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Erectile Dysfunction in Smokers: A Penile Dynamic and Vascular Study

MOSHE WALD

CRAIG S. NIEDERBERGER

From the ^* Department of Andrology, Mansoura University, Mansoura, Egypt; and the Department of Urology, University of Illinois at Chicago, Chicago, Illinois.

Correspondence to: Dr Craig Niederberger, Department of Urology, University of Illinois at Chicago, 515 CSN M/C 955, 840 S Wood St, Chicago, IL 60612 (e-mail: craign{at}uic.edu).

Received for publication May 5, 2004; accepted for publication July 6, 2004.

	Abstract

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In this study, we aimed to determine the hemodynamic mechanisms through which cigarette smoking, as an independent risk factor, induces erectile dysfunction (ED). We performed a standard ED evaluation that included history; a physical exam; and serum glucose, testosterone, and prolactin levels. We then excluded ED patients with abnormal androgen profiles and patients with ED risk factors other than smoking. A total of 109 ED patients entered the study, including 71 current smokers and 38 nonsmokers. All patients then underwent extensive evaluation, including nocturnal penile tumescence and rigidity (NPTR) monitoring with Rigiscan, followed by pharmacopenile duplex ultrasonography (PPDU) and redosing pharmacocavernosometry (RPC). Results of the above tests were compared in the smoker and nonsmoker groups. We also performed receiver operating characteristic (ROC) curve analysis to determine which diagnostic parameter is most affected by cigarette smoking. The 4 most significant variates served as input features for a logistic regression model, designed to predict smoking. The average age for smokers and nonsmokers was 44.3 and 51.2 years, respectively (P = .02). Eighty-six percent of smokers had abnormal NPTR testing compared with 55% of nonsmokers (P = .02). The average peak systolic velocity (PSV) was 26.8 and 31.2 cm/s for smokers and nonsmokers, respectively, and this difference was not found to be statistically significant (P = .19) in this study. On performing RPC, an abnormal maintenance flow (MF) of >5 mL/min was detected in 89% of smokers and in 47% of nonsmokers, and the difference was significant (P < .01). With the use of smoking as the outcome, the ROC area of different diagnostic parameters was as follows: 0.79 for penile base rigidity, 0.58 for PSV, and 0.77 for MF. A logistic regression model that used the 4 most significant variates as input features yielded a ROC of 0.857. The results of NPTR testing in our smoker and nonsmoker groups indicated that ED in smokers is mainly of organic etiology. On the basis of the PPDU findings and the higher incidence of abnormal MF in the smoker group and its relatively high ROC value, we concluded that dysfunction of penile veno-occlusive mechanisms plays a substantial role in the development of ED in smokers.

     Key words: Smoking, impotence, color duplex, pharmacocavernosometry, veno-occlusion

In a study of 1290 noninstitutionalized men aged 40–70 years old, impotence was complete in 11% of smokers and only 0.3% of nonsmokers (Feldman et al, 1994). In another study including 4462 Vietnam-era army veterans aged 31–49 years, ED was found in 2.2% of nonsmokers, 2.0% of ex-smokers, and 3.7% of current smokers (Mannino et al, 1994). The authors also found that ED was independent of the number of cigarettes smoked per day and the number of years of smoking. Condra et al (1986) reported that the incidence of ED among heavy smokers is twice that in the general population. In their study on 2010 men, Mirone et al (2002) concluded that the risk of ED is influenced by smoking and that the duration of the habit increases the risk. In a literature review of 18 studies, Dorey (2001) found a detrimental effect of smoking on erectile function and a 1.5 times more likely chance for smokers to suffer ED than nonsmokers.

Studies that investigated the mechanisms through which cigarette smoking causes ED have suggested that tobacco-induced ED is mainly a result of vasculogenic etiology. Rosen et al (1991) proposed that cigarette smoking is an independent risk factor in the development of atherosclerotic lesions in the internal pudendal and common penile arteries of young impotent men. Inhalation of cigarette smoke was found to inhibit smooth muscle relaxation and impair the release of neurovascular mediators (Jeremy et al, 1986). Another report indicated that smoking increases platelet aggregation, inducing catecholamines, and that nicotine and carbon monoxide have a direct toxic effect on vascular endothelium (Bornman and du-Plessis, 1986). Nicotine was also found to interfere with erectile response to the intracavernous injection of vasoactive drugs (Glina et al, 1988). In a comprehensive literature review, McVary et al (2001) posited that clinical and basic science studies provide indirect strong evidence that smoking affects penile erection by impairment of endothelium-dependent smooth muscle relaxation.

