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Cardiovascular Disease and Men's Health
CHAPTER 2.4
Cardiovascular Disease and Men’s Health € ˙Iyimser Ure*, John M. Masterson†, Ranjith Ramasamy† *
Eskis¸ehir Osmangazi University, Faculty of Medicine, Department of Urology, Eskis¸ehir, Turkey, † University of Miami, Miller School of Medicine, Department of Urology, Miami, FL, United States
CARDIOVASCULAR DISEASE AND ERECTILE DYSFUNCTION Erectile dysfunction (ED) is defined as inability to achieve adequate penile erection or to maintain an erection for satisfactory sexual performance. The incidence of ED increases with age with more than half of the over 70 population affected [1]. Many chronic diseases associated with advanced age are considered risk factors for ED. Hypertension, diabetes, and dyslipidemia have been found to be highly linked with ED [2]. Additionally, a strong correlation has been demonstrated between modifiable risk factors such as obesity and smoking and ED. In light of all these data, ED is thought to be a precursor and possibly predictor of systemic disease. Other chronic diseases may arise after some time in men who present with ED [3].
Pathophysiology Normal erection physiology depends on the interactions between vascular, hormonal, neurological, and psychological factors. For an erection to be suitable for sexual intercourse, there must be adequate arterial blood flow. This blood must then be trapped in penile structures and must not be able to leak back [4]. Thus, any problem affecting penile blood flow will disrupt erectile function. The mechanism of blood flow disruption in cardiovascular disease (CVD) is endothelial dysfunction. It is endothelial dysfunction that establishes the link between CVD and ED. According to results from the Massachusetts Male Aging Study, erectile dysfunction is more prevalent in men with CVD, regardless of age, than in men without CVD [5]. The first step in the formation of atherosclerotic plaques in CVD is endothelial dysfunction [6]. Endothelial dysfunction leads to disruption of Effects of Lifestyle on Men’s Health. https://doi.org/10.1016/B978-0-12-816665-9.00008-1 © 2019 Elsevier Inc. All rights reserved.
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nitric oxide (NO) production and increased permeability to cellular components such as low-density lipoproteins (LDL). As a result, free oxygen radicals and oxidative stress cause endothelial damage, and the clinical manifestations of CVD begin to emerge [7, 8]. Erectile dysfunction is associated with increased inflammatory and endothelial prothrombotic activation in the penile vasculature. Interestingly, this activation closely resembles the processes occurring in the coronary arteries of patients with CAD and no ED. Atherosclerotic plaque burden is greatest in patients with both CAD and ED [9]. The arterial structure of the penis is narrower than the coronary vascular structures. Additionally, penile endothelium and smooth muscle tissue are very sensitive to functional and structural changes. For this reason, plaques occurring in the penile arteries may result in earlier clinical findings than the same amount of plaque in the coronary arteries. Therefore, erectile dysfunction is more likely to occur before clinical entities like CAD, transient ischemic attack, or stroke [10]. This allows ED to be used as a marker of cardiovascular disease [11]. Vasculogenic ED can be considered an early manifestation of CVD. However, the presence of different factors in the etiology of ED may limit this relationship [12].
ED as a Predictor of CVD It has long been debated whether or not ED can predict CVD. The prevalence of ED in CVD patients was previously evaluated by many studies. As a result, ED was found to be more prevalent patients with CVD [13, 14]. In one of the first comprehensive studies, it was determined that 50% of patients with ED had comorbid CVD as proved by coronary angiography [15]. Of the CVD patients in this study, 70% had ED for more than 3 years. This study is one of the first to suggest that ED can be used as a marker for CVD that will occur later in life. In the Prostate Cancer Prevention Trial study of men aged 55 years and older, compelling data have been demonstrated regarding the association of ED and subsequent cardiovascular events [16]. This study primarily investigates whether finasteride can reduce the prevalence of prostate cancer. In order to assess the possible sexual side effects of finasteride, the prevalence of ED was measured in the subjects. In order to assess one of the possible side effects of the drug, prevalence of CVD was measured at baseline, and incidence of CVD was followed throughout the study period. The authors have detected that in men with ED, the risk of a cardiovascular incident is 45% greater than those without ED. Prostate Cancer Prevention Trial concluded that newly diagnosed ED is a risk factor for CVD on par with risk factors such as family history of myocardial infarction (MI) and medical history of smoking or hyperlipidemia. This study is considered a landmark study in establishing that ED is a marker for CVD and cardiovascular evaluation should be performed in patients presenting with ED.
Sexual Health in CVD Patients
Further studies have shown that ED is a precursor not only to CVD but also to many cardiovascular atherosclerotic diseases. ED has also been associated with coronary artery calcification, which is an important marker of coronary artery disease [17]. Additionally, the occurrence of ED at a younger age, smoking, the presence of other comorbidities, and poor socioeconomic status pose risks for possible atherosclerotic cardiovascular events [18]. In the Cost and Outcome of Behavioural Activation (COBRA) study investigating the relationship between ED and coronary artery disease, it is stated that the prevalence of ED differs according to the clinical presentation of coronary artery disease and the number of vessels involved [19]. In this study, the clinical presentation of coronary artery disease was classified as acute or chronic coronary artery syndrome. Overall prevalence of ED was found to be 47% in patients with coronary artery disease of any kind, as opposed to 24% for patients with normal coronary angiography. The rate of ED in patients with single-vessel acute coronary artery syndrome is 22%. Prevalence of ED increases to 55% in patients with multivessel acute coronary syndrome. This rate was found to be 65% in patients with chronic coronary syndrome. Men with severe coronary artery involvement as assessed by coronary angiography were more likely to have severe ED (International Index for Erectile Dysfunction (IEF) <10) or ED lasting greater than 24 months. The findings of this study show that systemic atherosclerosis significantly affects penile arterial structures and leads to higher ED rates. Not only are patients with ED at risk for coronary artery disease, but also there is evidence to suggest that ED is also a risk factor for all-cause death [9]. However, there are studies that do not accept ED as an independent factor in deaths due to coronary heart disease. The Vitamins and Lifestyle (VITAL) study included over 30,000 men over 50 years of age [20]. The authors reported that, when adjusting for age, marital status, and education, men with ED had a 23% increased risk of cardiovascular death (hazard ratio (HR) 1.23 and 95% confidence interval (CI) 1.01 and 1.49). When adjusted for known risk factors (diabetes, treatment for hypertension or hyperlipidemia, family history of MI, stroke, elevated body mass index, and exercise), ED no longer predicted cardiovascular death (HR 0.93 and 95% CI 0.76 and 1.15). These data serve to further obviate the fact that ED can be used as a reliable marker for systemic vascular diseases, considering the relationship with different vascular diseases such as cerebrovascular events and peripheral artery disease. Therefore, patients with ED should be investigated for possible underlying CVD [21].
