Testosterone and coronary heart disease: is there a link?

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Q) Med 1997; 90:787-791

Commentary

QJM

Testosterone and coronary heart disease: is there a link?

K.M. ENGLISH, R. STEEDS, T . H . JONES

1

and K.S. CHANNER

From the Departments of Cardiology and ^ Endocrinology, Royal Hallamshire Hospital,

Sheffield, UK

Introduction

Despite a ten-fold difference in total coronary artery disease (CAD) mortality in 50 countries, the male-to-female ratio remains remarkably constant at around two.1 How is this excess risk in men explained? There is a higher prevalence of hyperten-sion, smoking and hyperlipidaemia in men, and those males affected by these risk factors have higher mortality than similarly-affected women. However, when the risks associated with high systolic blood pressure, cigarette smoking, raised cholesterol, raised fasting plasma glucose, and obesity are controlled for by means of a multiple logistic analysis, a significant sex difference still remains.2

In women, early menopause is associated with an increased risk of cardiovascular disease,3 and myocardial infarction is more common following bilateral oopherectomy.4 By comparison, exogenous oestrogen use is protective against CAD in post-menopausal women,5 and high levels of endogenous oestrogen may explain the extremely low prevalence of CAD in pre-menopausal women. Women with the polycystic ovary syndrome have a higher than normal level of testosterone which is associated with obesity, insulin resistance, low levels of high-density lipoprotein cholesterol (HDLC),6 and an increased risk of myocardial infarction.7 It seems therefore, in women, that physiological levels of endogenous oestrogen are protective, while abnormally high levels of testosterone are detrimental.

By contrast, in men, high levels of oestrogen and oestrone are associated with increased risks of myocardial infarction, angina and CAD at angio-graphy.8 Giving oestrogens to men with prostatic car-cinoma is associated with increased mortality

from CAD,9 and oestrogens given to male survivors of myocardial infarction lead to an increased re-infarction rate.10 Not only do high levels of oestrogen appear detrimental in men, but there is evidence to suggest that low levels of testosterone are also associated with an increased risk of CAD. It may be the different balance of androgens and oestrogens in the two sexes which is important in determining the sex difference in mortality from CAD.

Testosterone and atherogenesis

The premature development and progression of ather-oma is dependent upon the interaction of a number of risk factors which have been identified in recent years. These risk factors (hypertension, dyslipidaemia, diabetes, high fibrinogen, obesity and smoking), tend to cluster in individuals and in families. Although there are substantial data regarding the risks associ-ated with these conditions, common causative links and the mechanisms by which they interact with each other are poorly understood. Abnormalities in the balance of sex hormones may be implicated.

Testosterone and lipids

Different lipoproteins are of varying importance in the development of atheroma. High levels of low-density lipoprotein cholesterol (LDLC) and lipopro-tein a are strongly associated with the development of CAD, whereas high levels of HDLC are protective. Men have an atherogenic profile, with lower levels of HDLC and higher levels of LDLC compared with pre-menopausal women or pre-pubescent boys.

Address correspondence to Dr K.M. English, Department of Cardiology, Royal Hallamshire Hospital, Glossop Road, Sheffield S10 2JF

by guest on June 23, 2015

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These differences between men and women may reflect an interaction with the balance of sex hor-mones, and since these are derivatives of cholesterol, a close link may be expected. Studies in normal men have consistently shown a positive correlation between total or free testosterone level and HDLC, and a negative correlation with LDLC and triglycer-ides.11"15 Serum lipoprotein a levels are decreased in normal men by the administration of exogenous testosterone.16'17 Thus, men with hypotestosteronae-mia have a pro-atherogenic lipid profile. However, intervention trials have produced conflicting results. Chemically-induced hypogonadism by gonadotro-phin-releasing-hormone analogues induces a rise in HDLC, which is corrected with intramuscular testosterone enanthate therapy.18"20 Results of these intervention studies should not to be used to draw conclusions about the lipid abnormalities seen in naturally occurring hypogonadism.

