|Year : 2019 | Volume
| Issue : 1 | Page : 18-24
Relationship of coronary artery disease with testosterone level in young men undergoing coronary angiography
Hala M Badran1, Mahmoud A Soliman1, Ibrahim Elmadbouh2, Waleed A Ibrahim1, Sameh F El Masry3
1 Department of Cardiology, Menoufia University, Menoufia, Egypt
2 Department of Medical Biochemistry, Menoufia University, Menoufia, Egypt
3 Department of Cardiology, Nassir Institute Hospital, Cairo, Egypt
|Date of Submission||08-Oct-2017|
|Date of Acceptance||06-Dec-2017|
|Date of Web Publication||17-Apr-2019|
Sameh F El Masry
Nasr City, Cairo, 11765
Source of Support: None, Conflict of Interest: None
This study aimed to investigate the relation of testosterone level with the extent of coronary artery disease (CAD) in young adult male undergoing coronary angiography.
Materials and methods
Medline databases (PubMed, Journal of Clinical Endocrinology and Metabolism, British Medical Journal, Journal of American College of Cardiology and European Heart Journal) and also materials available in the internet were searched. The search was performed in the electronic databases from 2014 to 2017. The initial search presented 127 articles of which 61 met the inclusion criteria. The articles studied premature CAD, relation of testosterone level to CAD, and testosterone replacement therapy. If the studies did not fulfill the inclusion criteria, they were excluded. Study quality assessment included whether ethical approval was gained, eligibility criteria specified, appropriate controls, adequate information, and defined assessment measures. Comparisons were made by structured review with the results tabulated.
In total, 61 potentially relevant publications were included. The studies indicate that the serum levels of both total and free testosterone were significantly lower in young males with CAD, and both were significantly correlated with the severity of CAD as assessed by Gensini score.
The low testosterone level is associated with both the incidence and severity of premature CAD in young adult males.
Keywords: Gensini score, hypogonadism, premature coronary artery disease, testosterone, young adults
|How to cite this article:|
Badran HM, Soliman MA, Elmadbouh I, Ibrahim WA, El Masry SF. Relationship of coronary artery disease with testosterone level in young men undergoing coronary angiography. Menoufia Med J 2019;32:18-24
|How to cite this URL:|
Badran HM, Soliman MA, Elmadbouh I, Ibrahim WA, El Masry SF. Relationship of coronary artery disease with testosterone level in young men undergoing coronary angiography. Menoufia Med J [serial online] 2019 [cited 2019 Jul 17];32:18-24. Available from: http://www.mmj.eg.net/text.asp?2019/32/1/18/256137
| Introduction|| |
Premature coronary artery disease (CAD), defined as CAD in men less than or equal to 45 years and women less than or equal to 55 years , is a rapidly increasing phenomenon in the developing world. The traditional cardiovascular risk factors seem to be closely associated with the risk of cardiovascular disease in young adults . Therefore, it is important to try to find other risk factors for this rising phenomenon that may enforce the effect of the traditional risk factors.
The relationship between serum testosterone level and CAD is usually considered as a hot topic in cardiovascular medicine. A significant association was noticed between cardiovascular risk factors and testosterone in the Framingham study .
Moreover, it was found in a meta-analysis that patients with CVD have, on average, lower testosterone level than healthy controls, and the presence of associated morbidities, such as diabetes, obesity, and hypertension, was associated with increased testosterone differences between cases and controls .
Present data show that testosterone level decreases with advancing age in both men and women and is association with age-related diseases . During male aging, serum testosterone level decreases gradually , meanwhile the risk of cardiovascular and thrombotic events starts to increase . Since the aging process begins after puberty, it can be assumed that the decrease in testosterone level begins at a younger age than what was generally expected.
Thus, younger patients with acquired cardiovascular diseases, in particular CAD, may have a lower level of testosterone. A low level of free testosterone (FT) was found to be associated with the development of premature CAD before the age of 45 years . However, current evidence is still incomplete, and the role of testosterone in premature CAD is not fully understood, emphasizing the serious need for more research on aging process . It was found that testosterone replacement in the elderly and middle-aged men with hypogonadism has offered a solution for better cardiovascular condition and even slowing down of the atherosclerosis process; it would be beneficial to clarify this relationship in this age group .