SEXUAL HEALTH IN CVD PATIENTS During sexual intercourse, many physiological and physical changes occur in the human body. Most of these changes are cardiovascular and endocrine processes.
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Cardiovascular changes and the risks of these changes have been attractive research topics for some time. During foreplay, the blood pressure rises slightly, and the pulse rate increases. The pulse rate is usually below 130 bpm, and systolic blood pressure remains below 170 mmHg [22]. During orgasm, these values reach the highest point and then descend to within normal range values after orgasm. These changes occur similarly in both men and women [23, 24]. Experiments have demonstrated that the amount of oxygen required for myocardium during sexual intercourse is equivalent to the amount of oxygen needed to climb the stairs for two flights of stairs [25]. However, since the studies that determine these data are generally done on young and healthy population, it is difficult to obtain similar findings in elderly and unhealthy populations. People with erectile problems or people who have a sexual desire problem for any reason may need more effort to reach orgasm, which means an increase in cardiovascular burden. The same can be said for older individuals, regardless of their health status [26]. Increased cardiovascular burden during sexual activity is the result of metabolic response to sexual stimulation rather than physical effort itself. It has been determined that the energy spent during different sexual activities did not differ according to the type of sexual activity [27]. Cardiovascular events that occur during sexual activity may be due to overactivation of the sympathetic system, and those who live sedentary lives at baseline are at increased risk. For individuals with atherosclerotic coronary disease, sexual activity should be considered heavy exercise, carrying with it some risk of acute MI [28]. According to a metaanalysis on this point, sexual activity was found to increase the risk of MI (RR ¼ 2.70; 95% CI 1.48–4.91) [29]. The risk of acute MI during sexual activity is reduced by having intercourse in a familiar environment, monogamy, no excessive eating before intercourse, and no prior alcohol intake. [30]. Sudden cardiac death rates due to sexual intercourse are low as reported in the literature. In one of the most extensive studies on this subject, only 68 deaths were detected in Berlin between 1972 and 2004 [31]. Of these 68 deaths, 92.6% were male. The most common cause of death was acute MI; 20 of these patients had coronary artery disease with no history of MI. In a similar study conducted in Korea, it was found that only 14 sudden cardiac deaths occurred during sexual intercourse in over a 4-year period [32]. Nine of these 14 people were men. Another issue related to sexual activity in CVD patients is ED after acute MI. Studies have shown that erectile function is adversely affected in patients following acute MI. It should be noted; however, there is no definitive information about the mechanism of this pathological change [33]. Interestingly, the majority of patients with ED after MI do not have any sexual dysfunction prior to their MI.
Sexual Health in CVD Patients
The likely mechanism responsible for ED after acute cardiac event is the progression of existing atherosclerotic disease in the cavernosal artery [34]. According to the Thompson study, 55% of 152 patients who experienced a vascular incident (acute MI, angina, stroke, TIA, chronic heart failure, and arrhythmia) with no prior ED developed ED after their vascular incident [16]. There are insufficient data to suggest whether the cause of ED in these patients is psychological, physiological, or medication side effect. If the development of ED is truly due to advancing atherosclerotic changes already present in the cavernosal arteries, it should be kept in mind that coronary artery disease may progress and new vascular events may occur.
CVD Drugs and ED While ED is common in men with CVD, a potentially confounding factor is that many CVD medications can cause ED as a side effect. One of the most frequently mentioned drug classes on this subject are betablockers. Studies have shown that beta-blockers can lead to reduced sexual desire and ED [35]. In the most comprehensive study on this topic, 35,000 patients were evaluated, and it was reported that ED may develop with betablocker use [36]. Within this group of drugs, nebivolol stands out as an exception. Some studies have shown that nebivolol may preserve erectile function due to its effect on nitric oxide, thereby promoting vasodilation [37]. There are also data to suggest that erectile function may be improved by switching to nebivolol from atenolol, metoprolol, or bisoprolol [38]. Unfortunately, information on the mechanism by which beta-blockers cause ED is limited. It is speculated that beta-blockade leads to low perfusion pressure on penis and smooth muscle cells secondary to the alpha receptor stimulatory effect of the drug [39]. An associated decrease in testosterone level due to the suppression of Leydig cell activity may be the source of beta-blocker use leading to reduced sexual desire [40]. Another group of drugs that may have a negative impact on erectile function is thiazide diuretics. In a study investigating the treatment of mild hypertension, different patient groups were administered placebo, beta-blocker, calcium channel blocker, thiazide diuretic, alpha-adrenergic blocker, and angiotensin-converting enzyme (ACE) inhibitor [41]. Although all treatment agents were used at low doses, ED was more common in the diuretic group. No difference was observed between the other agents and placebo in terms of causing ED. It has not yet been elucidated how thiazide diuretics affect erectile function. It is possible that these drugs lead to contraction of penile vascular smooth muscle cells or that thiazides impact the catecholamine synthesis pathway [42].
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Other agents used in the treatment of hypertension are calcium channel blockers, aldosterone receptor antagonists, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers (ARB). There are insufficient data in the current literature to show that these drug groups have negative effects on sexual function. In fact, there are studies to suggest that calcium channel blockers, ACE inhibitors, and ARBs do not adversely impact erectile function and may even show some beneficial effects [43–45].
