Abstract and Introduction

Abstract

It is unclear whether high blood pressure per se or antihypertensive drug use causes erectile dysfunction (ED). The aim of this study was to investigate the effect of cardiovascular diseases and their concomitant medications use on the incidence of ED. The target population consisted of men aged 55, 65 or 75 years old residing in the study area in Finland in 1999. Questionnaires were mailed to 2837 men in 1999 and to 2510 of them 5 years later. The follow-up sample consisted of 1665 men (66% of those eligible) who responded to both baseline and follow-up questionnaires. Men free of moderate or severe ED at baseline (N=1000) were included in the study. ED was assessed by two questions on subject ability to achieve or maintain an erection sufficient for intercourse. Poisson regression model was used in the multivariable analyses. The risk of ED was higher in men suffering from treated hypertension or heart disease than in those with the untreated condition. The risk of ED was higher in men using calcium channel inhibitor (adjusted relative risk (RR)=1.6, 95% confidence interval (CI) 1.0-2.4), angiotensin II antagonist (RR=2.2, 95% CI 1.0-4.7), non-selective β-blocker (RR=1.7, 95% CI 0.9-3.2) or diuretic (RR=1.3, CI 0.7-2.4) compared with non-users. ED was not associated with using organic nitrates, angiotensin-converting enzyme inhibitors, selective β-blockers and serum lipid-lowering agents. In summary, calcium channel inhibitors, angiotensin II antagonists, non-selective β-blockers and diuretics may increase the risk of ED.

Introduction

Erectile dysfunction (ED) is a common condition in men with cardiovascular disease.^[1,2,3,4,5] ED is considered as a manifestation of systemic vascular disease or atherosclerosis.^[6] Previous cross-sectional studies have shown associations between heart disease, high blood pressure and their medications use, and ED.^[1,5,7]

Longitudinal studies have also found a higher incidence of ED in men with hypertension than in those with normal blood pressure.^[3,4] In these studies, heart disease was not significantly associated with ED. In another prospective study,^[2] only treated hypertension and heart disease increased the risk of ED, but not the untreated conditions.

The association between cardiovascular diseases and ED is necessarily confounded by concomitant medications use. A drug-related effect on ED is difficult to distinguish from the effect of disease. It is unclear whether high blood pressure per se or antihypertensive drug use causes ED.

We investigated the effect of cardiovascular diseases and their concomitant medications use on the incidence of ED in a population-based follow-up study among Finnish men aged 55-75 years old at baseline.

Materials and Methods

The target population of this study consisted of men aged 55, 65 or 75 years old residing in the city of Tampere or 11 adjacent municipalities in Finland in 1999. The study population identified from the national population register. Information was collected by a mailed self-completed questionnaire, comprising of items on sociodemographic status, lifestyle factors, medical conditions, medications and erectile problems. The study protocol was approved by the Tampere University Hospital committee of research ethics.

A questionnaire was sent in May 1999 to 2837 men, with a reminder to the 1162 who did not respond to the first within 3 months. Overall, 2133 men (75%) responded to baseline inquiry. Subjects with missing information on erectile function were excluded and 1846 men included in the baseline sample.

A similar questionnaire was mailed to 2510 of the same men 5 years later in the last quarter of 2004, with a reminder to the 844 who did not respond to the first inquiry within 3 months. Between 1999 and 2004, 318 men died, three emigrated and six did not have an address in the population registry. Altogether, 1905 (76%) questionnaires were returned.

Overall, 1665 men (66% of those alive and eligible) responded to both baseline and follow-up surveys. Subjects with missing information on erectile function were excluded and finally 1374 were included in the follow-up sample. Men with moderate or severe ED at baseline (N=374) were excluded and those with no or mild ED (N=1000) included in the study.

Information on medical history and their concomitant medications use was obtained by separate and independent questions. Information on regular drug use and on the type of drugs was collected. The question for cardiovascular medication use was 'Do you regularly use cardiac or antihypertensive drug?' List the names of your drugs. The Anatomical Therapeutic Chemical classification system was used for the classification of cardiovascular drugs.

ED was assessed by two questions on subject erectile capacity: 'Have you had problems getting an erection before intercourse begins?' and 'Have you had problems maintaining an erection once intercourse has begun?' For both questions, the four response options were as follows: never, sometimes, quite often and intercourse does not succeed. Moderate or complete ED was defined as frequent failure of intercourse ('quite often' or 'does not succeed' at least in one of the two questions).

Poisson regression model was used in the multivariable analyses. Age, education, marital status, smoking, diabetes, cerebrovascular disease, depression, hypertension and heart disease were used as covariates. All baseline characteristics that influenced ED with P-value less than or equal to 0.20 in the age-adjusted models were entered into the multivariable model, followed by a stepwise backward elimination. The final models included age, cardiovascular disease, cardiovascular drug use and factors that had effects on ED at P-value less than or equal to 0.20 in the stepwise backward regression model. For stratified analysis, antihypertensive and cardiac drugs were combined into a single variable of cardiovascular medication.

Results

Men with complete follow-up information did not differ from those lost to or with incomplete data at follow-up with respect to hypertension and antihypertensive drugs use ( Table 1 ). However, men with incomplete follow-up were on average 4 years older and reported a higher prevalence of heart disease, diabetes, ED and heart drug use than those with complete follow-up.

Compared with men free of cardiovascular diseases and concomitant medications use ( Table 2 ), the risk of ED was higher in men with untreated heart disease, treated hypertension, treated heart disease and in those with both treated hypertension and heart disease. The incidence of ED was also higher in men using cardiovascular medication for conditions other than hypertension and heart disease. However, ED was significantly associated with only treated hypertension (adjusted relative risk (RR)=1.4, 95% confidence interval (CI) 1.0-2.0). The risk of ED was not elevated in men with untreated hypertension.