It was also found in a recent large observational cohort with extended follow-up that normalization of total testosterone levels after testosterone replacement therapy (TRT) was associated with a significant reduction in all-cause mortality, myocardial infarction (MI), and stroke .
| Materials and Methods|| |
We reviewed papers on premature CAD and relation of testosterone level with the incidence and severity of CAD from Medline databases, which include PubMed, Journal of Clinical Endocrinology and Metabolism, British Medical Journal, Journal of American College of Cardiology, and European Heart Journal, and also materials available in the internet. We used premature CAD/testosterone level in CAD as searching terms. The search was performed in the electronic databases from 2014 to 2017.
All the studies were independently assessed for inclusion. They were included if they fulfilled the following criteria:
- Published in English language
- Published in peer-reviewed journals
- Focused on testosterone level and cardiovascular disease
- Discussed the relation between testosterone level and incidence and severity of CAD.
If the studies did not fulfill the above criteria, they were excluded such as report without peer review or not within national research program, such as letters/comments/editorials/news.
The analyzed publications were evaluated according to evidence-based medicine (EBM) criteria using the classification of the US Preventive Services Task Force and UK National Health Service protocol for EBM in addition to the Evidence Pyramid [Figure 1].
US preventive services task force classification is as follows:
- Level I: evidence obtained from at least one properly designed randomized controlled trial
- Level II-1: evidence obtained from well-designed controlled trials without randomization
- Level II-2: evidence obtained from well-designed cohort or case–control analytic studies, preferably from more than one center or research group
- Level II-3: evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence
- Level III: opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.
The quality of all the studies was assessed. Important factors included study design, attainment of ethical approval, evidence of a power calculation, specified eligibility criteria, appropriate controls, adequate information, and specified assessment measures. It was expected that confounding factors would be reported and controlled for and appropriate data analysis made in addition to an explanation of missing data.
A structured systematic review was performed with the results tabulated.
| Results|| |
Study selection and characteristics
In total, 127 potentially relevant publications were identified; 66 articles were excluded as they did not meet our inclusion criteria. A total of 61 studies were included in the review as they were deemed eligible by fulfilling the inclusion criteria. Of these 61 articles included in this review, 55 were human studies and six were animal studies. Most studies evaluated the relationship between testosterone level and both incidence and severity of CAD. Some studies examined the effect of TRT on CAD outcome. The studies were analyzed with respect to the study design using the classification of the US Preventive Services Task Force and UK National Health Service protocol for EBM.
Association of testosterone level with the incidence of coronary artery disease
One systematic review  and two meta-analyses , showed that low testosterone level was associated with increased CVD risk. A meta-analysis of 70 studies has found that patients with CVD had significantly lower levels of testosterone and higher levels of 17-β estradiol, which were significant markers even after adjusting for age and BMI ; two cohort studies , and two case–control , studies have shown that patients with CAD disease had lower testosterone levels than controls. One case–control study  found that both serum testosterone levels and sex hormone-binding globulin levels were inversely related to the incidence of major adverse CV events. Meanwhile, one case–control study observed no difference between the group of patients with acute coronary syndrome and the group of healthy participants regarding the level of FT  [Table 1].
|Table 1: Studies investigating the association of testosterone level with the incidence of coronary artery disease|
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Association of testosterone level with the extent of coronary artery disease
A case–control study showed that testosterone is negatively associated with the severity of coronary atherosclerosis in men , and two cross-sectional observational studies showed that low testosterone was an independent predictor of severity of CAD ,. Another cross-sectional study revealed that testosterone level was negatively correlated with the severity of coronary artery stenosis . However, in one cross-sectional study, they did not manage to document the relation of testosterone level with disease severity by means of the Gensini score  [Table 2].