Testosterone and hypertension

Both systolic and diastolic hypertension are estab-lished risk factors for CAD. The direct influence of sex hormones on blood pressure control has not been studied as a primary objective. A number of investigators have looked at the relationship between blood pressure and testosterone as part of case-control studies of many CAD risk factors. They have found a consistent relationship between hypotestos-teronaemia and raised systolic and diastolic blood pressure.11 Low mean levels of testosterone have been found in populations of hypertensive men.21 Moreover, a high oestradiohtestosterone ratio is asso-ciated with a high renin-sodium profile in hypertens-ive men,22 suggesting a possible aetiological link.

Testosterone and insulin resistance/obesity

Hyperinsulinaemia is a risk factor for coronary artery disease.23 Many studies have investigated the rela-tionship between androgens and insulin level in women, but relatively few have studied the relation-ship in men. There is an association in men between low free and total testosterone and hyperinsulinae-mia; this relationship being converse to that seen in women.11'24 Similarly, total testosterone has been shown to be lower in non-insulin-dependent diabetic men who have higher plasma insulin levels than in normoglycaemic men.12 In centrally-obese middle-aged men, testosterone replacement reduces hyperin-sulinaemia.25

Obesity and increased waist:hip ratio are both predictors of hyperinsulinaemia. Free and total testo-sterone are decreased in proportion to the degree of obesity,26 and a significant correlation has been found between decreased testosterone blood level

and increased waistrhip ratio.11'24'42 This relationship may be explained by the fact that the oestrogen:testo-sterone ratio is determined, at least in part, by the peripheral conversion of androstenedione to oestrone by aromatase activity in adipose tissue and muscle. Thus, men with android obesity have lower testoster-one levels, secondary to increased conversion of androgens to oestrogens in peripheral fat, and have a higher risk of CAD.

Testosterone and smoking

Estradiol levels are increased in otherwise healthy, young male smokers.29 A recent study has demon-strated significant reductions in total testosterone levels in rats exposed to cigarette smoke for 60 days. This was associated with degeneration of Leydig cells on histological examination of the testis.28 However, human studies have shown conflicting results, with some authors reporting low serum testosterone levels in smokers,29 while others have found high levels.30'31

Testosterone and fibrinogen

Fibrinogen is an independent risk factor for myocard-ial infarction and atheroma formation.32'33 Low levels of serum testosterone are associated with high fib-rinogen levels,34'35'37 and administration of exogen-ous testosterone causes fibrinogen levels to fall.37 Low levels of testosterone may therefore predispose to accelerated atheroma formation through its effect on fibrinogen.

Testosterone and age

Increased age is one of the strongest predictors for coronary artery disease. The Telecom Study of 1400 males aged between 20 and 60 years demonstrated a significant stepwise decrease in testosterone con-centration with each decade. This relationship was maintained after the exclusion of patients with chronic disease and statistical correction for body mass index, alcohol consumption and subscapular skin-fold thickness.38

Testosterone and atheroma at coronary

angiography

The summary of the evidence above shows clearly that a low level of serum testosterone is associated with all the common risk factors for CAD. If the association were of pathogenic significance, it should be reflected in a correlation between testosterone concentration and findings at coronary angiography. A significant negative correlation between testoster-one level and the presence of CAD has been found in two studies using coronary angiography to detect

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Testosterone and CHD

789

evidence of atheroma.39'40 Furthermore, Philips et al. found a significant negative correlation between total or free testosterone and the degree of CAD (as defined by the mean % arterial occlusion) in 55 men undergoing coronary angiography.41

Testosterone and acute coronary

thrombosis

Ninety percent of cases of myocardial infarction follow an acute thrombotic occlusion of an already damaged coronary artery. As already discussed, a low level of testosterone is associated with coronary atheroma. Is low testosterone also implicated in acute thrombotic episodes?

