Sexual Inquiry of All Men
• ED provides an opportunity for CVD risk reduction.6
• ED not only shares risk factors with CVD7,8 but also is, in itself, an independent marker of increased risk for CVD (ACCF/AHA class Ia).9-15
• ED is a marker of significantly increased risk of CVD, coronary artery disease (CAD), stroke, and all-cause mortality.
Incident ED has a similar or greater predictive value for cardiovascular events as traditional risk factors, such as family history of myocardial infarction (MI), smoking, and hyperlipidemia.16,17
Erectile dysfunction commonly occurs in the presence of silent CAD,3,18-20
with a time window between ED onset and a CAD event of 2 to 5 years (class Ia).3,4,21
Furthermore, evidence suggests that ED is predictive of peripheral arterial disease (PAD)22
In a population-based study of men 40 to 70 years of age, addition of ED status to the Framingham Risk Score (FRS) in a multivariate statistical model resulted in reclassification of 5 of 78 low-risk patients (<5% risk) to intermediate risk (5% to <10% risk).9
In addition, data from the Olmsted County Study suggest that ED is far more predictive of CAD in men 40 to 49 years of age than in older men,24
and the incidence of atherosclerotic cardiovascular events in men younger than 40 years with ED was more than 7 times the incidence in a reference population representative of the general male population in Western Australia.25
Thus, ED may be particularly useful in assessing cardiovascular risk in younger men26
and in minorities,27
whose risk may be underestimated by global risk assessments such as the FRS. Finally, assessment of ED must include ED severity because more severe ED has been associated with greater risk of major cardiovascular events,28
extent of CAD,19,21,30
and risk of PAD (ACCF/AHA class Ia).22
These recommendations are supported by a meta-analysis of 12 prospective studies involving 36,744 men ().31
In this study and in a study of ED in men with known CVD, ED was found to be an independent marker of cardiovascular events and all-cause mortality additional to conventional risk factors (eg, age, weight, hypertension, diabetes, hyperlipidemia, and cigarette smoking).
Relative Risks for Men With Erectile Dysfunction
Recommended Assessments and Risk Clarification
• A man with organic ED should be considered at increased CVD risk until recommended checks suggest otherwise.
• ED identifies increased CVD risk in the presence or absence of CVD symptoms or history.
The consensus panel recommends the following risk assessments, which may be used to identify men with ED and no known CVD who may require additional cardiologic work-up. In the broadest sense, this risk refers to experiencing a significant cardiac event, including MI, acute coronary syndromes, angina pectoris, heart failure, and death.
• Patient history, including age, presence or absence of comorbid conditions (eg, abdominal obesity, hypertension, dyslipidemia, prediabetes, and symptoms suggestive of obstructive sleep apnea), family history of premature atherothrombotic CVD (father aged <55 years or mother aged <65 years; ACCF/AHA class I, LOE B), and lifestyle factors (eg, diet, excessive use of alcohol, limited physical activity, and smoking)
• Physical examination noting BP, waist circumference (WC), body mass index (BMI), fundal arterial changes, cardiac auscultation, carotid bruits, and palpation of femoral and pedal pulses
• ED severity (International Index of Erectile Function score or Sexual Health Inventory of Men) and duration
• Resting electrocardiogram (ACCF/AHA class IIa, LOE C in asymptomatic adults with hypertension or diabetes and ACCF/AHA class IIb, LOE C in asymptomatic adults without hypertension or diabetes)
• Fasting plasma glucose level
• Serum creatinine level (estimated glomerular filtration rate) and albumin to creatinine ratio
• Total testosterone (TT) level (before 11 am)
• Plasma lipid levels (total, low-density lipoprotein, and HDL cholesterol and triglyceride values)
Findings from a study of 4883 men and women 65 years and older who were followed up for 10 years suggest that 9 of 10 new cases of diabetes would have been avoided if patients were in the low-risk group for each of 5 lifestyle factors (physical activity, diet [combining intake of fiber, polyunsaturated vs saturated fat, trans fats, and glycemic index], smoking habits, alcohol use, and adiposity [measured by BMI or WC]).33
