one of the causes rather than the consequence of cardiovascular disease in men. These data complement those reported in larger studies54 and suggest the importance to evaluate the androgen status in patients with CAD and the eventual need of androgen replacement therapy.
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Rosano, G., Sheiban, I., Massaro, R. et al. Low testosterone levels are associated with coronary artery disease in male patients with angina. Int J Impot Res 19, 176–182 (2007). https://doi.org/10.1038/sj.ijir.3901504
- coronary artery disease
- sex hormones
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