Relationship of coronary artery disease with testosterone level in young men undergoing coronary angiography

Hala M Badran; Mahmoud A Soliman; Ibrahim Elmadbouh; Waleed A Ibrahim; Sameh F El Masry

doi:10.4103/mmj.mmj_657_17

REVIEW ARTICLE

Year : 2019 | Volume : 32 | 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

Correspondence Address:
Sameh F El Masry
Nasr City, Cairo, 11765
Egypt

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/mmj.mmj_657_17

Abstract

Objective
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.
Findings
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.
Conclusion
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 2023 Sep 26];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 ^[1], 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 ^[2]. 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 ^[3].

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 ^[4].

Present data show that testosterone level decreases with advancing age in both men and women and is association with age-related diseases ^[5]. During male aging, serum testosterone level decreases gradually ^[6], meanwhile the risk of cardiovascular and thrombotic events starts to increase ^[7]. 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 ^[8]. 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 ^[9]. 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 ^[10].

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 ^[11].

Materials and Methods

Search strategy

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.

Study selection

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.

Data extraction

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].

Figure 1: Evidence pyramid.

Click here to view

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.

Quality assessment

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.

Data synthesis

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 ^[19] and two meta-analyses ^[4],[12] 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 ^[4]; two cohort studies ^[13],[14] and two case–control ^[15],[16] studies have shown that patients with CAD disease had lower testosterone levels than controls. One case–control study ^[17] 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 ^[18] [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 ^[20], and two cross-sectional observational studies showed that low testosterone was an independent predictor of severity of CAD ^[21],[22]. Another cross-sectional study revealed that testosterone level was negatively correlated with the severity of coronary artery stenosis ^[14]. 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 ^[23] [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 ^[24] 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 ^{[14],[22],[23]} [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 ^[25] 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 ^[26] showed that testosterone deficiency is common in patients with CAD and has a significant negative effect on survival. One review article ^[19] 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 ^[27] 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 ^{[28],[29],[30]} 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 ^[11] 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 ^[19].

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. ^[31] used the term 'young' as less than 40 years, Awad-Elkarim et al. ^[32] defined young as less than 50 years, whereas Oliveira et al. ^[33] 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 ^[34]. 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 ^{[35],[36],[37]}. Testosterone additionally enhances functional capacity and insulin resistance in males with heart failure ^[38],[39].

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 ^[40]. 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) ^[41].

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. ^[42], 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 ^[43]. This effect was thought to be because of intake of supraphysiologic doses of oral androgens by young males ^[44], but it was much less evident when testosterone replacement was given at physiologic doses to regain eugonadal levels, especially in elderly ^[45]. 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 ^[46], whereas there was no significant alterations in HDL-C level after 3 months of treatment of older males with hypogonadism with transdermal testosterone ^[45]. 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 ^[47].

An animal study showed a direct beneficial effect of testosterone on plaque development, possibly attributed to the vascular androgen receptor ^[48]. Endothelium-independent relaxation was induced by testosterone in isolated rabbit ^[49] and rat ^[50] aorta, and testosterone looks to have a favorable effect on myocardial ischemia ^[51] and coronary blood flow in male patients with CAD ^[52]. Campelo et al. ^[53] 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 ^[51],[54].

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 ^[20]. On the contrary, Alkamel et al. ^[22] 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 ^[55].

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 ^[56],[57].

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 ^[58]. 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 ^[59]. 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