HYPOGONADISM AND CVD Historically, androgens were thought to increase the risk of cardiovascular disease. Studies investigating the risk of cardiovascular events of athletes and body builders with excessive exogenous testosterone use supported this view [46]. However, currently, testosterone is considered to have a protective role against cardiometabolic diseases. Low testosterone can lead to increased body fat content and increase the risk of obesity [47]. In fact, the relationship between testosterone and fat can be considered bidirectional in that increased aromatization activity in people with a larger waist circumference decreases testosterone levels [48]. Low testosterone is also associated with the development of impaired glucose tolerance and metabolic syndrome in men. Considering the absence of a protective effect of estrogen, it is reasonable to conclude that the risk of CVD will increase in such patients [47]. In most men, serum testosterone levels decrease with age. In a meta-analysis of 70 studies, it was found that testosterone levels were lower in men with a history of CVD than in the other subjects [49]. This study showed that baseline testosterone levels were lower in patients who died from cardiovascular causes. It has also been reported that testosterone replacement therapy (TRT) improves cardiac stress tests and prolongs the time to 1 mm ST segment depression. There are, however, conflicting results in the literature about the effect of TRT on this issue. Prior meta-analyses have reported that TRT has no effect on the risk of cardiovascular events [50]. In men with high serum testosterone and free testosterone levels, the risk of abdominal aortic atherosclerosis is found to be lower than in men with lower levels of testosterone [51]. In men with heart failure, total and free testosterone levels may be lower compared with healthy individuals. There are also data to suggest that the prevalence of hypogonadism in these men is more than 40% [50]. While testosterone has historically been thought to increase the risk of CVD, the amount of evidence to suggest that testosterone, like estrogen, has a protective
References
role against CVD is rapidly growing. Another important question requiring investigation is, does low testosterone increase the risk of CVD or does the development of CVD lead to low testosterone?
References [1] Gandaglia G, Briganti A, Jackson G, Kloner RA, Montorsi F, Montorsi P, et al. A systematic review of the association between erectile dysfunction and cardiovascular disease. Eur Urol 2014;65(5):968–78. [2] Fung MM, Bettencourt R, Barrett-Connor E. Heart disease risk factors predict erectile dysfunction 25 years later: the Rancho Bernardo Study. J Am Coll Cardiol 2004;43(8):1405–11. [3] Montorsi P, Ravagnani PM, Galli S, Salonia A, Briganti A, Werba JP, et al. Association between erectile dysfunction and coronary artery disease: matching the right target with the right test in the right patient. Eur Urol 2006;50(4):721–31. [4] Shin D, Pregenzer G, Gardin JM. Erectile dysfunction: a disease marker for cardiovascular disease. Cardiol Rev 2011;19(1):5–11. [5] Feldman HA, Johannes CB, Derby CA, Kleinman KP, Mohr BA, Araujo AB, et al. Erectile dysfunction and coronary risk factors: prospective results from the Massachusetts male aging study. Prev Med 2000;30(4):328–38. [6] Cooke JP. The endothelium: a new target for therapy. Vasc Med Lond Engl 2000;5(1):49–53. [7] Jeremy JY, Angelini GD, Khan M, Mikhailidis DP, Morgan RJ, Thompson CS, et al. Platelets, oxidant stress and erectile dysfunction: an hypothesis. Cardiovasc Res 2000;46(1):50–4. [8] Guay AT. ED2: erectile dysfunction ¼ endothelial dysfunction. Endocrinol Metab Clin N Am 2007;36(2):453–63. [9] Vlachopoulos C, Jackson G, Stefanadis C, Montorsi P. Erectile dysfunction in the cardiovascular patient. Eur Heart J 2013;34(27):2034–46. [10] Montorsi P, Montorsi F, Schulman CC. Is erectile dysfunction the “tip of the iceberg” of a systemic vascular disorder? Eur Urol 2003;44(3):352–4. [11] Katsiki N, Wierzbicki AS, Mikhailidis DP. Erectile dysfunction and coronary heart disease. Curr Opin Cardiol 2015;30(4):416–21. [12] Jain A, Harvey D, Robertson L, Mikhailidis DP, Nair DR. Gender-based cardiometabolic risk evaluation in minority and non-minority men grading the evidence of non-traditional determinants of cardiovascular risk. Int J Clin Pract 2011;65(6):715–6. [13] Jackson G. Erectile dysfunction and cardiovascular disease. Int J Clin Pract 1999;53(5):363–8. [14] O’Kane PD, Jackson G. Erectile dysfunction: is there silent obstructive coronary artery disease? Int J Clin Pract 2001;55(3):219–20. [15] Montorsi F, Briganti A, Salonia A, Rigatti P, Margonato A, Macchi A, et al. Erectile dysfunction prevalence, time of onset and association with risk factors in 300 consecutive patients with acute chest pain and angiographically documented coronary artery disease. Eur Urol 2003;44(3):360–5. [16] Thompson IM, Tangen CM, Goodman PJ, Probstfield JL, Moinpour CM, Coltman CA. Erectile dysfunction and subsequent cardiovascular disease. JAMA 2005;294(23):2996–3002. [17] Lee JH, Ngengwe R, Jones P, Tang F, O’Keefe JH. Erectile dysfunction as a coronary artery disease risk equivalent. J Nucl Cardiol Off Publ Am Soc Nucl Cardiol 2008;15(6):800–3. [18] Chew K-K, Finn J, Stuckey B, Gibson N, Sanfilippo F, Bremner A, et al. Erectile dysfunction as a predictor for subsequent atherosclerotic cardiovascular events: findings from a linked-data study. J Sex Med 2010;7(1 Pt 1):192–202.
