¹Department of Urology, Kyoto Prefectural University of Medicine, Kyoto, Japan

²Department of Urology, Toujinkai Hospital, Kyoto, Japan

³Department of Urology, Kyoto First Red-Cross Hospital, Kyoto, Japan

⁴Department of Urology, Nishijin Hospital, Kyoto, Japan

⁵Department of Internal Medicine I, Kyoto Prefectural University of Medicine, Kyoto, Japan

⁶Department of Pharmacology, Kyoto Prefectural University of Medicine, Kyoto, Japan

Correspondence to: Y Mizutani, Department of Urology, Kyoto Prefectural University of Medicine, Kawaramachi-Hirokoji, Kyoto. 602-8566, Japan. E-mail: ymizutan@koto.kpu-m.ac.jp

Erectile dysfunction (ED) is a common complication of diabetes mellitus. Erythrocyte aldose reductase (AR) has been implicated in a variety of diabetic complications. The subjects were 62 diabetic patients, of whom 25 were treated with hemodialysis (chronic renal failure CRF group) and the remaining 37 did not have chronic renal failure (DM group). The controls were 20 healthy volunteers age-matched to the patients. The level of AR was measured by the quantitative determination kit for AR in all patients and controls. In this study, ED was diagnosed by 5-item version of the International Index of Erectile Function (IIEF-5). The average level of AR in the CRF group was significantly higher than that in the DM group and controls (P<0.001). The average level of AR in the DM group without ED was significantly lower than that in the DM group with ED and controls (P<0.005). These results suggest that the level of AR may be a useful modality for prediction of ED in diabetic patients.

International Journal of Impotence Research (2002) 14, 213-216. doi:10.1038/sj.ijir.3900855

erectile dysfunction; erythrocyte aldose reductase; diabetes mellitus; IIEF-5; chronic renal failure

Introduction

Erectile dysfunction (ED) is one of common complications of diabetes mellitus.¹ Erythrocyte aldose reductase (AR) has been implicated in various diabetic complications.² AR is an enzyme in the polyol pathway, and catalyzes the reduction of glucose to sorbitol. The acceleration of this pathway and ensuing metabolic imbalances have been postulated to play a key role in the pathogenesis of diabetic complications. The enzyme level did not correlate with age, duration of diabetes, fasting blood glucose, or glycosylated hemoglobin (Hb A_1C) levels, which represent glycemic control of the patient. The level of AR may affect the susceptibility and prognosis of diabetic retinopathy.^3,4 AR level was higher in diabetic patients with complications than in those showing no sign of complications.⁴

Nitric oxide (NO) is the mediator of penile erection.⁵ The enhanced polyol pathway activity suppressed the production of NO by NO synthase.^6,7 We researched the relationship between ED and AR in diabetic patients and studied the usefulness of AR for prediction of ED in diabetic patients.

Patients and methods

Patients

The subjects were 62 diabetic patients, of whom 25 had chronic renal failure treated with hemodialysis (CRF group) and the remaining 37 did not have chronic renal failure (DM group). The patients in the CRF group ranged from 45 to 69 y old (mean 59.6±6.6). The patients in the DM group ranged from 25 to 69 y old (mean 52.9±12.2). There were no significant differences in age between the CRF group and the DM group. The controls were 20 healthy volunteers age-matched to the patients (from 25 to 69 y old, mean 55.3±11.2).

Questionnaire

We used the Japanese 5-item version of the International Index of Erectile Function (IIEF-5). The IIEF-5 questionnaire was self-administered in their homes. Sixty-six out of the 85 male diabetic patients who were given the IIEF-5 questionnaire responded (response rate; 77.6%).

Measurement of AR

The level of AR in the blood was measured in all the patients and controls by the quantitative determination kit for AR using enzyme immunoassay (Mitsubishi Gas Chemical Company Inc. Tokyo, Japan). The enzyme level was corrected by hemoglobin level.

Statistical analysis

The average score of IIEF-5 and the average level of AR were compared among the control, DM and CRF groups. We evaluated the prevalence of ED using IIEF-5. ED was diagnosed when the severity of ED by IIEF-5⁸ was mild to moderate, moderate or severe (the score of IIEF-5£16). The data were analyzed using the Mann-Whitney U-test.

Results

IIEF-5

The average score of IIEF-5 in the control, DM and CRF groups were 21.3±2.5, 13.0±7.8 and 5.2±6.7, respectively (Table 1). The average score of IIEF-5 in the DM group was significantly lower than that in the control group. The average score of IIEF-5 in the CRF group was significantly lower than those in the control and the DM groups. The prevalence of ED in the control, DM and CRF groups were 0%, 51.3% and 92.0%, respectively. There was a significant difference between each group and controls (P<0.0001).