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1.	De Sutter J, De Bacquer D, Kotseva K, Sans S, Pyörälä K, Wood D, et al. Screening of family members of patients with premature coronary heart disease: results from the EUROASPIRE II family survey. Eur Heart J 2003; 24:249–257.
2.	Hassan Z, Farooq S, Nazir N, Iqbal K. Coronary artery disease in young: a study of risk factors and angiographic characterization in the Valley of Kashmir. Int J Sci Res Pub 2014; 4:1.
3.	Chock B, Lin TC, Li CS, Swislocki A. Plasma testosterone is associated with Framingham risk score. Aging Male 2012; 15:134–139.
4.	Corona G, Rastrelli G, Monami M, Guay A, Buvat J, Sforza A, et al. Hypogonadism as a risk factor for cardiovascular mortality in men: a meta-analytic study. Eur J Endocrinol 2011; 165:687–701.
5.	Fukai S, Akishita M, Yamada S, Hama T, Ogawa S, Iijima K, et al. Association of plasma sex hormone levels with functional decline in elderly men and women. Geriatr Gerontol Int 2009; 9:282–289.
6.	Yeap BB. Testosterone and ill-health in aging men. Nat Clin Pract Endocrinol Metab 2009; 5:113–121.
7.	North BJ, Sinclair DA. The intersection between aging and cardiovascular disease. Circ Res 2012; 110:1097–1108.
8.	Turhan S, Tulunay C, Gulec S, Ozdol C, Kilickap M, Altin T, et al. The association between androgen levels and premature coronary artery disease in men. Coron Artery Dis 2007; 18:159–162.
9.	Shafiee A, Van Bodegom D. The necessity for research on the elderly in Iran. J Tehran Heart Cent 2012; 7:40.
10.	Shores MM, Smith NL, Forsberg CW, Anawalt BD, Matsumoto AM. Testosterone treatment and mortality in men with low testosterone levels. J Clin Endocrinol Metab 2012; 97:2050–2058.
11.	Sharma R, Oni OA, Gupta K, Chen G, Sharma M, Dawn B, et al. Normalization of testosterone level is associated with reduced incidence of myocardial infarction and mortality in men. Eur Heart J 2015; 36:2706–2715.
12.	Ruige JB, Mahmoud AM, De Bacquer D, Kaufman JM. Endogenous testosterone and cardiovascular disease in healthy men: a meta-analysis. Heart 2011; 97:870–875.
13.	Rosano GM, Sheiban I, Massaro R, Pagnotta P, Marazzi G, Vitale C, et al. Low testosterone levels are associated with coronary artery disease in male patients with angina. Int J Impot Res 2007; 19:176–182.
14.	Hu X, Rui L, Zhu T, Xia H, Yang X, Wang X et al. Low testosterone level in middle-aged male patients with coronary artery disease. Eur J Intern Med 2011; 22:e133–e136.
15.	English KM, Mandour O, Steeds RP, Diver MJ, Jones TH, Channer KS. Men with coronary artery disease have lower levelsof androgens than men with normal coronary angiograms. Eur Heart J 2000; 21:890–894.
16.	Helaly M, Daoud E, El-Mashad N. Does the serum testosterone level have a relation to coronary artery disease in elderly men? Curr Gerontol Geriatr Res 2011; 2011:1–6.
17.	Ohlsson C, Barrett-Connor E, Bhasin S, Orwoll E, Labrie F, Karlsson MK, et al. High serum testosterone is associated with reduced risk of cardiovascular events in elderly men. The MrOS (Osteoporotic Fractures in Men) study in Sweden. J Am Coll Cardiol 2011; 58:1674–1681.
18.	Dellal FD, Niyazoǧlu M, Çeviker T, Görar S, Taşan E. Evaluation of androgen levels in patients with acute coronary syndrome. Med Sci 2012; 1:323–330.
19.	Araujo AB, Dixon JM, Suarez EA, Murad MH, Guey LT, Wittert GA. Clinical review: endogenous testosterone and mortality in men: a systematic review and meta-analysis. J Clin Endocrinol Metab 2011; 96:3007–3019.
20.	Li L, Guo C, Jia E, Zhu T, Wang L, Cao K, et al. Testosterone is negatively associated with the severity of coronary atherosclerosis in men. Asian J Androl 2012; 14:875–878.
21.	Gururani K, Jose J, George PV. Testosterone as a marker of coronary artery disease severity in middle aged males. Indian Heart J 2016; 68:S16–S20.
22.	Alkamel A, Shafiee A, Jalali A, Boroumand M, Nozari Y. The association between premature coronary artery disease and level of testosterone in young adult males. Arch Iran Med 2014; 17:545–550.
