Figure 29-1.
The relationship of endothelial dysfunction, low-grade chronic inflammation, and atherosclerosis in the pathogenesis of erectile dysfunction and coronary artery diseases.
A commonly proposed mechanism correlating erectile dysfunction and coronary artery disease is the artery-size hypothesis. Common risk factors such as hypertension, diabetes mellitus, obesity and smoking predispose to endothelial dysfunction and flow-limiting stenosis. Atherosclerosis is a generalized process, therefore it is hypothesized that all vascular beds are impacted the same. It is the artery size itself that determines the onset and severity of symptoms. Larger vessels adapt to the same amount of endothelial dysfunction and resulting atherosclerosis better than smaller vessels. Due to the small vessel size of penile arteries (1–2 mm) compared to that of coronary arteries (3–4 mm), atherosclerosis leads to a more significant reduction of blood flow to erectile tissues compared to that seen in coronary arteries. Based on this pathophysiologic mechanism, the penile vascular bed is an indicator of systemic vascular diseases and erectile dysfunction should precede coronary artery disease . In this framework, Montorsi et al. investigated the prevalence of erectile dysfunction in patients with coronary artery disease and evaluated the association between the severity of erectile dysfunction and the degree of coronary vessel involvement. One hundred and eighty patients with coronary artery disease confirmed via angiography were divided into three groups: (1) acute coronary syndrome and one-vessel disease, (2) acute coronary syndrome and two- to three-vessel disease, and (3) chronic stable angina. In each group of patients, the extent of erectile dysfunction was determined by the International Index of Erectile Function (IIEF) questionnaire. The key finding of the study demonstrated that erectile dysfunction occurs prior to cardiac symptoms in virtually all patients with chronic coronary syndrome with a time interval of 3 year, whereas patients with acute coronary syndrome have a low prevalence of sexual dysfunction.
Arterial Hypertension and Erectile Dysfunction
Arterial hypertension is a major cardiovascular risk factor that is strongly associated with erectile dysfunction. Erectile dysfunction is frequently encountered in hypertensive men compared to normotensive individuals. The coexistence of arterial hypertension and erectile dysfunction increases with advancing age, the severity and duration of hypertension, and the presence of additional cardiovascular risk factors [6].
Erectile dysfunction is an indicator of asymptomatic coronary artery disease, hence the importance of identifying early symptoms in patients with hypertension. Erectile dysfunction represents a vascular compromise in penile arteries resulting from atheroscelortic lesions. Sexual problems precede cardiovascular symptoms due to the remarkably small diameter of penile arteries in comparison to coronary arteries. Erectile dysfunction is said to appear 3–5 years before the onset of symptomatic coronary artery disease, therefore representing an early diagnostic sign of heart disease. However, despite its clinical significance, erectile dysfunction remains a largely unidentified and undertreated disease entity [7].
Data gathered from multiple studies indicate a positive association between elevated blood pressure and the structural compromise noted in penile arteries . Although arterial hypertension should be treated as a protective measure, reduction in blood pressure attenuates the vascular compromise and thereby worsens erectile function [8]. Many antihypertensive agents further exacerbate erectile dysfunction a drug-specific side effect. The older antihypertensive agents such as thiazide diuretics and beta-adrenergic receptor blockers have the highest incidence of erectile dysfunction [9]. Newer agents such as angiotensin receptor blockers exert neutral effects while agents such as nebivolol provide beneficial effects [10].
Diabetes Mellitus and Erectile Dysfunction
Whether the association of diabetes mellitus with erectile dysfunction is termed vascular-type erectile dysfunction or is summarized as endocrine related remains an academic debate. In any event, diabetes is an established risk factor for sexual dysfunction in men as documented by the Massachusetts Male Aging Study where a threefold increased risk of erectile dysfunction seen in diabetic compared with nondiabetic men [11]. The numerous epidemiological studies do not distinguish between type 1 and type 2 diabetes in being associated with an increased risk of erectile dysfunction [12].