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[19] Montorsi P, Ravagnani PM, Galli S, Rotatori F, Veglia F, Briganti A, et al. Association between erectile dysfunction and coronary artery disease. Role of coronary clinical presentation and extent of coronary vessels involvement: the COBRA trial. Eur Heart J 2006;27(22):2632–9. [20] Hotaling JM, Walsh TJ, Macleod LC, Heckbert S, Pocobelli G, Wessells H, et al. Erectile dysfunction is not independently associated with cardiovascular death: data from the vitamins and lifestyle (VITAL) study. J Sex Med 2012;9(8):2104–10. [21] Polonsky TS, Taillon LA, Sheth H, Min JK, Archer SL, Ward RP. The association between erectile dysfunction and peripheral arterial disease as determined by screening ankle-brachial index testing. Atherosclerosis 2009;207(2):440–4. [22] Levine GN, Steinke EE, Bakaeen FG, Bozkurt B, Cheitlin MD, Conti JB, et al. Sexual activity and cardiovascular disease: a scientific statement from the American Heart Association. Circulation 2012;125(8):1058–72. [23] Exton NG, Truong TC, Exton MS, Wingenfeld SA, Leygraf N, Saller B, et al. Neuroendocrine response to film-induced sexual arousal in men and women. Psychoneuroendocrinology 2000;25(2):187–99. [24] Holloway IW. Substance use homophily among geosocial networking application using gay, bisexual, and other men who have sex with men. Arch Sex Behav 2015;44(7):1799–811. [25] Bohlen JG, Held JP, Sanderson MO, Patterson RP. Heart rate, rate-pressure product, and oxygen uptake during four sexual activities. Arch Intern Med 1984;144(9):1745–8. [26] Lindau ST, Schumm LP, Laumann EO, Levinson W, O’Muircheartaigh CA, Waite LJ. A study of sexuality and health among older adults in the United States. N Engl J Med 2007;357 (8):762–74. [27] Bispo GS, de Lima Lopes J, de Barros ALBL. Cardiovascular changes resulting from sexual activity and sexual dysfunction after myocardial infarction: integrative review. J Clin Nurs 2013;22 (23–24):3522–31. [28] Stein RA. Cardiovascular response to sexual activity. Am J Cardiol 2000;86(2A):27F–9F. [29] Dahabreh IJ, Paulus JK. Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis. JAMA 2011;305(12):1225–33. [30] DeBusk R, Drory Y, Goldstein I, Jackson G, Kaul S, Kimmel SE, et al. Management of sexual dysfunction in patients with cardiovascular disease: recommendations of The Princeton Consensus Panel. Am J Cardiol 2000;86(2):175–81. [31] Parzeller M, Bux R, Raschka C, Bratzke H. Sudden cardiovascular death associated with sexual activity: a forensic autopsy study (1972-2004). Forensic Sci Med Pathol 2006;2(2):109–14. [32] Lee S, Chae J, Cho Y. Causes of sudden death related to sexual activity: results of a medicolegal postmortem study from 2001 to 2005. J Korean Med Sci 2006;21(6):995–9. [33] Hardin SR. Cardiac disease and sexuality: implications for research and practice. Nurs Clin North Am 2007;42(4):593–603. vii. [34] Montorsi P, Ravagnani PM, Vlachopoulos C. Clinical significance of erectile dysfunction developing after acute coronary event: exception to the rule or confirmation of the artery size hypothesis? Asian J Androl 2015;17(1):21–5. [35] Baumh€akel M, Schlimmer N, Kratz M, Hackett G, Hacket G, Jackson G, et al. Cardiovascular risk, drugs and erectile function–a systematic analysis. Int J Clin Pract 2011;65(3):289–98. [36] Ko DT, Hebert PR, Coffey CS, Sedrakyan A, Curtis JP, Krumholz HM. Beta-blocker therapy and symptoms of depression, fatigue, and sexual dysfunction. JAMA 2002;288(3):351–7. [37] Brixius K, Middeke M, Lichtenthal A, Jahn E, Schwinger RHG. Nitric oxide, erectile dysfunction and beta-blocker treatment (MR NOED study): benefit of nebivolol versus metoprolol in hypertensive men. Clin Exp Pharmacol Physiol 2007;34(4):327–31.
References
[38] Doumas M, Tsakiris A, Douma S, Grigorakis A, Papadopoulos A, Hounta A, et al. Beneficial effects of switching from beta-blockers to nebivolol on the erectile function of hypertensive patients. Asian J Androl 2006;8(2):177–82. [39] Shiri R, Koskim€aki J, H€akkinen J, Auvinen A, Tammela TLJ, Hakama M. Cardiovascular drug use and the incidence of erectile dysfunction. Int J Impot Res 2007;19(2):208–12. [40] Boydak B, Nalbantgil S, Fici F, Nalbantgil I, Zoghi M, Ozerkan F, et al. A randomised comparison of the effects of nebivolol and atenolol with and without chlorthalidone on the sexual function of hypertensive men. Clin Drug Investig 2005;25(6):409–16. [41] Grimm RH, Grandits GA, Prineas RJ, McDonald RH, Lewis CE, Flack JM, et al. Long-term effects on sexual function of five antihypertensive drugs and nutritional hygienic treatment in hypertensive men and women Treatment of Mild Hypertension Study (TOMHS). Hypertension 1997;29(1 Pt 1):8–14. [42] Chrysant SG. Antihypertensive therapy causes erectile dysfunction. Curr Opin Cardiol 2015;30(4):383–90. [43] Omvik P, Thaulow E, Herland OB, Eide I, Midha R, Turner RR. Double-blind, parallel, comparative study on quality of life during treatment with amlodipine or enalapril in mild or moderate hypertensive patients: a multicentre study. J Hypertens 1993;11(1):103–13. [44] Speel TGW, Kiemeney LA, Thien T, Smits P, Meuleman EJ. Long-term effect of inhibition of the angiotensin-converting enzyme (ACE) on cavernosal perfusion in men with atherosclerotic erectile dysfunction: a pilot study. J Sex Med 2005;2(2):207–12. [45] B€ ohm M, Baumh€akel M, Teo K, Sleight P, Probstfield J, Gao P, et al. Erectile dysfunction predicts cardiovascular events in high-risk patients receiving telmisartan, ramipril, or both: the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial/Telmisartan Randomized AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (ONTARGET/TRANSCEND) Trials. Circulation 2010;121(12):1439–46. [46] Cheever K, House MA. Cardiovascular implications of anabolic steroid abuse. J Cardiovasc Nurs 1992;6(2):19–30. [47] Cattabiani C, Basaria S, Ceda GP, Luci M, Vignali A, Lauretani F, et al. Relationship between testosterone deficiency and cardiovascular risk and mortality in adult men. J Endocrinol Investig 2012;35(1):104–20. [48] Snyder PJ. Decreasing testosterone with increasing age: more factors, more questions. J Clin Endocrinol Metab 2008;93(7):2477–8. [49] 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 (5):687–701. [50] Corona G, Rastrelli G, Vignozzi L, Mannucci E, Maggi M. Testosterone, cardiovascular disease and the metabolic syndrome. Best Pract Res Clin Endocrinol Metab 2011;25(2):337–53. [51] Hak AE, Witteman JCM, de Jong FH, Geerlings MI, Hofman A, Pols HAP. Low levels of endogenous androgens increase the risk of atherosclerosis in elderly men: the Rotterdam study. J Clin Endocrinol Metab 2002;87(8):3632–9.