Recent evidence suggests that measures of abdominal adiposity (eg, WC and waist to hip ratio) are better predictors of adverse cardiovascular outcomes than is BMI.34,35
Abdominal obesity is associated with secretion of excess free fatty acids, release of inflammatory cytokines, and reduced secretion of adiponectin.36
Furthermore, diabetes is associated with a 2-fold increase in the prevalence of CVD,37
and estimated glomerular filtration rates less than 60 mL/min and urinary albumin to creatinine ratios greater than 10 mg/g are associated with increased cardiovascular mortality independent of other risk factors.38,39
The consensus panel recommends that testosterone levels be measured in all men with a diagnosis of organic ED, especially in those for whom PDE5 inhibitor therapy failed.6
This recommendation may be controversial, and it differs from the guideline published by the American College of Physicians,40
which does not recommend for or against routine hormonal blood tests or treatment in patients with ED. However, the British Society for Sexual Medicine and the International Society for Sexual Medicine advocate testosterone measurements (≥2) in all men with ED. The American College of Physicians urges physicians to consider the presence or absence of symptoms of hormonal dysfunction (eg, decreased libido and decreased spontaneous erection) and of physical findings (eg, testicular or muscle atrophy) when considering whether to measure testosterone levels in individual patients with ED. The consensus panel recommendation for evaluation of testosterone levels in all men with ED is based on evidence from an accumulation of recent studies linking low testosterone levels to ED and CVD.41
Testosterone is a key central and peripheral modulator of erectile function in animal studies.42-45
Consistent with these observations, a single-center study of 1050 men seeking new consultation for sexual dysfunction found that 36% had hypogonadism.46
Buvat and Bou Jaoude,47
in a compilation of data from 7000 men with ED in 9 large series, reported serum testosterone levels less than 300 ng/dL (to convert to nmol/L, multiply by 0.0347) in 12%, including 4% before and 15% after age 50 years. Hypogonadism is a potential cause of lack of response to PDE5 inhibitor therapy,48,49
and TRT improves response.49
This finding suggests that a minimal level of testosterone is required for a complete effect of PDE5 inhibitor therapy.49,50
However, testosterone assay methods differ, and there are no generally accepted lower limits of normal TT.
Several epidemiologic studies have associated low testosterone levels with increased all-cause and cardiovascular mortality ().51-59
However, a 2010 meta-analysis limited to longitudinal (cohort) studies in middle-aged men found no association between endogenous TT levels and risk of CVD in middle-aged men.60
A more recent study by Corona et al61
found significant associations between low TT levels and high estradiol levels and CVD in a meta-analysis of 49 cross-sectional studies. Conversely, in a meta-analysis of 10 longitudinal studies, TT levels were significantly lower in patients with incident overall and cardiovascular mortality compared with controls, but there were no differences in baseline TT and estradiol levels between cases and controls for incident CVD.60
The authors of both studies acknowledged that low testosterone levels may be a marker of poor general health rather than CVD risk per se. Consistent with this notion, androgen deficiency has been associated with insulin resistance, type 2 diabetes mellitus, metabolic syndrome, and increased deposition of visceral fat.62-65
In the TIMES2 (Testosterone Replacement In Hypogonadal Men With Either Metabolic Syndrome or Type 2 Diabetes) study, 6 to 12 months of transdermal TRT (vs placebo) significantly improved insulin resistance and glycemic control in a large randomized study of hypogonadal men with type 2 diabetes mellitus (ACCF/AHA class Ib).66
A meta-analysis of 5 other randomized controlled trials (including 3 placebo-controlled trials) with mean follow-up of 58 weeks found that TRT was associated with a significant reduction in fasting plasma glucose levels, homeostasis model assessment of insulin resistance index, triglycerides, and WC. An increase in HDL cholesterol level was also observed, whereas no significant differences were observed for total cholesterol level, BP, or BMI.67
In summary, the panel recommended:
• All men with ED should have their cardiovascular risk assessed.