The pathogenesis of erectile dysfunction in diabetes mellitus is multifactorial. Diabetic vasculopathy encompasses macroangiopathy, microangiopathy, and endothelial dysfunction [13]. Macrovascular disease is the result of atherosclerotic damage in the blood vessels, limiting circulation to vascular beds. The endothelial dysfunction caused by the atherosclerotic lesions leads to penile arterial insufficiency, thus the culprit to vascular erectile dysfunction seen in diabetic men.
Similarly, the chronic insult of hyperglycemia on the endothelium results in endothelial dysfunction, linking erectile dysfunction to coronary artery disease . Endothelial dysfunction in diabetes is manifested as the decreased bioavailability of nitric oxide, resulting in insufficient relaxation of the vascular smooth muscle of the corpora cavernosa.
Microvascular disease encompasses ischemic damage in the distal circulation and neuropathic complications. In diabetics, sensory impulses from the penis to the reflexogenic erectile center are impaired, and the reduced or absent parasympathetic activity necessary for relaxation of the smooth muscle of the corpus cavernous contributes to the erectile dysfunction seen in these patients [14].
Due to its multifactorial etiology, the treatment of erectile dysfunction in diabetic men requires a comprehensive approach. For diabetic patients a strong association between glycemic control and the prevalence of erectile dysfunction is well established. Therefore, initial treatment focuses to correct the modifiable risk factors and promote lifestyle changes. Tight glycemic control, achieved by increased physical activity, a Mediterranean diet, and reduced caloric intake, so as to maintain an HbA1c concentration < 7%, is recommended for adults with diabetes to minimize the risk of long-term complications. However, reversal of erectile dysfunction after aggressive treatment of diabetes mellitus has not been compelling. Most likely, treatment must be initiated at a very early stage of the disease process to be effective. Intensified glucose control, along with treatment of associated risk factors, may also prevent sexual dysfunction, even if improvement is not achieved [15].
Heart Failure and Erectile Dysfunction
Heart failure is the leading entity in cardiovascular medicine and the prevalence in the USA is estimated at 5.3 million by the American Heart Association [16].
According to the Massachusetts Male Aging study, in healthy men between the ages of 40 and 70 years, over half reported some degree of erectile dysfunction [4]. Sharing similar risk factors, patients concomitantly present with heart failure and erectile dysfunction. In particular, diabetes mellitus, hypertension, obesity, and smoking are underlying factors in cardiovascular disease and erectile dysfunction. In addition, side effects from drugs such as thiazide diuretics, digoxin, and some beta-adrenergic receptor blockers are reported to induce and worsen erectile dysfunction in men [17]. Moreover, left ventricular dysfunction in advanced stages leads to reduced cardiac capacity, reduced physical functioning, and decreased exercise tolerance secondary to generalized muscle weakness. These combined factors augment the development and worsening of erectile dysfunction in men. Heart failure patients experience symptoms of decreased libido and frequency of sexual intercourse, erectile dysfunction, negative changes in sexual performance, and general dissatisfaction related to their sexual function. The multifactorial causes of sexual dysfunction in heart failure include reduced cardiac capacity, endothelial dysfunction, hormonal imbalances, as well as medication side effects. It is estimated that 60–89% of heart failure patients have some extent of erectile dysfunction [16].
Medications and Erectile Dysfunction
Antihypertensive agents represent one of the most implicated classes of drugs in erectile dysfunction. Older antihypertensive drugs (central-acting, beta-adrenergic receptor blockers, and diuretics) are commonly associated with erectile dysfunction, while the newer agents such as calcium antagonists, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) have demonstrated neutral or possible beneficial effects with regard to sexual function (Table 29-1). Several studies revealed that patients discontinued treatment for hypertension due to erectile dysfunction, albeit real or perceived. Whether the high prevalence of erectile dysfunction seen in hypertensive patients is a result of the disease process, the antihypertensive treatment agents or the combination of both remains to be clarified [26].
Table 29-1.