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Cardiovascular Disease and Men’s Health € ˙Iyimser Ure*, John M. Masterson†, Ranjith Ramasamy† *
Eskis¸ehir Osmangazi University, Faculty of Medicine, Department of Urology, Eskis¸ehir, Turkey, † University of Miami, Miller School of Medicine, Department of Urology, Miami, FL, United States
CARDIOVASCULAR DISEASE AND ERECTILE DYSFUNCTION Erectile dysfunction (ED) is defined as inability to achieve adequate penile erection or to maintain an erection for satisfactory sexual performance. The incidence of ED increases with age with more than half of the over 70 population affected [1]. Many chronic diseases associated with advanced age are considered risk factors for ED. Hypertension, diabetes, and dyslipidemia have been found to be highly linked with ED [2]. Additionally, a strong correlation has been demonstrated between modifiable risk factors such as obesity and smoking and ED. In light of all these data, ED is thought to be a precursor and possibly predictor of systemic disease. Other chronic diseases may arise after some time in men who present with ED [3].
Pathophysiology Normal erection physiology depends on the interactions between vascular, hormonal, neurological, and psychological factors. For an erection to be suitable for sexual intercourse, there must be adequate arterial blood flow. This blood must then be trapped in penile structures and must not be able to leak back [4]. Thus, any problem affecting penile blood flow will disrupt erectile function. The mechanism of blood flow disruption in cardiovascular disease (CVD) is endothelial dysfunction. It is endothelial dysfunction that establishes the link between CVD and ED. According to results from the Massachusetts Male Aging Study, erectile dysfunction is more prevalent in men with CVD, regardless of age, than in men without CVD [5]. The first step in the formation of atherosclerotic plaques in CVD is endothelial dysfunction [6]. Endothelial dysfunction leads to disruption of Effects of Lifestyle on Men’s Health. https://doi.org/10.1016/B978-0-12-816665-9.00008-1 © 2019 Elsevier Inc. All rights reserved.
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nitric oxide (NO) production and increased permeability to cellular components such as low-density lipoproteins (LDL). As a result, free oxygen radicals and oxidative stress cause endothelial damage, and the clinical manifestations of CVD begin to emerge [7, 8]. Erectile dysfunction is associated with increased inflammatory and endothelial prothrombotic activation in the penile vasculature. Interestingly, this activation closely resembles the processes occurring in the coronary arteries of patients with CAD and no ED. Atherosclerotic plaque burden is greatest in patients with both CAD and ED [9]. The arterial structure of the penis is narrower than the coronary vascular structures. Additionally, penile endothelium and smooth muscle tissue are very sensitive to functional and structural changes. For this reason, plaques occurring in the penile arteries may result in earlier clinical findings than the same amount of plaque in the coronary arteries. Therefore, erectile dysfunction is more likely to occur before clinical entities like CAD, transient ischemic attack, or stroke [10]. This allows ED to be used as a marker of cardiovascular disease [11]. Vasculogenic ED can be considered an early manifestation of CVD. However, the presence of different factors in the etiology of ED may limit this relationship [12].
ED as a Predictor of CVD It has long been debated whether or not ED can predict CVD. The prevalence of ED in CVD patients was previously evaluated by many studies. As a result, ED was found to be more prevalent patients with CVD [13, 14]. In one of the first comprehensive studies, it was determined that 50% of patients with ED had comorbid CVD as proved by coronary angiography [15]. Of the CVD patients in this study, 70% had ED for more than 3 years. This study is one of the first to suggest that ED can be used as a marker for CVD that will occur later in life. In the Prostate Cancer Prevention Trial study of men aged 55 years and older, compelling data have been demonstrated regarding the association of ED and subsequent cardiovascular events [16]. This study primarily investigates whether finasteride can reduce the prevalence of prostate cancer. In order to assess the possible sexual side effects of finasteride, the prevalence of ED was measured in the subjects. In order to assess one of the possible side effects of the drug, prevalence of CVD was measured at baseline, and incidence of CVD was followed throughout the study period. The authors have detected that in men with ED, the risk of a cardiovascular incident is 45% greater than those without ED. Prostate Cancer Prevention Trial concluded that newly diagnosed ED is a risk factor for CVD on par with risk factors such as family history of myocardial infarction (MI) and medical history of smoking or hyperlipidemia. This study is considered a landmark study in establishing that ED is a marker for CVD and cardiovascular evaluation should be performed in patients presenting with ED.
Sexual Health in CVD Patients
Further studies have shown that ED is a precursor not only to CVD but also to many cardiovascular atherosclerotic diseases. ED has also been associated with coronary artery calcification, which is an important marker of coronary artery disease [17]. Additionally, the occurrence of ED at a younger age, smoking, the presence of other comorbidities, and poor socioeconomic status pose risks for possible atherosclerotic cardiovascular events [18]. In the Cost and Outcome of Behavioural Activation (COBRA) study investigating the relationship between ED and coronary artery disease, it is stated that the prevalence of ED differs according to the clinical presentation of coronary artery disease and the number of vessels involved [19]. In this study, the clinical presentation of coronary artery disease was classified as acute or chronic coronary artery syndrome. Overall prevalence of ED was found to be 47% in patients with coronary artery disease of any kind, as opposed to 24% for patients with normal coronary angiography. The rate of ED in patients with single-vessel acute coronary artery syndrome is 22%. Prevalence of ED increases to 55% in patients with multivessel acute coronary syndrome. This rate was found to be 65% in patients with chronic coronary syndrome. Men with severe coronary artery involvement as assessed by coronary angiography were more likely to have severe ED (International Index for Erectile Dysfunction (IEF) <10) or ED lasting greater than 24 months. The findings of this study show that systemic atherosclerosis significantly affects penile arterial structures and leads to higher ED rates. Not only are patients with ED at risk for coronary artery disease, but also there is evidence to suggest that ED is also a risk factor for all-cause death [9]. However, there are studies that do not accept ED as an independent factor in deaths due to coronary heart disease. The Vitamins and Lifestyle (VITAL) study included over 30,000 men over 50 years of age [20]. The authors reported that, when adjusting for age, marital status, and education, men with ED had a 23% increased risk of cardiovascular death (hazard ratio (HR) 1.23 and 95% confidence interval (CI) 1.01 and 1.49). When adjusted for known risk factors (diabetes, treatment for hypertension or hyperlipidemia, family history of MI, stroke, elevated body mass index, and exercise), ED no longer predicted cardiovascular death (HR 0.93 and 95% CI 0.76 and 1.15). These data serve to further obviate the fact that ED can be used as a reliable marker for systemic vascular diseases, considering the relationship with different vascular diseases such as cerebrovascular events and peripheral artery disease. Therefore, patients with ED should be investigated for possible underlying CVD [21].