Testosterone and haemostasis/fibrinolysis

A number of studies have investigated the role of testosterone in the haemostatic/fibrinolytic pathways, with uniform results.34"36 Testosterone has been posit-ively correlated with tissue plasminogen activator (the major stimulator of fibrinolysis) and negatively with the procoaguable factors, plasminogen activator inhibitor, fibrinogen, alpha-2 antiplasmin and factor Vile. These results remain significant after control for other variables. Furthermore, exogenous testosterone administration causes a fall in plasma fibrinogen and plasminogen activator inhibitor.37 Hypotestosteron-aemia is therefore implicated in a pro-thrombotic tendency, and theoretically would be associated with an increased risk of acute myocardial infarction and thrombotic stroke, whereas a physiological level of testosterone should decrease thrombotic risk by redu-cing fibrinogen and increasing fibrinolytic activity.

Testosterone and myocardial infarction

Numerous studies have attempted to clarify the relationship between sex hormones and acute myocardial infarction. Many of these primarily studied oestrogen, oestradiol and oestrone, with testosterone being a secondary measurement. The period immediately prior to myocardial infarction is inevitably difficult to study, but a number of centres have demonstrated significantly low levels of testo-sterone immediately following myocardial infarc-tion.42'43 This is, however, not a consistent finding, with the majority of studies showing no significant differences,44"47 Profiling of testosterone has demon-strated that the low levels seen post infarct may be due to an immediate fall in testosterone which subsequently returns to normal.48 This is mirrored by similar falls following surgery and trauma, suggesting it may be an acute response.49 A recent study in Denmark has examined the relationship between low testosterone and acute ischaemic stroke in 144 men. The authors found that total testosterone level

was inversely associated with stroke severity, infarct size and six-month mortality.50 Again, these results may be due to an acute fall in testosterone levels following acute stroke. These studies do not show a causative link between a low level of testosterone and acute thrombotic events, but raise enough ques-tions to warrant further studies.

Testosterone and coronary artery disease

mortality

Work to date provides circumstantial evidence of a link between low testosterone levels, atherogenesis and acute arterial thrombosis. However, studies examining the association between low testosterone and CAD mortality have been inconclusive. A study of 1000 men aged between 40 and 79 years looked at the development of cardiovascular disease (heart attack, heart failure or stroke) over a 12-year period, and correlated this with total testosterone level taken at the beginning of the trial. The investigators found no significant association between total testosterone at baseline and the prevalence or development of cardiovascular disease.51 A further study of the stored sera of 163 men who died from a definite myocardial infarct or from coronary heart disease compared with 163 matched controls found no significant difference between free or total testosterone in cases or con-trols.52 The Caerphilly Heart Study again did not find testosterone level to be a primary risk factor for CAD mortality.53 All these studies have limitations: particu-larly, Barrett-Connor et a/.51 did not examine free testosterone levels, and the population in the Caerphilly Heart Study53 was relatively young (aged 45-59 years) and followed for only 5 years. Stronger evidence might have been produced had the study been extended for a longer period. A further limita-tion in the study of the relalimita-tionship between testoster-one and CAD is that the measurement of testostertestoster-one has only been possible since the 1960s, and is still being developed. It can be subject to methodological problems, which arise from the fact that 98% of testosterone is bound to sex-hormone-binding globu-lin, and to a lesser extent, albumin. The assays for free testosterone are improving, but their sensitivity is not good enough to define borderline hypogonad-ism clearly. The measurement of testosterone is further complicated by its diurnal and circannual variation and wide intra-individual variability.

Conclusions

The protective value of sex hormones appears to be sex-specific, and the ratio of oestrogen to testosterone may be important. Oestrogens appear protective in women but detrimental in men, whereas it appears

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that testosterone is protective in men, yet deleterious in women. A normal physiological level of testoster-one in men may protect against the development of hyperlipidaemia, hyperinsulinism, hypertension, thrombophilic tendency, obesity and increased wais-t:hip ratio, all of which predispose to the develop-ment of CAD. Low or low normal testosterone may also be implicated in the pathogenesis of acute myocardial infarction and acute stroke. The decline of testosterone with age may partly explain the greater risk of CAD with advancing years. Moreover, there may be a population of younger men with relative hypogonadism who are at increased risk of premature CAD, complaining only of fatigue and depression, in whom the true diagnosis is unsuspec-ted and undiagnosed.