AR

The average level of AR in controls, DM group and CRF were 9.9±1.0, 9.4±1.3 and 16.4±9.5 ng/mg Hb, respectively (Table 2). The average level of AR in the CRF group was significantly higher than those in the control and DM groups (P<0.0001). The average level of AR in the DM group without and with ED was 8.7±1.0 and 10.0±1.1, respectively (Table 3). The average level of AR in the DM group without ED was significantly lower than those in the DM group with ED and the control group (P<0.005). The average level of AR in the CRF group with and without ED was 16.4±9.9 and 16.6±3.0, respectively. There was no significant difference between AR level in the CRF group with and without ED. The average AR level in all diabetic patients without and with ED was 9.5±2.7 and 13.5±8.0, respectively. The average AR level in all diabetic patients without ED was significantly lower than that with ED (P<0.005).

Discussion

The present study demonstrated that the prevalence of ED in the DM group was significantly higher than that of the control group. The prevalence of ED in the CRF group was significantly higher than those of the control and DM groups. In addition, the average IIEF-5 score in the DM group was lower than that of the control group. The average IIEF-5 score in the CRF group was lowest among the three groups. These results suggest that the severity of ED in diabetic patients with severe complications such as chronic renal failure may be more severe than that with no or mild complications.

Most of the cellular glucose is phosphorylated into glucose 6-phosphate by hexokinase under normoglycemic conditions.² A minor part of nonphosphorylated glucose enter the so-called polyol pathway. AR, an enzyme in the polyol pathway, catalyzes the reduction of glucose to sorbitol. Sorbitol is subsequently converted to fructose by sorbitol dehydrogenase. The two enzymes constitute the polyol pathway, the alternate route of glucose metabolism. The acceleration of this pathway and ensuing metabolic imbalances have been postulated to play a key role in the pathogenesis of diabetic complications.² Nitric oxide (NO) is the mediator of penile erection.⁵ Under the enhanced polyol pathway activity, the production of NO from L-arginine by NO synthase is suppressed by the depletion of NADPH, thereby reducing the release of NO.^6,7 Therefore the acceleration of this pathway under hyperglycemia may cause ED.

In our study, the average level of AR in the CRF group was significantly higher than those in the control and DM groups. The level of AR was corrected by hemoglobin in this study. When the patients had severe anemia, the level of AR might be high. The patients with chronic renal failure had renal anemia. In this study, there were no significant differences of the hemoglobin level between the CRF group and other groups because of erythropoietin therapy for the CRF group. Hamada et al reported that the enzyme activity of AR was significantly higher in diabetic patients with complications than those without complications.⁹ Chronic renal failure is one of the severe complications of diabetes.

The average level of AR in all diabetic patients (DM and CRF groups) with ED was significantly higher than in those without ED. The average level of AR in the DM group without ED was significantly lower than those in the control and DM groups with ED. The level of AR in diabetic patients without complications may be lower than that in diabetic patients with complications. Ito et al reported that the AR level was significantly higher in patients with overt neuropathy than that in patients without demonstrable neuropathy.¹⁰ In their study, multivariate logistic regression analysis identified that a higher level of AR is one of the independent risk factors for overt neuropathy. A high level of AR may affect the susceptibility and prognosis of diabetic retinopathy.^3,4 These findings suggest that diabetic patients whose AR level is low may have a low risk for ED.

Although the average level of AR in the DM group with ED was significantly higher than that in the DM group without ED, there were no differences in the AR level between the DM group with ED and control groups in this study. Ito et al reported that the AR level in diabetic patients with overt neuropathy was higher than that without neuropathy, and that there was no difference in AR level between the controls and diabetic patients with overt neuropathy.¹⁰ These results were comparable to our results.

The level of AR expressed in the erythrocyte seems to be stable, as no apparent alteration in the enzyme level was observed during the follow-up period of 12 months in the studied patients.¹⁰ In their study, the enzyme level remained unchanged irrespective of improved or stably high HbA_1C levels during the follow-up period. The enzyme level was not correlated with age or duration of diabetes.² Therefore the measurement of the AR may be a good method for prediction of ED.

In conclusion, this study suggests that the lower level of AR may be a lower risk for ED in diabetic patients without chronic renal failure. Since the level of AR is stable and did not correlate with age, duration of diabetes and glycemic control, the measurement of AR may be a useful modality for prediction of ED in diabetic patients without renal dysfunction.

Acknowledgements

We gratefully acknowledge Dr M Maegawa and Dr M Kondo for assistance, with the IIEF-5 questionnaire and measurement of AR in male dialysis patients.

Some of the results in this paper were presented at the 9th World Meeting on Impotence Research held in Perth, Western Australia, in November 2000 and at the 96th Annual Meeting of the American Urological Association held in Anaheim, California in June 2001.

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Table 1 The average score of IIEF-5 and the prevalence of ED in control, DM and CRF groups

Table 2 The average level of AR in control, DM and CRF groups

Table 3 The average level of AR in DM and CRF groups with or without ED