SEXUAL HEALTH IN CVD PATIENTS During sexual intercourse, many physiological and physical changes occur in the human body. Most of these changes are cardiovascular and endocrine processes.
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Cardiovascular changes and the risks of these changes have been attractive research topics for some time. During foreplay, the blood pressure rises slightly, and the pulse rate increases. The pulse rate is usually below 130 bpm, and systolic blood pressure remains below 170 mmHg [22]. During orgasm, these values reach the highest point and then descend to within normal range values after orgasm. These changes occur similarly in both men and women [23, 24]. Experiments have demonstrated that the amount of oxygen required for myocardium during sexual intercourse is equivalent to the amount of oxygen needed to climb the stairs for two flights of stairs [25]. However, since the studies that determine these data are generally done on young and healthy population, it is difficult to obtain similar findings in elderly and unhealthy populations. People with erectile problems or people who have a sexual desire problem for any reason may need more effort to reach orgasm, which means an increase in cardiovascular burden. The same can be said for older individuals, regardless of their health status [26]. Increased cardiovascular burden during sexual activity is the result of metabolic response to sexual stimulation rather than physical effort itself. It has been determined that the energy spent during different sexual activities did not differ according to the type of sexual activity [27]. Cardiovascular events that occur during sexual activity may be due to overactivation of the sympathetic system, and those who live sedentary lives at baseline are at increased risk. For individuals with atherosclerotic coronary disease, sexual activity should be considered heavy exercise, carrying with it some risk of acute MI [28]. According to a metaanalysis on this point, sexual activity was found to increase the risk of MI (RR ¼ 2.70; 95% CI 1.48–4.91) [29]. The risk of acute MI during sexual activity is reduced by having intercourse in a familiar environment, monogamy, no excessive eating before intercourse, and no prior alcohol intake. [30]. Sudden cardiac death rates due to sexual intercourse are low as reported in the literature. In one of the most extensive studies on this subject, only 68 deaths were detected in Berlin between 1972 and 2004 [31]. Of these 68 deaths, 92.6% were male. The most common cause of death was acute MI; 20 of these patients had coronary artery disease with no history of MI. In a similar study conducted in Korea, it was found that only 14 sudden cardiac deaths occurred during sexual intercourse in over a 4-year period [32]. Nine of these 14 people were men. Another issue related to sexual activity in CVD patients is ED after acute MI. Studies have shown that erectile function is adversely affected in patients following acute MI. It should be noted; however, there is no definitive information about the mechanism of this pathological change [33]. Interestingly, the majority of patients with ED after MI do not have any sexual dysfunction prior to their MI.
Sexual Health in CVD Patients
The likely mechanism responsible for ED after acute cardiac event is the progression of existing atherosclerotic disease in the cavernosal artery [34]. According to the Thompson study, 55% of 152 patients who experienced a vascular incident (acute MI, angina, stroke, TIA, chronic heart failure, and arrhythmia) with no prior ED developed ED after their vascular incident [16]. There are insufficient data to suggest whether the cause of ED in these patients is psychological, physiological, or medication side effect. If the development of ED is truly due to advancing atherosclerotic changes already present in the cavernosal arteries, it should be kept in mind that coronary artery disease may progress and new vascular events may occur.
CVD Drugs and ED While ED is common in men with CVD, a potentially confounding factor is that many CVD medications can cause ED as a side effect. One of the most frequently mentioned drug classes on this subject are betablockers. Studies have shown that beta-blockers can lead to reduced sexual desire and ED [35]. In the most comprehensive study on this topic, 35,000 patients were evaluated, and it was reported that ED may develop with betablocker use [36]. Within this group of drugs, nebivolol stands out as an exception. Some studies have shown that nebivolol may preserve erectile function due to its effect on nitric oxide, thereby promoting vasodilation [37]. There are also data to suggest that erectile function may be improved by switching to nebivolol from atenolol, metoprolol, or bisoprolol [38]. Unfortunately, information on the mechanism by which beta-blockers cause ED is limited. It is speculated that beta-blockade leads to low perfusion pressure on penis and smooth muscle cells secondary to the alpha receptor stimulatory effect of the drug [39]. An associated decrease in testosterone level due to the suppression of Leydig cell activity may be the source of beta-blocker use leading to reduced sexual desire [40]. Another group of drugs that may have a negative impact on erectile function is thiazide diuretics. In a study investigating the treatment of mild hypertension, different patient groups were administered placebo, beta-blocker, calcium channel blocker, thiazide diuretic, alpha-adrenergic blocker, and angiotensin-converting enzyme (ACE) inhibitor [41]. Although all treatment agents were used at low doses, ED was more common in the diuretic group. No difference was observed between the other agents and placebo in terms of causing ED. It has not yet been elucidated how thiazide diuretics affect erectile function. It is possible that these drugs lead to contraction of penile vascular smooth muscle cells or that thiazides impact the catecholamine synthesis pathway [42].
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Other agents used in the treatment of hypertension are calcium channel blockers, aldosterone receptor antagonists, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers (ARB). There are insufficient data in the current literature to show that these drug groups have negative effects on sexual function. In fact, there are studies to suggest that calcium channel blockers, ACE inhibitors, and ARBs do not adversely impact erectile function and may even show some beneficial effects [43–45].