Trials examining the association between CAD mortality and morbidity and sex hormone levels in men need to be large and over long time periods to identify trends associated with small differences in sex hormones. The importance of testosterone in the pathogenesis of CAD may be in part due its effect in the short or medium term on lipids or coagulation factors. Clearly, studies to determine the significance of these different effects in different time scales need to be sophisticated in design.

Now is the time to undertake the large prospective trials required to establish a cause and effect relation-ship between low testosterone levels and CAD.

References

1. British Heart Foundation Statistics Database. BHF, 1996:21-2.

2. Wingard DL, Suarez L, Barrett-Connor E. The sex differential in mortality from all causes and ischaemic heart disease. Am J Epidemiol 1983; 117(2): 165-72.

3. Kannel WB, Hjortland MC, McNamara PM, Gordon T. Menopause and the risk of cardiovascular disease. The Framingham Study. Ann Intern Med 1976; 85:447-52. 4. Colditz CA, Willett MD, Stampfer MJ, Rosner B, Speizer FE,

Hennekens CH. Menopause and the risk of coronary heart disease in women. N EnglJMed 1987; 316(18):1105-10. 5. Stampfer MJ, Colditz CA, Willett WC, Manson JE, Rosner B,

Speizer FE, et al. Postmenopausal estrogen therapy and cardiovascular disease. N EnglJ Med 1991; 325:756-62. 6. Conway CS, Agrawal R, Betteridge DJ, Jacobs HS. Risk

factors for coronary artery disease in lean and obese women with the polycystic ovary syndrome. Clin Endocrinol 1992; 37:119-25.

7. La Vecchia C, Decarli A, Franceschi S, Gentile A, Negri E, Parazzini F. Menstrual and reproductive factors and the risk of myocardial infarction in women under fifty-five years of age. Am) Obstet Gynaecol 1987; 157:1108-12.

8. Luria MH, Johnson MW, Pego R, Seuc CA, Manubens SJ, Wieland MR. Relationship between sex hormones, myocardial infarction and occlusive coronary disease. Ann Intern Med 1982; 142:42-4.

9. Gardner AM, Setakis N. Carcinoma of the prostate.

Increased mortality and cardiovascular complications associated with oestrogen therapy as compared with orchidectomy. Bristol Medico-Chirurgical J 1983; 98:117-19.

10. Coronary Drug Project Research Group(1970). Initial findings leading to a modification of its research protocol.

1970; 214:1303-5.

11. Simon D, Charles MA, Nahoul K, Orssaud G, Kremski J, Hully V, et al. Association between plasma total

testosterone and cardiovascular risk factors in healthy adult men: The Telecom Study. J Clin Endocrinol Metab 1997; 82(2):682-5.

12. Barrett-Connor E. Lower endogenous androgen levels and dyslipidaemia in men with NIDDM. Ann Intern Med 1992; 117:807-11.

13. Mendoza S, Osuna A, Zerpa A. Hypertriglyceridaemia and hypoalphalipoproteinaemia in oligospermic and

azoospermic young men; Relationships of endogenous testosterone to triglyceride and HDL cholesterol metabolism. Metabolism 1981; 30(5):481-6.

14. Dai WS, Gutai JP, Kuller LH. Relation Between plasma HDL cholesterol and sex hormone concentrations in men. Am J Cardiol 1984; 53:1259-63.

15. Heller R, Wheeler MJ, Micallef J. Relationship of HDL cholesterol with total and free testosterone and SHBG. Acta Endocrinologica 1983; 194:253-6.

16. Berglund L, Carlstrom K, Stege R, Gottlieb C, Eriksson M, Angelin B, era/. Hormonal regulation of serum lipoprotein a levels: Effects of parenteral administration of estrogen or testosterone in males. J Clin Endocrinol Metab 1996; 81(7):2633-7.

17. Zmuda JM, Thompson PD, Dickenson R, Bausserman LL. Testosterone decreases lipoprotein a in men. Am J Cardiol 1996; 77:1244-7.