• Testosterone level should be routinely measured.
Low Testosterone Levels and Increased Mortality Rates in Recent Publications With Populations Greater Than 500
Treatment, Additional Cardiovascular Evaluation, and Referral
• In all patients, lifestyle changes are likely to reduce cardiovascular risk and improve erectile function.
• All men with ED should have their testosterone level measured and replacement considered when appropriate.
A meta-analysis of lifestyle modification strengthened the evidence for improvement in ED and maintenance of sexual function as well as cardiovascular risk reduction in addition to previous reviews.31
Lifestyle advice should include the following: smoking cessation, regular dynamic exercise, weight loss, a healthy diet (eg, the Mediterranean diet, which emphasizes fruits, vegetables, beans and legumes, whole grains, nuts, fish, poultry, lean red meat, cheese, and yogurt),68
and moderate alcohol consumption (<14 U/wk for women and <21 U/wk for men, in which number of units is calculated as percentage of alcohol × volume/1000).
Although compliance with lifestyle advice can be difficult to achieve, population-based studies suggest that changes in lifestyle may be most important for primary prevention. Managing cardiovascular risk with lifestyle change also permits avoidance or reduction of adverse drug effects. In a meta-analysis of prospective cohort studies of patients with coronary heart disease, smoking cessation reduced total mortality by 36%.69
The pleiotropic effects of physical activity (eg, improved lipid profiles, BP, glucose-insulin homeostasis, endothelial function, inflammatory markers, and psychological well-being) 70-73
likely account for 30% to 50% reductions in incident type 2 diabetes and coronary heart disease in physically active vs sedentary individuals.72
Diet can reduce death from coronary heart disease by up to 36% and can improve many established risk factors.73
Consistent with the British Society for Sexual Medicine's guidelines on the management of ED,74
the Third International Consultation of Sexual Medicine,75
the Endocrine Society guidelines,41
and a combined guidance of the International Society of Andrology, International Society for the Study of the Aging Male, European Association of Urology, European Academy of Andrology, and American Society of Andrology,76
the panel agreed that a TT level greater than 350 ng/dL does not usually require substitution and that men with TT levels less than 230 ng/dL usually benefit from TRT. If there are no contraindications, symptomatic men (decreased libido or ED) with TT levels of 231 to 346 ng/dL may be considered for a 4- to 6-month trial of TRT but only after careful discussion about the potential risks and benefits. Beyond 6 months, TRT should be continued only in cases of clinical benefit.77
Caution is warranted in men with a history of congestive heart failure (risk of fluid retention); repletion goals should be in the middle range (ie, 350-600 ng/dL) for this group. In patients older than 70 years and those with chronic illness, the consensus panel suggests use of an easily titratable testosterone formulation (eg, gel, spray, or patch) rather than intermediate and long-acting injectable formulations. Also note that randomized trials are needed to establish the risks and benefits of TRT regarding cardiovascular risk and all-cause mortality. Baseline hematocrit and prostate-specific antigen testing and 6-month monitoring are necessary.
As the consensus panel considers all men with ED who are older than 30 years to be at increased CVD risk, a thorough noninvasive and, when indicated, invasive evaluation of CVD status is recommended.
A collaborative management approach incorporating primary care and cardiology expertise should include lifestyle advice and pharmacotherapy to aggressively control cardiovascular risk factors (eg, BP, hyperlipidemia, and hyperglycemia), with follow-up at routine intervals.