Our study was designed to determine the hemodynamic mechanisms through which cigarette smoking, as an independent risk factor, induces ED. The evaluation of the differential effect of cigarette smoking on the arterial and venous components of penile vasculature can be used to localize the pathophysiology of vasculogenic ED in smokers, thus adding to a better understanding of this problem.

	Patients and Methods

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Patients

This prospective study was conducted on 109 impotent males, 71 current smokers and 38 nonsmokers. Men were included in the study if they had ED of more than 3 months duration. We excluded ED patients with abnormal androgen profiles and patients with ED risk factors other than smoking. The study population underwent a thorough ED evaluation—personal history (age, occupation, marital status), sexual history, medical and surgical history, and psychological history—and an in-depth review of systems. The physical exam consisted of a general physical, neurologic, and urologic examination. All patients had blood chemistry and serum glucose, testosterone, and prolactin levels evaluated. Patients who met the inclusion criteria after this extensive evaluation underwent the following tests.

Nocturnal Penile Tumescence and Rigidity Monitoring

Nocturnal penile tumescence and rigidity (NPTR) monitoring in this study was performed (1–3 nights) in the sleep unit of the medical center with the use of the Rigiscan device (Dacomed Corporation, Minneapolis, Minn). To ensure a restful night's sleep, the patient was asked to avoid napping, alcohol, and caffeine and to evacuate bladder and bowel prior to going to sleep. Data were collected each morning. The following criteria were considered normal: at least 1 nocturnal erection with at least a 2-cm change in tip circumference and a 3-cm or greater change in base circumference. Also required for normalcy was a rigidity measurement of at least 70% at tip and base and duration of greater than 10 minutes.

Pharmacopenile Doppler Ultrasonography

We used a Toshiba color duplex ultrasound unit with a 7 MHz linear transducer. Each examination commenced with a general penile evaluation for corporal fibrosis, Peyronie plaques, and bilateral cavernosal artery diameter (CAD). Next, we performed intracavernosal injection (ICI) with 1 mL of Trimix (papaverine, prostaglandin E1 [PGE1], and phentolamine combined so that each 1 mL of mixture contained 15 mg papaverine, 5 µg PGE1, and 0.5 mg phentolamine). Patients with suspected venous leak had a tourniquet placed for 2 minutes around the base of the penis prior to the ICI. The patients were scanned at 5-minute interval post-ICI to record internal diameters and Doppler waveforms of the right and left cavernosal arteries. Values for maximal peak systolic velocity (PSV) and end diastolic velocity (EDV) were obtained for both arteries during maximal clinical response. Resistive index (RI) was calculated for each patient by the following formula:

Systematic ultrasound inspection of the corpora revealed no fibrosis or Peyronie plaques. On interpreting pharmacopenile duplex ultrasonography (PPDU) studies, we considered the following figures as normal: PSV > 25 cm/s, increase in CAD of >75%, EDV < 5 cm/s, and RI > 0.9.

Redosing Pharmacocavernosometry

In redosing, complete cavernous smooth muscle relaxation was indicated by demonstration of a linear relationship between the maintenance flow and the intracorporeal pressure (ICP). If this linear relationship was not demonstrated in the first redosing pharmacocavernosometry (RPC) setting, we performed 1 or 2 further measurements with a higher dose of Trimix. Repeated RPC measurements were separated by 1-week intervals. Briefly, a 21-G butterfly needle attached to the Cavomat-7000 Device (Weist Medizintechnik, GMBH Munch, Germany) was inserted into 1 corpora cavernosum. Inserted into the other corpora cavernosum was a 19-G butterfly needle attached to an automatic saline infusion pump. The penis was then injected with 1 mL of Trimix. Five minutes later, saline infusion began and was increased gradually until a predefined baseline erect ICP of 90 mm Hg was reached. The flow required to achieve this initial erection ICP was defined as the induction flow (IF). The flow required to maintain the initial ICP was defined as the maintenance flow (MF). Different MFs were then calculated at different pressures until a steady MF at an ICP of 150 mm Hg was obtained. Pressure loss (PL) was calculated by the following formula: PL = (150 mm Hg) - (ICP reached 30 seconds after flow arrest)/30. Under the above conditions of complete cavernous smooth muscle relaxation, we considered the following RPC criteria as indicative of incompetent penile veno-occlusion: an IF > 30 mL/min, a MF > 5 mL/min, and a PL > 1.5 mm Hg/s.