18. Bagatell CJ, Knopp RH, Vale WW, Rivier JE,

Bremner WJ. Physiological testosterone levels in normal men suppress HDL cholesterol levels. Ann Intern Mec/1992; 116(12.1):967-73.

19. Sorva R, Kuusi T, Taskinen MR, Perheentupa J, Nikkila EA. Testosterone substitution increases the activity of lipoprotein lipase and hepatic lipase in hypogonadal males.

Atherosclerosis 1988; 69:191 - 7 .

20. Goldberg RB, Rabin D, Alexander AN, Doelle GC, Getz GS. Suppression of plasma testosterone leads to an increase in serum total and high density lipoprotein cholesterol and apoproteins A1 and B. J Clin Endoc and Metab 1985; 60(1):203-7.

21. Phillips GB, Jing TY, Resnick LM, Barbagallo M, Laragh JH, Sealey JE. Sex hormones and haemostatic risk factors for coronary heart disease in men with hypertension. J Hypertens 1993; 11:699-702.

22. Phillips GB, Jing TY, Laragh JH, Sealey JE. Serum sex hormone levels and renin-sodium profile in men with hypertension. Am J Hypertens 1995; 8(6):626-9.

23. Ducimetiere p, Eschwege E, Papoz L, Richard JL, Claude JR, Rosselin G. Relationship of plasma insulin levels to the incidence of myocardial infarction and coronary heart disease mortality in a middle aged population. Diabetologia 1980; 19:205-10.

24. Haffner SM, Karhapaa P, Mykkanen L, Laakso M. Insulin resistance, body fat distribution and sex hormones in men. Diabetes 1994; 43:212-19.

25. Marin P, Holmang S, Jonsson L, Sjostrom L, Kvist H, Holm G, ef al. The effects of testosterone on body composition

(5)

Testosterone and CHD

791

and metabolism in middle aged men. IntJ Obes Relat Metab Disord 1992; 16:991-7.

26. Zumoff B, Strain GS, Miller LK, Rosner W, Senie R, Seres S, Rosenfeld RS. Plasma free and non-sex-hormone-binding-globulin-bound testosterone are decreased in obese men in proportion to their degree of obesity. J Clin Endocrinol Metab 1990; 71:929-31.

27. Klaiber EL, Broverman DM, Dalen JE. Serum estradiol levels in male cigarette smokers. AmJ Med 1984; 77:858-62. 28. Yardimci S, Atan A, Delibasi T, Sunguroglus K, Cuven MC.

Long-term effects of cigarette smoke exposure on plasma testosterone, luteinizing hormone and follicle stimulating hormone levels in male rats. BrJ Urol 1997; 79:66-9. 29. Anderson AN, Semczuk M, Tabor A. Prolactin and

pituitary-gonadal function in cigarette smoking infertile patients. Andrologia 1984; 16:391-6.

30. Vermeulen A, Kaufman JM, Ciagulli VA. Influence of some biological indexes on sex hormone binding globulin and androgen levels in ageing or obese males. J Clin Endocrinol /Vfefab1996;81(5):1821-6.

31. Field AE, Colditz CA, Willett WC, Longcope C, McKinley JB. The relation of smoking, age relative weight and dietary intake to serum adrenal steroids, sex hormones, and sex hormone binding globulin in middle-aged men. J Clin Endocrinol Metab 1994; 79(5):1310-16.

32. Meade TW, Ruddock V, Stirling Y, Chakrabarti R, Miller GJ. Fibrinolytic activity, clotting factors, and long term incidence of ischaemic heart disease in the Northwick Park Heart Study. Lancet 1993; 342:1076-9.

33. Meade TW. Fibrinogen in ischaemic heart disease. Eur Heart J 1995; 16(supplement A):31-5.

34. Glueck CJ, Glueck HI, Stroop D, Spiers J, Hamer T, Tracy T. Endogenous testosterone, fibrinolysis, and coronary heart disease risk in hyperlipidaemic men. J Lab Clin Med 1993; 122:412-20.