HYPOGONADISM AND CVD Historically, androgens were thought to increase the risk of cardiovascular disease. Studies investigating the risk of cardiovascular events of athletes and body builders with excessive exogenous testosterone use supported this view [46]. However, currently, testosterone is considered to have a protective role against cardiometabolic diseases. Low testosterone can lead to increased body fat content and increase the risk of obesity [47]. In fact, the relationship between testosterone and fat can be considered bidirectional in that increased aromatization activity in people with a larger waist circumference decreases testosterone levels [48]. Low testosterone is also associated with the development of impaired glucose tolerance and metabolic syndrome in men. Considering the absence of a protective effect of estrogen, it is reasonable to conclude that the risk of CVD will increase in such patients [47]. In most men, serum testosterone levels decrease with age. In a meta-analysis of 70 studies, it was found that testosterone levels were lower in men with a history of CVD than in the other subjects [49]. This study showed that baseline testosterone levels were lower in patients who died from cardiovascular causes. It has also been reported that testosterone replacement therapy (TRT) improves cardiac stress tests and prolongs the time to 1 mm ST segment depression. There are, however, conflicting results in the literature about the effect of TRT on this issue. Prior meta-analyses have reported that TRT has no effect on the risk of cardiovascular events [50]. In men with high serum testosterone and free testosterone levels, the risk of abdominal aortic atherosclerosis is found to be lower than in men with lower levels of testosterone [51]. In men with heart failure, total and free testosterone levels may be lower compared with healthy individuals. There are also data to suggest that the prevalence of hypogonadism in these men is more than 40% [50]. While testosterone has historically been thought to increase the risk of CVD, the amount of evidence to suggest that testosterone, like estrogen, has a protective
References
role against CVD is rapidly growing. Another important question requiring investigation is, does low testosterone increase the risk of CVD or does the development of CVD lead to low testosterone?
References [1] Gandaglia G, Briganti A, Jackson G, Kloner RA, Montorsi F, Montorsi P, et al. A systematic review of the association between erectile dysfunction and cardiovascular disease. Eur Urol 2014;65(5):968–78. [2] Fung MM, Bettencourt R, Barrett-Connor E. Heart disease risk factors predict erectile dysfunction 25 years later: the Rancho Bernardo Study. J Am Coll Cardiol 2004;43(8):1405–11. [3] Montorsi P, Ravagnani PM, Galli S, Salonia A, Briganti A, Werba JP, et al. Association between erectile dysfunction and coronary artery disease: matching the right target with the right test in the right patient. Eur Urol 2006;50(4):721–31. [4] Shin D, Pregenzer G, Gardin JM. Erectile dysfunction: a disease marker for cardiovascular disease. Cardiol Rev 2011;19(1):5–11. [5] Feldman HA, Johannes CB, Derby CA, Kleinman KP, Mohr BA, Araujo AB, et al. Erectile dysfunction and coronary risk factors: prospective results from the Massachusetts male aging study. Prev Med 2000;30(4):328–38. [6] Cooke JP. The endothelium: a new target for therapy. Vasc Med Lond Engl 2000;5(1):49–53. [7] Jeremy JY, Angelini GD, Khan M, Mikhailidis DP, Morgan RJ, Thompson CS, et al. Platelets, oxidant stress and erectile dysfunction: an hypothesis. Cardiovasc Res 2000;46(1):50–4. [8] Guay AT. ED2: erectile dysfunction ¼ endothelial dysfunction. Endocrinol Metab Clin N Am 2007;36(2):453–63. [9] Vlachopoulos C, Jackson G, Stefanadis C, Montorsi P. Erectile dysfunction in the cardiovascular patient. Eur Heart J 2013;34(27):2034–46. [10] Montorsi P, Montorsi F, Schulman CC. Is erectile dysfunction the “tip of the iceberg” of a systemic vascular disorder? Eur Urol 2003;44(3):352–4. [11] Katsiki N, Wierzbicki AS, Mikhailidis DP. Erectile dysfunction and coronary heart disease. Curr Opin Cardiol 2015;30(4):416–21. [12] Jain A, Harvey D, Robertson L, Mikhailidis DP, Nair DR. Gender-based cardiometabolic risk evaluation in minority and non-minority men grading the evidence of non-traditional determinants of cardiovascular risk. Int J Clin Pract 2011;65(6):715–6. [13] Jackson G. Erectile dysfunction and cardiovascular disease. Int J Clin Pract 1999;53(5):363–8. [14] O’Kane PD, Jackson G. Erectile dysfunction: is there silent obstructive coronary artery disease? Int J Clin Pract 2001;55(3):219–20. [15] Montorsi F, Briganti A, Salonia A, Rigatti P, Margonato A, Macchi A, et al. Erectile dysfunction prevalence, time of onset and association with risk factors in 300 consecutive patients with acute chest pain and angiographically documented coronary artery disease. Eur Urol 2003;44(3):360–5. [16] Thompson IM, Tangen CM, Goodman PJ, Probstfield JL, Moinpour CM, Coltman CA. Erectile dysfunction and subsequent cardiovascular disease. JAMA 2005;294(23):2996–3002. [17] Lee JH, Ngengwe R, Jones P, Tang F, O’Keefe JH. Erectile dysfunction as a coronary artery disease risk equivalent. J Nucl Cardiol Off Publ Am Soc Nucl Cardiol 2008;15(6):800–3. [18] Chew K-K, Finn J, Stuckey B, Gibson N, Sanfilippo F, Bremner A, et al. Erectile dysfunction as a predictor for subsequent atherosclerotic cardiovascular events: findings from a linked-data study. J Sex Med 2010;7(1 Pt 1):192–202.