23.	Durukan AB, Gurbuz HA, Tanalp AC, Durukan E, Ucar HI, Yorgancioglu C. The association between serum testosterone levels and coronary artery disease in middle-aged men. Kardiochir Torakochirurgia Pol 2013; 10:211–215.
24.	Akishita M, Hashimoto M, Ohike Y, Qgawa S, Iijima K, Eto M, et al. Low testosterone level as a predictor of cardiovascular events in Japanese men with coronary risk factors. Atherosclerosis 2010; 210:232–236.
25.	Yeap BB, Alfonso H, Chubb SA, Handelsman DJ, Hankey GJ, Almeida OP, et al. In older men an optimal plasma testosterone is associated with reduced all-cause mortality and higher dihydrotestosterone with reduced ischemic heart disease mortality, while estradiol levels do not predict mortality. J Clin Endocrinol Metab 2014; 99:e9–e18.
26.	Malkin CJ, Pugh PJ, Morris PD, Asif S, Jones TH, Channer KS. Low serum testosterone and increased mortality in men with coronary heart disease. Heart 2010; 96:1821–1825.
27.	Militaru C, Donoiu I, Dracea O, Ionescu DD. Serum testosterone and short-term mortality in men with acute myocardial infarction. Cardiol J 2010; 17:249–253.
28.	Calof OM, Singh AB, Lee ML, Kenny AM, Urban RJ, Tenover J, et al. Adverse events associated with testosterone replacement in middle-aged and older men: a meta-analysis of randomized, placebo-controlled trials. J Gerontol A Biol Sci Med Sci 2005; 60:1451–1457.
29.	Haddad RM, Kennedy CC, Caples SM, Tracz MJ, Boloña ER, Sideras K, et al. Testosterone and cardiovascular risk in men: a systematic review and meta-analysis of randomized placebo-controlled trials. Mayo Clin Proc 2007; 82:29–39.
30.	Fernández-Balsells MM, Murad MH, Lane M, Lampropulos JF, Albuquerque F, Mullan RJ, et al. Clinical review 1: adverse effects of testosterone therapy in adult men: a systemic review and meta-analysis. J Clin Endocrinol Metab 2010; 95:2560–2575.
31.	Aggarwal A, Aggarwal S, Goel A, Sharma V, Dwivedi S. A retrospective case-control study of modifiable risk factors and cutaneous markers in Indian patients with young coronary artery disease. JRSM Cardiovasc Dis 2012; 1:1–8.
32.	Awad-Elkarim AA, Bagger JP, Albers CJ, Skinner JS, Adams PC, Hall RJ. A prospective study of long term prognosis in young myocardial infarction survivors: the prognostic value of angiography and exercise testing. Heart 2003; 89:843–847.
33.	Oliveira A, Barros H, Azevedo A, Bastos J, Lopes C. Impact of risk factors for non-fatal acute myocardial infarction. Eur J Epidemiol 2009; 24:425–432.
34.	Malkin CJ, Pugh PJ, Morris PD, Kerry KE, Jones RD, Jones TH, et al. Testosterone replacement in hypogonadal men with angina improves ischaemic threshold and quality of life. Heart 2004; 90:871–876.
35.	Kapoor D, Goodwin E, Channer KS, Jones TH. Testosterone replacement therapy improves insulin resistance, glycaemic control, visceral adiposity and hypercholesterolaemia in hypogonadal men with type 2 diabetes. Eur J Endocrinol 2006; 154:899–906.
36.	Malkin CJ, Pugh PJ, Jones RD, Kapoor D, Channer KS, Jones TH. The effect of testosterone replacement on endogenous inflammatory cytokines and lipid profiles in hypogonadal men. J Clin Endocrinol Metab 2004; 89:3313–3318.
37.	Heufelder AE, Saad F, Bunck MC, Gooren L. 52-Week treatment with diet and exercise plus transdermal testosterone reverses the metabolic syndrome and improves glycaemic control in men with newly diagnosed type 2 diabetes and subnormal plasma testosterone. J Androl 2009; 30:726–733.
38.	Malkin CJ, Jones RD, Jones TH, Channer KS. Effect of testosterone on ex vivo vascular reactivity in man. Clin Sci 2006; 111:265–274.
39.	Malkin CJ, Jones TH, Channer KS. The effect of testosterone on insulin sensitivity in men with heart failure. Eur J Heart Fail 2007; 9:44–50.