|Table 2: Studies investigating the association of testosterone level with the severity of coronary artery disease|
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Association of testosterone level with coronary artery disease in young and middle-aged males
A case–control study  showed that a low testosterone level was an independent risk factor for CVD events in middle-aged Japanese men with coronary risk factors. In addition, three cross-sectional studies showed that young and middle-aged male patients with CAD showed a lower level of serum testosterone ,, [Table 3].
|Table 3: Studies investigating the association of testosterone level with coronary artery disease in young and middle-aged males|
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Association of low testosterone level with the prognosis of coronary artery disease
One cohort study  found that the highest quartile for serum testosterone was associated with the lowest mortality and the lowest two quartiles with higher mortality. Another prospective cohort study  showed that testosterone deficiency is common in patients with CAD and has a significant negative effect on survival. One review article  concluded that low endogenous testosterone levels are associated with increased risk of all-cause and CVD death in community-based studies of men, and one case–control study  evaluated the association between serum testosterone levels and 30-day mortality in 126 patients with acute MI; testosterone levels were significantly lower in the 16 patients who died than in survivors (P < 0.001) [Table 4].
|Table 4: Studies investigating the association of low testosterone level with the prognosis of coronary artery disease|
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Testosterone replacement therapy and coronary artery disease
Three meta-analyses ,, show that TRT, in general, had neutral effects on the occurrence of major adverse CV events; testosterone increased hematocrit and hemoglobin levels and showed various mild effects on lipid profile [Table 5].
|Table 5: Studies investigating the relation between testosterone replacement therapy and coronary artery disease|
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One large cohort study  showed that normalization of total testosterone levels after TRT was associated with a significant reduction in all-cause mortality, MI, and stroke.
| Discussion|| |
Nowadays, growing amounts of data show that testosterone has significant cardiovascular metabolic effects, and its deficiency was found to increase the risk of premature CAD .
As the relation of testosterone and CAD in young individuals is the aim of this article, on reviewing the studies on premature CAD, we found that the definition of young varied among different studies regarding premature coronary heart disease and MI. Aggarwal et al.  used the term 'young' as less than 40 years, Awad-Elkarim et al.  defined young as less than 50 years, whereas Oliveira et al.  suggested 45 years as a cutoff age when defining 'young' with respect to MI.
Testosterone was found to have beneficial effects in men with cardiac disease. It is a strong coronary vasodilator through calcium channel antagonist action, and therefore has benefits on the angina threshold, especially in men with low baseline testosterone . Testosterone therapy was found to be associated with decreased total cholesterol, fat mass, waist circumference, and proinflammatory cytokines associated with atherosclerosis, diabetes, and the metabolic syndrome ,,. Testosterone additionally enhances functional capacity and insulin resistance in males with heart failure ,.
The main bulk of cross-sectional studies revealed a positive correlation of endogenous testosterone with high-density lipoprotein (HDL) and a negative correlation with total cholesterol, low-density lipoprotein, and triglycerides. Therefore, males with low testosterone seem to have unfavorable lipid profiles, whereas those with hypogonadism have a potentially atherogenic dyslipidemia before treatment . In a recently published trial, there was a highly significant negative correlation between androgens (total testosterone, FT, and dehydroepiandrosterone) and BMI, total cholesterol, and low-density lipoprotein, and a highly significant positive correlation with HDL (P = 0.001) .
The link between testosterone and HDL-C is rather conflicting. On one hand, a positive correlation was an interesting finding in a lot of trials, such as that by Stanworth et al. , which revealed a positive correlation between testosterone and HDL-C in patients with diabetes type II, suggesting that increasing HDL is the main effect of testosterone in this group of patients. On the other hand, an opposite correlation, but with exogenous testosterone, was found in other studies, where observations of athletes consuming androgenic anabolic steroids were the source of evidence for the HDL-C lowering effect of testosterone . This effect was thought to be because of intake of supraphysiologic doses of oral androgens by young males , but it was much less evident when testosterone replacement was given at physiologic doses to regain eugonadal levels, especially in elderly . Furthermore, it seems that the action of exogenous testosterone on lipid profile is strongly dependent on the route of administration, whether parenteral or oral. Its oral administration considerably reduced HDL-C levels in young, healthy males , whereas there was no significant alterations in HDL-C level after 3 months of treatment of older males with hypogonadism with transdermal testosterone . These trials highlight that the beneficial cardiovascular effect of testosterone is not applied to the exogenous testosterone, particularly in supraphysiologic doses. On the contrary, a few other cross-section studies showed no correlation between endogenous androgens and lipid profile .