Statistical Methods

Statistical comparisons between groups were made with Student's t tests. P < .05 was considered statistically significant. To quantify the relative strength of each variable and to determine which diagnostic parameter was most affected by cigarette smoking, we calculated the receiver operating characteristic (ROC) curve areas for each variable with smoking as the outcome. Diagnostic variables more affected by smoking would thus display an area under the curve (AUC) closer to 1.0. In addition, we have used the most significant variates from the Wald test of the beta weights to build a model for the prediction of smoking.

	Results

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Patient Profile

The average age in the group of smokers was 44.3 ± 7.6 years compared with 51.2 ± 6.3 years in the nonsmoking group. For the 71 smoking subjects, the average number of cigarettes smoked per day was 18.6 ± 7.4 cigarettes per day (current smokers). For the nonsmokers, none smoked a cigarette before (never smoked). All patients had ED for more than 3 months, but no patient had any vascular risk factor other than smoking. All had normal postprandial blood sugars, normal blood pressures, and normal serum androgen profiles.

NPTR Results

All patients were monitored with Rigiscan for 3 nights, except those with normal NPTR results in the first or second nights. We considered the patient as having normal NPTR if he had at least 1 episode of nocturnal erection of at least 10 minutes duration with a 2-cm increase in tumescence of the tip and 3-cm increase in tumescence of the base, together with 70% rigidity in the tip and base. According to the above criteria, 61 patients (86%) in the smoker group had abnormal NPTR compared with only 21 patients (55%) in the nonsmoker group (Table 1). The average base and tip tumescence in the smoker and nonsmoker groups (Table 2) was 2.17 vs 2.83 cm and 1.34 vs 1.78 cm, respectively, and the difference was significant for the base and tip (P = .01). Average penile rigidity (Table 2) was 45.7 vs 58.6% for the base and 44.1 vs 55.9% for the tip; again, the difference was statistically significant (P < .05).

PPDU Results

We considered PSV < 25 cm/s and RI < 0.9 as abnormal. In the smoking group, 36 patients (51%) had abnormal PSV compared with 42% in the nonsmoking group. On calculating the RI, 58 patients (82%) had RI < 0.9 between smokers compared with 39% of nonsmokers (Table 1). The average PSV (indicator of arterial perfusion) in the smoking group was 26.8 cm/s compared with 31.2 cm/s in the nonsmokers, and the difference was not found to be statistically significant (P = .19; Table 2). Another indicator of penile arterial perfusion is the percent change in the cavernosal artery after ICI. This percentage was 77.2 vs 86.3% for the smokers and nonsmokers, respectively; again, the difference was not found to be statistically significant (P = .14). The RI (indicator of competence of penile veno-occlusion) was 0.62 for smokers and 0.78 for nonsmokers, and the difference was significant (P = .001; Table 2).

RPC Results

We considered MF > 5 mL/min as an indication of disturbed penile veno-occlusive mechanisms. The average MF among smokers was 20.9 mL/min compared with 11.7 mL/min among nonsmokers, and the difference was statistically significant (P = .001; Table 2). In the smoker group, 63 patients (89%) had an abnormal MF compared with 18 patients (47%) in the nonsmoker group (Table 1).

ROC Curve Analysis

Using smoking as the outcome, we calculated the AUC for each diagnostic parameter in order to quantify its strength in relation to smoking (Table 3). The AUC for those parameters reflecting venous integrity, namely the MF and RI, was 0.77 and 0.74, respectively, compared with 0.58 for the PSV, which reflects the integrity of the arterial side. The ROC for the linear regression model with the use of the 4 most significant variates (base rigidity, tip rigidity, RI, MF) as input features was 0.857.

	Discussion

Top Abstract Patients and Methods Results Discussion Conclusions References

 
The average age in the smoker group in this study was 44.3 years compared with 51.2 years in the nonsmoker group, and the difference was statistically significant (P = .02; Table 2). This implies that smokers presented with ED nearly 7 years earlier than did nonsmokers. This finding was previously reported by Tan and Philip (1999), who found that smoking more than 10 cigarettes a day was independently associated with an earlier onset of andropause symptoms like impotence, weakness, and memory loss. The average age in our smoking group (44.3 years) is relatively younger than that of ED smokers in most other studies. For instance, the average age was 50.5 years in the study of Gray et al (1982), and it was 54.3 years in the study of Bornman and du-Plessis (1986). This interesting observation can be explained by the younger age at which Egyptians start smoking compared with other populations.