40.	Oppenheim DS, Greenspan SL, Zervas NT, Schoenfeld DA, Klibanski A. Elevated serum lipids in hypogonadal men with and without hyperprolactinaemia. Ann Intern Med 1989; 111:288–292.
41.	Abdelazez WF, Elmadbouh I, Mena MB, Zewain AA. Relation between serum androgen levels and dyslipidemia in acute coronary syndrome. Menoufia Med J 2017; 30:196–202.
42.	Stanworth RD, Kapoor D, Channer KS, Jones TH. Testosterone levels correlate positively with HDL cholesterol levels in men with type 2 diabetes. Endocrine Abstracts 2007; 14:628.
43.	Basaria S. Androgen abuse in athletes: detection and cosequencies. J Clin Endocrinol Metab 2010; 95:1533–1543.
44.	Shabsigh R, Katz M, Yan G, Makhsida N. Cardiovascular issues in hypogonadism and testosterone therapy. Am J Cardiol 2005; 96:67–72.
45.	Rubinow KB, Vaisar T, Tang C, Matsumoto AM, Heinecke JW, Page ST. Testosterone replacement in hypogonadal men alters the HDL proteome but not HDL cholesterol efflux capacity. J Lipid Res 2012; 53:1376–1383.
46.	Amory JK, Kalhorn TF, Page ST. Pharmachokinetics and pharmacodynamics of testosterone enanthate plus dutasteroid for 4 weeks in normal male: implications for male hormone contraception. J Androl 2008; 29:260–271.
47.	Denti L, Pasolini G, Sanfelici L, Benede R, Cecchetti A, Ceda GP, et al. Aging-related decline of gonodal function in healthy men: correlation with body composition and lipoproteins. J Am Geriatr Soc 2000; 48:51–58.
48.	Hanke H, Lenz C, Hess B, Spindler KD, Weidermann W. Effect of testosterone on plaque development and androgen receptor expression in the arterial vessel wall. Circulation 2001; 103:1382–1385.
49.	Yue P, Chatterjee K, Beale C, Poole-Wilson PA, Collin P. Testosterone relaxes rabbit coronary arteries and aorta. Circulation 1995; 91:1154–1160.
50.	Costarella CE, Stallone JN, Rutecki GW, Whittier FC. Testosterone causes direct relaxation of rat thoracic aorta. J Pharmacol Exp Ther 1996; 277:34–39.
51.	Alexandersen P, Haarbo J, Byrjalsen I, Lawaetz H, Christiansen H. Natural androgens inhibit male atherosclerosis: a study in castrated, cholesterol-fed rabbits. Circ Res 1999; 84:813–819.
52.	Webb CM, McNeill JG, Hayward CS, de Zeigler D, Collins P. Effects of testosterone on coronary vasomotor regulation in men with coronary heart disease. Circulation 1999; 100:1690–1696.
53.	Campelo AE, Cutini PH, Massheimer VL. Testosterone modulates platelet aggregation and endothelial cell growth through nitric oxide pathway. J Endocrinol 2012; 213:77–87.
54.	Nettleship JE, Jones TH, Channer KS, Jones RD. Physiological testosterone replacement therapy attenuates fatty streak formation and improves high-density lipoprotein cholesterol in the Tfm mouse: an effect that is independent of the classic androgen receptor. Circulation 2007; 116:2427–2434.
55.	Hu X, Jiang H, Bai Q, Zhou X, Xu C, Lu Z, et al. Increased serum HMGB1 is related to the severity of coronary artery stenosis. Clin Chim Acta 2009; 406:139–142.
56.	Capodanno D, Caggegi A, Miano M, Cincotta G, Dipasqua F, Giacchi G, et al. Global risk classification and clinical SYNTAX (synergy between percutaneous coronary intervention with TAXUS and cardiac surgery) score in patients undergoing percutaneous or surgical left main revascularization. JACC Cardiovasc Interv 2011; 4:287–297.
57.	Capodanno D, Miano M, Cincotta G, Caggegi A, Ruperto C, Bucalo R, et al. EuroSCORE refines the predictive ability of SYNTAX score in patients undergoing left main percutaneous coronary intervention. Am Heart J 2010; 159:103–109.
58.	Hamur H, Duman H, Keskin E, Inci S, Kucuksu Z, Degirmenci H, Topal E. The relation between erectile dysfunction and extent of coronary artery disease in the patients with stable coronary artery disease. Int J Clin Exp Med 2015; 8:21295.
59.	Sinning C, Lillpopp L, Appelbaum S, Ojeda F, Zeller T, Schnabel R, et al. Angiographic score assessment improves cardiovascular risk prediction: the clinical value of SYNTAX and Gensini application. Clin Res Cardiol 2013; 102:495–503.