Antihypertensive agents and their effect on erectile function
Antihypertensive drug | Effect on erectile function | Clinical study | Results |
|---|---|---|---|
Angiotensin receptor blockers | |||
Losartan | + | Llisterri et al. [18] | Marked increase of self-reported sexual satisfaction; losartan treatment improved sexual satisfaction from an initial 7.3 to 58.5% (chi2; p = 0.001) |
Valsartan | + | Fogari et al. [19] | Improved sexual activity; 1st month of valsartan treatment, sexual activity declined from 8.3 to 6.6 sexual intercourse episodes (p = NS). With ongoing valsartan treatment, sexual activity fully recovered and improved (10.2 sexual intercourse episodes per month) |
Della Chiesa et al. [20] | Increase in sexual intercourse per week from 1.0 to 1.6 times during follow-up (p < 0.0001) | ||
Angiotensin-converting enzyme inhibitors | |||
Lisinopril | +/− | Fogari et al. [21] | Neutral effects on sexual interest, erectile function, orgasmic ability, and satisfaction. Initial treatment showed significant decline in sexual intercourse episodes per month from 7.1 ± 4.0 to 5.0 ± 2.5, p < .05 v placebo. With ongoing lisinopril treatment, sexual activity recovered (7.7 ± 4.0 sexual intercourse episodes per month) |
Calcium channel antagonists | |||
Nifedipine | +/− | Kroner et al. [22] | Neutral effects on sexual function |
Beta-adrenergic receptor blockers | |||
Atenolol | − | Suzuki et al. [23] | Significantly reduced the number of intercourse events per month from 7.8 to 4.2 (p < 0.01 compared with pretreatment and placebo) |
Carvedilol | − | Kloner et al. [24] | Sexual intercourse episodes per month were reduced from 8.2 to 3.7 (p < 0.01 compared with baseline) |
x | + | Brixius et al. [25] | Substitution of β adrenergic receptor blockers with nebivolol resulted in significant improvement in erectile function in patients |
Thiazide diuretics | |||
Chlorthalidone | − | Trial of Antihypertensive Interventions and Management (TAIM) trial [27] | Erection-related problems worsened in 28% of men receiving chlorthalidone, compared with 11% of those receiving atenolol and 3% of those receiving placebo (p < 0.009) |
Treatment of Mild Hypertension Study (TOMHS) | Participants randomized to chlorthalidone reported a significantly higher incidence of erection problems at 2 years than participants randomized to placebo (17.1% vs. 8.1%; p = 0.025). However, the difference between the two groups was not statistically significant at 4 years (chlorthalidone 18.3% and placebo 16.7%) | ||
Aldosterone receptor antagonists | Limited information | ||
Renin inhibitor | Limited information | ||
Centrally acting antihypertensives | Limited information | ||
Angiotensin Receptor Blockers
As supported by several clinical studies, ARBs have a beneficial effect on sexual function in hypertensive patients. In a cohort of small studies conducted during the past 20 years, patients on ARB therapy showed increased sexual activity and sexual satisfaction. In a study conducted by Llisterri et al., 82 hypertensive patients with erectile dysfunction treated with losartan reported improved sexual satisfaction from an initial 7.3–58.5% (p = 0.001). An additional study comparing valsartan with carvedilol on untreated hypertensive patients without erectile dysfunction, demonstrated improved sexual activity with valsartan treatment. During the first month of treatment, sexual activity declined from 8.3 to 6.6 sexual intercourse episodes per month. With ongoing valsartan treatment, sexual activity fully recovered and improved to 10.2 sexual intercourse episodes per month [18].
In a larger study conducted by Della Chiesa et al., hypertensive patients treated with valsartan reported an increase in sexual intercourse per week from 1.0 to 1.6 times during follow-up (p < 0.0001). The initial outcomes reporting beneficial effects on erectile function with ARB treatment require further studies to confirm these findings [20].
Angiotensin Converting Enzyme Inhibitors
When compared to ARBs, ACE inhibitors have neutral effects on erectile dysfunction in hypertensive patients. Multiple studies provide data that treatment with ACE inhibitors provide no significant impact on sexual interest, erectile function, orgasmic ability, and sexual satisfaction. In examining the quality of life of patients on antihypertensive therapy, Fogari et al. demonstrated the neutral effects seen with ACE inhibitors. Initial treatment with lisinopril showed significant decline in sexual intercourse episodes per month from 7.1 ± 4.0 to 5.0 ± 2.5 (p < .05) versus placebo; however, with continued treatment, sexual activity recovered in patients (7.7 ± 4.0 sexual intercourse episodes per month) [21].
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