We used the Rigiscan device to monitor NPTR in our patients to investigate the organic nature of ED in smokers. In the smoking group, only 86% of our patients had abnormal NPTR compared with 55% in the nonsmoking group (Table 1). Of note, the average base rigidity was 45.7% and 58.6% in the smoking and nonsmoking groups, respectively (P < .05; Table 2). Moreover, on performing ROC curve analysis with smoking as the outcome, the AUC value for base rigidity was 0.79 (Table 3). These NPTR figures suggest an organic etiology underlying ED in cigarette smokers. Impairment of NPTR in cigarette smokers was previously reported by Hirshkowitz et al (1992), who indicated that penile rigidity during nocturnal erections was inversely correlated with the number of cigarettes smoked per day. The organic nature of ED in cigarette smoking was also reported by Xie et al (1997), Jeremy and Mikhailidis (1998), and Tan and Philip (1999).

Numerous previous studies have indicated that ED in smokers is mainly due to underlying vascular pathology. Chronic smoking in the rat was found to produce age-independent moderate hypertension and considerable decreases in penile nitric oxide synthetase activity (Xie et al, 1997). Cigarette smoking was determined to be an independent risk factor in the development of atherosclerotic lesions in the internal pudendal and common penile arteries of young impotent men (Rosen et al, 1991). Purvis et al (1996) demonstrated a correlation between the response to intracorporeal injection of PGE1 and tobacco consumption. Another study showed that inhalation of cigarette smoke inhibits smooth muscle relaxation and impairs the release of neurovascular mediators (Jeremy et al, 1986). Using echo-Doppler and ICI, Vidal-Moreno et al (1996) studied the effect of tobacco on penile vascularization and concluded that cigarette smoking causes ED from vascular damage that is as severe as the damage caused by other factors like arteriosclerosis, diabetes, or hypertension. One report indicated that smoking increases platelet aggregation and induces catecholamines and that nicotine and carbon monoxide has a direct toxic effect on vascular endothelium (Bornman and du-Plessis, 1986).

Most previous studies thus demonstrated a strong link between vascular involvement and the development of ED in smokers. However, most of these studies did not indicate whether the arterial or the venous compartment is more involved in tobacco-induced ED. The unique feature of our trial is that we not only investigated the arterial supply of the penis, but we also studied venous drainage by both PPDU and RPC. To make a pathophysiologic distinction, we calculated ROC curve area to quantify the relative strength of the PSV as an indicator of arterial integrity and of both the RI and MF as indicators of competence of the veno-occlusive system.

Interestingly, the difference in the average PSV between the smoking and the nonsmoking groups was not statistically significant (P = .19), whereas the average MF was significantly higher in the smoking group. This result signifies that MF (indicator of venous involvement) is more impaired by smoking than the PSV (indicator of arterial involvement). These results might be explained by the lower average age in our smoking group (44.3 years) compared with that of ED smokers in most other studies. It could be speculated that impairment of venous drainage plays a more significant role in younger ED patients because smoking-induced atherosclerotic changes affecting the arterial system develop over a longer period. The clinical significance of base and tip rigidity, RI, and MF is underscored by the high ROC produced by a logistic regression model that used these parameters as input features.

To our knowledge, this study is the first to investigate the venous system in smokers with the use of the redosing technique of pharmacocavernosometry. Many previous studies indicated that smoking is a cause for penile arterial insufficiency. For example, smoking was shown to decrease the intracavernosal pressure and penile brachial index (Condra et al, 1986; Glina et al, 1988; Morales et al, 1998). Other studies have shown that smoking predisposes men to premature atherosclerosis in the internal pudendal, common penile, and cavernosal arteries (Forsberg et al, 1989; Rosen et al, 1991). Degenerative changes in the corpus cavernosum of smokers was reported by Mersdorf et al (1991). A later ultrastructural study demonstrated a statistically significant reduction in the amount of corporeal smooth muscle, endothelial cells, and elastic fibers in smokers compared with nonsmokers (Yaman et al, 2003). None of these studies investigated the venous system of impotent smokers, which, as evident from our results, is highly involved in the development of ED.

	Conclusions

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On the basis of our findings, we concluded that ED in smokers is a result largely of impaired penile veno-occlusive mechanisms. This finding might serve to guide further studies investigating the biological basis of erectile pathology in smoking males.

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