An animal study showed a direct beneficial effect of testosterone on plaque development, possibly attributed to the vascular androgen receptor . Endothelium-independent relaxation was induced by testosterone in isolated rabbit  and rat  aorta, and testosterone looks to have a favorable effect on myocardial ischemia  and coronary blood flow in male patients with CAD . Campelo et al.  found an evidence linking testosterone's effect on endothelial nitric oxide production with the hormonal variation of platelet aggregation and endothelial cell growth, and testosterone in physiological concentrations stimulates endothelial cell growth and inhibits platelet aggregation, through its direct action on endothelial nitric oxide production.
Another source of evidence for the beneficial effect of testosterone was found in animal studies, which showed that the induction of hypogonadal state or castration promotes atherosclerosis and testosterone replacement abolishes it ,.
To investigate the relation of testosterone with severity of CAD, a study measured the testosterone levels in 803 male patients who were divided into three groups according to testosterone tertiles. The severity of CAD was determined by the Gensini score. It was found that patients with lower testosterone levels had higher Gensini scores. However, the study enrolled patients between 28 and 83 years of age (mean: 62 years), and there was a significant difference in age between the three tertiles . On the contrary, Alkamel et al.  targeted the younger age group (younger than 45 years) to evaluate the relation of testosterone with premature CAD. They proved the association between low total and FT and incidence of CAD in young males, and also they have found that serum testosterone levels were conversely correlated with the Gensini score and the unadjusted effect of low total testosterone on CAD showed that low total testosterone is a significant predictor for CAD.
However, these trials used the Gensini score for assessment of CAD severity which is based on the number of diseased coronary artery segments, including both the degree and the site of the stenosis as follows: 1–25% stenosis = 1; 26–50% stenosis = 2; 51–75% stenosis = 4; 76–90% stenosis = 8; 91–99% stenosis = 16; and total occlusion = 32. The score is then multiplied by a factor which is dependent on the importance of the lesion position as follows: ×5 for the left main coronary artery; ×2.5 for the proximal left anterior descending or left circumflex coronary artery; ×1.5 for the midsegment of the left anterior descending; ×1 for the distal left anterior descending, right coronary artery, or middistal left circumflex; and ×0.5 for any other arteries .
A more recent score, which is the synergy between percutaneous coronary intervention with TAXUS and cardiac surgery (SYNTAX) score, which was established during the SYNTAX trial, is a helpful tool for treatment decision as regard the complexity of the CAD. Retrospective analyses suggest that CAD severity by SYNTAX scoring might help to direct the selection of revascularization strategies and, therefore, enhance therapeutic decision ,.
It determines the extent and severity of CAD based on the coronary anatomic risk factors including lesion number, total occlusion, bifurcation, trification, aorta–osteal stenosis, tortuosity, calcification, thrombosis, and diffuse lesion. Any lesion of more than 50% in the vessels with diameter more than 1.5 mm is graded, and the sum of the scores of all lesions constitutes syntax score . Both Gensini and SYNTAX scores evaluate the anatomy, morphology, and severity of stenosis; however, the SYNTAX score extends to evaluation of calcification, tortuosity, stenoses of bifurcation or trifurcation, and the dominance all of, which are important factors for therapeutic decision. Another difference between both scores is that stenosis in the Gensini score begins at 25%, whereas SYNTAX score evaluates stenosis starting at 50% obstruction . However, in our search, we could not find trials that incorporate the SYNTAX score in assessment of the relation between testosterone and CAD.
| Conclusion|| |
Young adult males with premature CAD have lower testosterone level, and the lower levels of testosterone were correlated with the severity of CAD as assessed by Gensini score.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]