Men taking angiotensin II antagonist (adjusted RR=2.2, 95% CI 1.0-4.7) or calcium channel inhibitor (RR=1.6, 95% CI 1.0-2.4) were significantly at higher risk of ED compared with non-users ( Table 3 ). A higher risk of ED was also found in men using non-selective β-blocker (RR=1.7, 95% CI 0.9-3.2) or diuretic (adjusted RR=1.3, CI 0.7-2.4) relative to non-users. The estimates, however, were not statistically significant. ED was not associated with using organic nitrates, angiotensin-converting enzyme inhibitors, selective β-blockers, serum lipid-lowering agents and other cardiovascular medication.

Discussion

Our findings suggest that the use of cardiovascular medication increases the risk of ED. The most likely drugs were calcium channel inhibitors, non-selective β-blockers, angiotensin II antagonists and diuretics. ED was not associated with using organic nitrates, angiotensin-converting enzyme inhibitors, selective β-blockers and serum lipid-lowering agents.

In line with the Massachusetts Male Aging Study,^[2] we found the association of ED with treated hypertension, but not with the untreated condition. A higher risk of ED has been reported in men using calcium channel antagonist, non-selective β-blocker or diuretic compared with non-users.^{[7,8,9,10,11]} Consistent with other studies,^[8,11] we found no increased risk of ED in men using angiotensin-converting enzyme inhibitors or serum lipid-lowering agents.

Unlike other studies,^[12,13] we found a higher incidence of ED in men using angiotensin II inhibitor compared with non-users. Angiotensin II is produced by the corpus cavernosum and causes contraction of cavernosal smooth muscle.^[14,15] On the other hand, angiotensin II receptor antagonist induces smooth muscle relaxation. Cavernosal smooth muscle tone is controlled by a balance between angiotensin II and nitric oxide,^[15] and imbalance between them may induce ED.

The mechanisms by which medications contribute to ED have not been clearly identified. Antihypertensive drugs may cause ED through reducing perfusion pressure by a drop in blood pressure. They may also induce ED by direct or indirect effect on cavernosal smooth muscle. β-Blockers may cause ED through increasing the latency to initial erection and reducing the number of erectile reflexes. In addition, they may cause ED by increasing the smooth muscle contraction. They are also associated with a reduction in testosterone level.^[11,16]

An important aspect from the point of view of health services and preventability of ED is whether the disease, the biological process or its treatment causes ED. In a non-selected population-based sample, we showed an increased risk of ED in men with cardiovascular disease. Our findings are consistent with the hypothesis that the antihypertensive drugs more likely increase the risk of ED than hypertension per se. However, medication use is related to disease severity and drug effect on ED is difficult to distinguish from disease severity. Men with hypertension who use antihypertensive drug are likely to have more aggressive disease than untreated patients. Antihypertensive drugs are not used only in mild cases of hypertension. Long-term and severe systemic arterial hypertension can lead to vascular-endothelial damage.

A limitation of the study is that allocation of men into different combinations resulted in eight groups and, hence, small numbers of observations. Therefore, the results were not statistically significant, but consistent patterns emerged. The combined sample of any disease without any medication showed RR somewhat less than unity compared to those with no disease and no medication. In contrast, all those with any medication independently of disease status showed an adjusted RR of 1.4. Especially, there was no indication that hypertension without any medication use would increase the risk of ED. Instead, there was an increased risk of ED in all categories with medication independently of the presence or absence of heart disease or hypertension or both. The numbers after sufficient grouping remained small and the individual differences only seldom reached statistical significance.

We started with a well-defined and relatively large target population of about 2800 men. According to international experience or standards, the response rates were relatively high. ED is a sensitive and confidential area of human life, but the coverage of ED answers in the questionnaire was also high. There is a high correlation between any disease and treatment for it. Therefore, the discordant observations of disease without treatment and treatment without disease remained rare and are probably selected. In this study, there were only few cases of most extreme combinations and, hence, the statistical power remained low and our findings should be confirmed by subsequent studies.

Because of long, 5-year, follow-up, most severe cases at entry were likely to get removed at the end of follow-up, as a result of death or inability of filling the questionnaire. Men lost to or with no information at follow-up did not differ from those with completed follow-up, regarding hypertension and antihypertensive drug use. As expected, men with incomplete follow-up were on average older and had more often heart disease and ED than the study population. Therefore, the RRs of ED by cardiovascular disease or medications use may have been diluted. The consistent results within the users of any medication independently of disease or their combination are also an indication for the lack of etiological role of the disease. Therefore, the medication remains as a plausible hypothesis.

Conclusion

Calcium channel inhibitors, non-selective β-blockers, angiotensin II antagonists and diuretics may increase the risk of ED. ED does not seem to be a problem in men using organic nitrates, angiotensin-converting enzyme inhibitors, selective β-blockers or serum lipid-lowering agents.

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Abbreviation: ED, erectile dysfunction.

 

Abbreviations: ED, erectile dysfunction; RR, relative risk.
^aAdjustment for age, diabetes and depression.

 

Abbreviations: ED, erectile dysfunction; RR, relative risk.
^aAdjustment for age, diabetes, depression and cardiovascular disease.

 

Financial support for this study was provided by the Medical Research Fund of Tampere University Hospital.

Dr R Shiri, Tampere School of Public Health, University of Tampere, Klaneettitie 1 D 105, Helsinki Fin-00420, Finland. E-mail: r_shiri@yahoo.com