175
176
C HA PT E R 2 . 4 :
Cardiovascular Disease and Men’s Health
[19] Montorsi P, Ravagnani PM, Galli S, Rotatori F, Veglia F, Briganti A, et al. Association between erectile dysfunction and coronary artery disease. Role of coronary clinical presentation and extent of coronary vessels involvement: the COBRA trial. Eur Heart J 2006;27(22):2632–9. [20] Hotaling JM, Walsh TJ, Macleod LC, Heckbert S, Pocobelli G, Wessells H, et al. Erectile dysfunction is not independently associated with cardiovascular death: data from the vitamins and lifestyle (VITAL) study. J Sex Med 2012;9(8):2104–10. [21] Polonsky TS, Taillon LA, Sheth H, Min JK, Archer SL, Ward RP. The association between erectile dysfunction and peripheral arterial disease as determined by screening ankle-brachial index testing. Atherosclerosis 2009;207(2):440–4. [22] Levine GN, Steinke EE, Bakaeen FG, Bozkurt B, Cheitlin MD, Conti JB, et al. Sexual activity and cardiovascular disease: a scientific statement from the American Heart Association. Circulation 2012;125(8):1058–72. [23] Exton NG, Truong TC, Exton MS, Wingenfeld SA, Leygraf N, Saller B, et al. Neuroendocrine response to film-induced sexual arousal in men and women. Psychoneuroendocrinology 2000;25(2):187–99. [24] Holloway IW. Substance use homophily among geosocial networking application using gay, bisexual, and other men who have sex with men. Arch Sex Behav 2015;44(7):1799–811. [25] Bohlen JG, Held JP, Sanderson MO, Patterson RP. Heart rate, rate-pressure product, and oxygen uptake during four sexual activities. Arch Intern Med 1984;144(9):1745–8. [26] Lindau ST, Schumm LP, Laumann EO, Levinson W, O’Muircheartaigh CA, Waite LJ. A study of sexuality and health among older adults in the United States. N Engl J Med 2007;357 (8):762–74. [27] Bispo GS, de Lima Lopes J, de Barros ALBL. Cardiovascular changes resulting from sexual activity and sexual dysfunction after myocardial infarction: integrative review. J Clin Nurs 2013;22 (23–24):3522–31. [28] Stein RA. Cardiovascular response to sexual activity. Am J Cardiol 2000;86(2A):27F–9F. [29] Dahabreh IJ, Paulus JK. Association of episodic physical and sexual activity with triggering of acute cardiac events: systematic review and meta-analysis. JAMA 2011;305(12):1225–33. [30] DeBusk R, Drory Y, Goldstein I, Jackson G, Kaul S, Kimmel SE, et al. Management of sexual dysfunction in patients with cardiovascular disease: recommendations of The Princeton Consensus Panel. Am J Cardiol 2000;86(2):175–81. [31] Parzeller M, Bux R, Raschka C, Bratzke H. Sudden cardiovascular death associated with sexual activity: a forensic autopsy study (1972-2004). Forensic Sci Med Pathol 2006;2(2):109–14. [32] Lee S, Chae J, Cho Y. Causes of sudden death related to sexual activity: results of a medicolegal postmortem study from 2001 to 2005. J Korean Med Sci 2006;21(6):995–9. [33] Hardin SR. Cardiac disease and sexuality: implications for research and practice. Nurs Clin North Am 2007;42(4):593–603. vii. [34] Montorsi P, Ravagnani PM, Vlachopoulos C. Clinical significance of erectile dysfunction developing after acute coronary event: exception to the rule or confirmation of the artery size hypothesis? Asian J Androl 2015;17(1):21–5. [35] Baumh€akel M, Schlimmer N, Kratz M, Hackett G, Hacket G, Jackson G, et al. Cardiovascular risk, drugs and erectile function–a systematic analysis. Int J Clin Pract 2011;65(3):289–98. [36] Ko DT, Hebert PR, Coffey CS, Sedrakyan A, Curtis JP, Krumholz HM. Beta-blocker therapy and symptoms of depression, fatigue, and sexual dysfunction. JAMA 2002;288(3):351–7. [37] Brixius K, Middeke M, Lichtenthal A, Jahn E, Schwinger RHG. Nitric oxide, erectile dysfunction and beta-blocker treatment (MR NOED study): benefit of nebivolol versus metoprolol in hypertensive men. Clin Exp Pharmacol Physiol 2007;34(4):327–31.
References
[38] Doumas M, Tsakiris A, Douma S, Grigorakis A, Papadopoulos A, Hounta A, et al. Beneficial effects of switching from beta-blockers to nebivolol on the erectile function of hypertensive patients. Asian J Androl 2006;8(2):177–82. [39] Shiri R, Koskim€aki J, H€akkinen J, Auvinen A, Tammela TLJ, Hakama M. Cardiovascular drug use and the incidence of erectile dysfunction. Int J Impot Res 2007;19(2):208–12. [40] Boydak B, Nalbantgil S, Fici F, Nalbantgil I, Zoghi M, Ozerkan F, et al. A randomised comparison of the effects of nebivolol and atenolol with and without chlorthalidone on the sexual function of hypertensive men. Clin Drug Investig 2005;25(6):409–16. [41] Grimm RH, Grandits GA, Prineas RJ, McDonald RH, Lewis CE, Flack JM, et al. Long-term effects on sexual function of five antihypertensive drugs and nutritional hygienic treatment in hypertensive men and women Treatment of Mild Hypertension Study (TOMHS). Hypertension 1997;29(1 Pt 1):8–14. [42] Chrysant SG. Antihypertensive therapy causes erectile dysfunction. Curr Opin Cardiol 2015;30(4):383–90. [43] Omvik P, Thaulow E, Herland OB, Eide I, Midha R, Turner RR. Double-blind, parallel, comparative study on quality of life during treatment with amlodipine or enalapril in mild or moderate hypertensive patients: a multicentre study. J Hypertens 1993;11(1):103–13. [44] Speel TGW, Kiemeney LA, Thien T, Smits P, Meuleman EJ. Long-term effect of inhibition of the angiotensin-converting enzyme (ACE) on cavernosal perfusion in men with atherosclerotic erectile dysfunction: a pilot study. J Sex Med 2005;2(2):207–12. [45] B€ ohm M, Baumh€akel M, Teo K, Sleight P, Probstfield J, Gao P, et al. Erectile dysfunction predicts cardiovascular events in high-risk patients receiving telmisartan, ramipril, or both: the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial/Telmisartan Randomized AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (ONTARGET/TRANSCEND) Trials. Circulation 2010;121(12):1439–46. [46] Cheever K, House MA. Cardiovascular implications of anabolic steroid abuse. J Cardiovasc Nurs 1992;6(2):19–30. [47] Cattabiani C, Basaria S, Ceda GP, Luci M, Vignali A, Lauretani F, et al. Relationship between testosterone deficiency and cardiovascular risk and mortality in adult men. J Endocrinol Investig 2012;35(1):104–20. [48] Snyder PJ. Decreasing testosterone with increasing age: more factors, more questions. J Clin Endocrinol Metab 2008;93(7):2477–8. [49] 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 (5):687–701. [50] Corona G, Rastrelli G, Vignozzi L, Mannucci E, Maggi M. Testosterone, cardiovascular disease and the metabolic syndrome. Best Pract Res Clin Endocrinol Metab 2011;25(2):337–53. [51] Hak AE, Witteman JCM, de Jong FH, Geerlings MI, Hofman A, Pols HAP. Low levels of endogenous androgens increase the risk of atherosclerosis in elderly men: the Rotterdam study. J Clin Endocrinol Metab 2002;87(8):3632–9.
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