Noninvasive cardiovascular evaluation may include measurement of biomarkers and physiologic stress testing for ischemia or anatomical clarification by coronary computed tomographic angiography (CCTA) for diagnosis of asymptomatic or undiagnosed CAD.78-81
This evaluation can be requested by a cardiologist, primary care physician, andrologist, or urologist with specialized training in cardiovascular risk assessment. The 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults5
provides recommendations and LOEs for the following techniques:
• Exercise stress testing (EST) (ACCF/AHA class IIb, LOE B in asymptomatic, intermediate-risk adults, particularly when nonelectrocardiogram markers are considered [ie, exercise capacity] rather than ST-segment changes)5,82
• Carotid intima-media thickness (CIMT) (ACCF/AHA class IIa, LOE B in asymptomatic, intermediate-risk adults)
• Computed tomography for coronary artery calcium scoring (CACS) (ACCF/AHA class IIa, LOE B in asymptomatic, intermediate-risk men ≥40 years old; ACCF/AHA class IIb, LOE B in low- to intermediate-risk [6%-10% 10-year risk] men ≥40 years old)
• Ankle-brachial index (ABI) (ACCF/AHA class IIa, LOE B in asymptomatic, intermediate-risk adults)
• CCTA (ACCF/AHA class III, LOE C in asymptomatic patients)
• Pulse wave velocity (PWV) (ACCF/AHA class III, LOE C in asymptomatic patients)
• Noninvasive assessment of endothelial function (ie, brachial artery flow-mediated dilation) (ACCF/AHA class III, LOE B in asymptomatic adults)
Despite its limitations in detecting CVD without significant stenosis, EST (with or without imaging) can further define the cardiovascular risk in patients with ED and may be particularly helpful for identifying silent CAD in patients with diabetes. In a study of patients with type 2 diabetes, ED was significantly more prevalent in men with silent CAD (33.8%) identified by EST than in those without silent CAD (4.7%).18
Chemical stress tests (dipyridamole [Persantine, Boehringer Ingellheim GmbH, Ingelheim, Germany] or adenosine with nuclear imaging) are appropriate for patients who cannot complete an EST (eg, inability to exercise due to a disabling condition such as arthritis). If the baseline electrocardiogram makes EST unavailable or noninterpretable, the consensus panel recommends referral to a cardiologist or a practice with cardiology expertise for further evaluation.
The order of testing that men with ED should undergo is the decision of the primary care physician or cardiologist. However, it makes sense for noninvasive tests (ie, EST, CIMT, and ABI) to be performed before those that require radiation/contrast (eg, CCTA and CACS). However, CCTA or CACS as the first test may be appropriate for younger patients (aged <50 years) with a family history of CVD, severe ED, diabetes, or multiple risk factors. Invasive coronary angiography should be considered when noninvasive evaluation suggests significantly increased CVD risk.
The 2010 ACCF/AHA guideline asserts that it is “reasonable” to perform CIMT, CACS, and ABI during assessment of intermediate-risk patients.5
The Society for Heart Attack Prevention and Eradication task force issued a stronger recommendation, suggesting that all asymptomatic men 45 to 75 years of age and women 55 to 75 years of age who do not have very-low-risk characteristics (ie, absence of any traditional cardiovascular risk factors) or a documented history of CVD undergo CACS or CIMT screening for the detection of subclinical atherosclerosis.83
In an analysis from the Atherosclerosis Risk in Communities study, addition of CIMT and plaque detection via ultrasonography to traditional risk factors improved coronary heart disease risk prediction.84
In the Multi-Ethnic Study of Atherosclerosis, CACS was a better predictor of CVD than was CIMT.85
In a meta-analysis of 16 population-based cohort studies, a low ABI (≤0.90) was associated with approximately twice the 10-year total mortality, cardiovascular mortality, and major coronary event rates compared with the overall rate in each FRS category,86
suggesting that ABI assessment may improve cardiovascular risk prediction beyond the FRS. Although the ACCF/AHA does not currently recommend assessment of arterial stiffness (eg, PWV) for cardiovascular risk determination in asymptomatic individuals, a meta-analysis of 17 longitudinal studies (mean follow-up, 7.7 years) showed that participants with high aortic PWV were at higher risk for total cardiovascular events, cardiovascular mortality, and all-cause mortality compared with participants with low PWV.87
Similarly, impaired endothelial dysfunction detected by EndoPAT (Itamar Medical Ltd, Caesarea, Israel) was an independent predictor of cardiac death, MI, revascularization or cardiac hospitalization in symptomatic outpatients over 7-year follow-up.88
Similarly, endothelial function assessed in the brachial artery by flow-mediated dilation89,90
or in the forearm microvasculature by Doppler91
predicted outcome independently of FRS. However, the role of measures of endothelial function in the evaluation of men with ED has yet to be established.