35. Caron P, Benet A, Camare R, LouvetJP. Plasminogen activator inhibitor in plasma is related to testosterone in men. Metabolism 1988; 38(10):! 010-15.

36. Bonithon-Kopp C, Scarabin PY, Bara L. Relationship between sex hormones and haemostatic factors in healthy middle-aged men. Atherosclerosis 1988; 71:71-6. 37. Anderson RA, Ludlam CA, Wu FC. Haemostatic effects of

supraphysiological levels of testosterone in normal men. Thromb Haemostas 1995; 74(2):693-7.

38. Simon D, Preziosi P, Barrett-Connor E, Roger M, Sait-Paul M, Nahoul K, Papoz L. The influence of ageing on plasma sex hormones in men. The Telecom Study. Am J Epidemiol 1992; 135(7)783-91.

39. Barth JD, Jansen H, Hugenholtz PG, Birkenhager JC. Postheparin lipases, lipids and related hormones in men

undergoing arteriography to assess atherosclerosis. Atherosclerosis 1983; 48:235-41.

40. Chute CG, Baron JA, Plymate SR, Kiel DP, Pavia AT, Lozner EC, etal. Sex hormones and coronary artery disease. Am J Med 1987; 83:853-9.

41. Phillips GB, Pinkernell BH, Jing TY. The association of hypotestosteronaemia with coronary artery disease in men. Arterioscler Thromb Vase Biol 1994; 14(5):701-6. 42. Aksut SV, Aksut G, Karamehmetoglu A, Oram E. The

determination of serum estradiol, testosterone and progesterone in acute myocardial infarction. Jpn Heart 71986; 27:825-37.

43. Kahl Von PE, Lampe D, Schollberg K, Lachman I, Mai I. Serum estradiol levels in the post acute phase of myocardial infarction. Deutsche Gesundh-Wesen 1979; 34:1 784-8. 44. Heller RF, Jacobs HS, Vermeulen A, Deslypere JP.

Androgens, oestrogens and coronary heart disease. Br Med 71981; 282:438-9.

45. Franzen J, Fex G. Low serum apolipoprotein A-1 in acute myocardial infarction survivors with normal HDL cholesterol. Atherosclerosis 1986; 59:37-42.

46. Small M, Lowe GDO, Beastall GH, Beattie JM, McEachern M, Hutton I, etal. Serum oestradiol and ischaemic heart disease—Relationship with myocardial infarction but not coronary atheroma or haemostasis. QJ Med 1985; 57(223)775-82.

47. Luria MH, Johnson MW, Pego R, Seuc CA, Manubens SJ, Wieland MR, Wieland RG. Relationship between sex hormones, myocardial infarction, and occlusive coronary disease. Arch Intern Med 1982; 142:42-4.

48. Wang C, Chan V, Tse TF, Yeung RT. Effect of acute myocardial infarction on pituitary-testicular function. Clin Endocrinol 1978; 9:249-53.

49. Woolf PD, Hamill RW, McDonald JV, Lee LA, Kelly M. Transient hypogonadotrophic hypogonadism caused by critical illness. J Clin Endocrinol Metab 1985; 60:444-50. 50. Jeppeson LL, Jorgensen HS, Nakayama H, Raaschou HO,

Olsen TS, Winther K. Decreased testosterone in men with acute ischaemic stroke. Arterioscler Thromb Vase Biol 1996; 16(6)749-54.

51. Barrett-Connor E, Khaw KT. Endogenous sex hormones and cardiovascular disease in men. A prospective population based study. Circulation. 1988; 78:539-45.

52. Cauley JA, Gutai JP, Kuller LH, Dai WS. Usefulness of sex steroid hormone levels in predicting coronary artery disease in men. Am J Carc//o/1987; 60771-7.

53. Yarnell JW, Beswick AD, Sweetnam PM, Riad-Fahmy D. Endogenous sex hormones and ischaemic heart disease in men. The Caerphilly Heart Study. Arterioscler Thromb Vase Biol 1993; 13(4):517-20.