Assessment of circulating or noncirculating biomarkers may also help detect subclinical CVD in the indeterminate-risk patient. Consistent with the 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults,5
the consensus panel recommends that physicians consider evaluation of the following nontraditional risk factors: high-sensitivity C-reactive protein (hsCRP) level (ACCF/AHA class IIb, LOE B in asymptomatic, intermediate-risk men ≤50 years),5
glycated hemoglobin level (ACCF/AHA class IIb, LOE B in asymptomatic adults without a diagnosis of diabetes),5
urinary albumin excretion (ACCF/AHA class IIa, LOE B in asymptomatic adults with hypertension or diabetes; and ACCF/AHA class IIb, LOE B in asymptomatic, intermediate-risk adults without hypertension or diabetes),5
serum uric acid level, and lipoprotein-associated phospholipase A2 level (ACCF/AHA class IIb, LOE B in asymptomatic, intermediate-risk adults).5
The hsCRP level is an independent predictor of incident coronary events after adjustment for traditional risk factors (ie, age, total cholesterol level, HDL cholesterol level, smoking status, BMI, diabetes, history of hypertension, exercise level, and family history of coronary disease).92-94
Thus, in 2003, the Centers for Disease Control and Prevention and the AHA endorsed measurement of the hsCRP level as an adjunct to global risk prediction, particularly in patients at intermediate risk (10%-20% over 10 years).95
More recently, the hsCRP level improved the predictive value of the FRS in patients at high risk for coronary heart disease.96
The independent prognostic value of the hsCRP level was also evident in a meta-analysis of 160,309 people without a history of vascular disease (ie, 1.31 million person-years at risk and 27,769 fatal or nonfatal disease outcomes) from 54 long-term prospective studies.97
reviewed evidence that hsCRP level correctly reclassifies a substantial proportion of patients at intermediate risk for CVD into clinically relevant higher- or lower-risk groups.
Although not specifically addressed in the 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults,5
the consensus panel recommends evaluation of serum uric acid levels. Similar to hsCRP levels, the recent literature supports the serum uric acid level as an inexpensive marker of increased cardiovascular risk.99
There is inconsistency regarding the incremental benefit of adding the glycated hemoglobin level or microalbuminuria to standard risk factors in prediction of CVD and reclassification of cardiovascular risk. However, a recent analysis of data from the Atherosclerosis Risk in Communities study showed that addition of the glycated hemoglobin level to prediction models incorporating traditional risk factors and the fasting glucose level improved coronary heart disease risk prediction in nondiabetic patients with no history of CVD.100
In a meta-analysis of 26 cohort studies, microalbuminuria was associated with a 50% greater risk of coronary heart disease, and macroalbuminuria more than doubled coronary heart disease risk.101
Finally, the lipoprotein-associated phospholipase A2 level seems to be an independent predictor of CVD events in apparently healthy adults after adjustment for hsCRP levels and standard risk factors.102-105
The 2010 ACCF/AHA guideline5
, p.e66 states that measurement of lipoprotein-associated phospholipase A2 “might be reasonable for cardiovascular risk assessment in intermediate-risk asymptomatic adults.”