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Keywords:

  • Diabetes mellitus;
  • neuropathy;
  • male erectile dysfunction

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Objective

To correlate abnormalities of nerve fibres in the lower limbs with erectile dysfunction in male diabetic patients, using a range of quantitative sensory and autonomic function tests.

Patients and methods

The study included 68 male diabetic patients with symptomatic erectile dysfunction and 11 matched diabetics without erectile dysfunction; none had clinical evidence of peripheral vascular disease or psychological disorder. Patients were evaluated with a symptom questionnaire based on the Michigan Neuropathy Screening Instrument questionnaire and examined clinically. Sural and peroneal nerve-conduction studies, and quantitative sensory and autonomic tests (vibration, thermal, light-touch thresholds, sensory and autonomic cutaneous axon-reflexes) were used to detect nerve abnormalities in the lower limbs, which were correlated with erectile dysfunction.

Results

Symptoms of neuropathy were more common in the group with male erectile dysfunction (MED), but statistically significant only for neuropathic pain (53% MED, 18% nonMED, P<0.05, chi-square test) and gastroparesis (44% MED, 0% nonMED, P<0.05). Tests of unmyelinated afferents (warming perception and capsaicin-induced sensory axon-reflex vasodilatation) were most often abnormal, sometimes with no other abnormalities on tests or neurological examination. However, abnormality of warm perception was not significantly different between groups (81% MED, 70% nonMED), suggesting that it is a poorer discriminant than abnormal sensory axon-reflex vasodilatation (89% MED, 22% nonMED, P<0.001). The only other significant test difference was decreased sural nerve action potential (70% MED, 22% non-MED, P<0.01).

Conclusions

There appeared to be preferential involvement of unmyelinated sensory fibres that mediate axon-reflex vasodilatation in the limbs of diabetic patients with erectile dysfunction. This test appears to be a helpful indicator of neurological involvement in erectile dysfunction, and may be used to monitor the effect of new treatments.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Male erectile dysfunction (MED) is a serious and common complication in diabetes mellitus; its prevalence varies considerably between studies, at 20–77.5% [1[2]–3]. The aetiology of organic MED in diabetics can be multifactorial, i.e. neurogenic, vascular, pharmacological and endocrine [2]. Peripheral neuropathy is the most important cause of MED in diabetics [4], but it remains poorly characterized.

Erectile function depends on a complex interaction of sensory and autonomic fibres [5,6]. Direct involvement of pelvic nerves has been tested in diabetic MED with various electrophysiological methods, including recordings of the bulbocavernous [7,8] and other sacral reflexes (pudendo-anal, pudendo-urethral) [9], dorsal penile cerebral-evoked responses [8,10] and sympathetic skin responses [10]. Nocturnal penile tumescence studies may be helpful in differentiating between organic and psychogenic MED in neuropathy, and may also be used to quantify erectile dysfunction in diabetics [3]. However, these studies are difficult to perform routinely and may not identify the nerve fibre types that are preferentially affected in diabetics with MED.

Clinical evidence of peripheral neuropathy on examination and nerve tests have often been used to support a neurogenic cause of MED. The diagnosis of peripheral neuropathy in a clinical setting may be difficult in itself and should involve quantitative sensory testing [11]. Cardiovascular reflex tests [12] have been used to detect generalized autonomic nerve dysfunction in MED. Fowler et al. [13] and Vardi et al. [14] used peripheral quantitative sensory tests (QSTs) to study the prevalence of neuropathy, and to identify particular test abnormalities, in diabetic patients with MED. More recent investigations have also used QSTs on the penile skin [15[16]–17]; whereas penile thermal sensation may have a place in the evaluation of MED, biothesiometry is unlikely to be of value, as few large nerve fibres innervate penile skin [17].

Therefore we studied diabetic patients systematically, with and without MED but matched in other respects, to characterize the neuropathy in MED and to identify nerve fibre subtypes that may be preferentially affected.

Patients and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

The study included 68 diabetic patients with symptomatic MED and 11 matched diabetic patients without MED. The patients’ characteristics are shown in Table 1. A standardized symptom questionnaire based on the Michigan Neuropathy Screening Instrument questionnaire [18], with additional questions to assess autonomic nervous system function, was administered. The additional questions included those eliciting ‘sensation of fullness after meals’ as a measure of gastroparesis, nocturnal diarrhoea, constipation, postural symptoms including dizziness and bladder dysfunction. Questions about erectile dysfunction included the presence of morning and nightly erections, rigidity sufficient for intercourse, and whether erections could be sustained for the duration of intercourse; the patient was included in the MED group if the last two questions were answered negatively. The presence of a generalized peripheral neuropathy was assessed, based on neuropathic symptoms (NS), abnormalities on neurological examination (NE), quantitative sensory examination (QSE), quantitative autonomic examination (QAE) and nerve-conduction studies (NC), using the staging system of Dyck [11]. In brief, stage 0 (no neuropathy) was the presence of <2 abnormalities among NC, NE, QSE, QAE and NS; stage 1 (asymptomatic neuropathy), the presence of ≥2 abnormalities among NC, NE, QSE and QAE, but no abnormality of NS, and in the absence of any other cause of neuropathy; stage 2 (symptomatic neuropathy), as stage 1, but with NS of lesser severity than in stage 3; stage 3 (disabling neuropathy) as stage 1, but with disabling NS. No patient had evidence of peripheral vascular disease by assessing foot pulses and baseline cutaneous laser Doppler flowmetry, or psychological disorder. Additional vascular risk factors were recorded, including any history of ischaemic heart disease, smoking and hypertension.

Table 1.  Patient characteristics, staging of neuropathy (Dyck criteria) and results of sensory and autonomic tests in diabetic patients Thumbnail image of

The methods of quantitative sensory and autonomic testing have been described previously [19]. Briefly, for the thermal threshold, a computer-driven Marstock Thermal Threshold Testing System (Somedic Thermotest, Stockholm, Sweden) was used. The device was set at a rate of rise of 1 °C/s. The thermode was placed under the instep of the right foot. The baseline temperature was set at a neutral point, usually 30–32°C. Thermal thresholds were determined for cool and warm sensation as a mean of four consecutive tests. Vibration thresholds were determined using a biothesiometer placed at the distal interphalangeal joint of the right big toe. Three ascending and three descending trials were carried out, and after deletion of the highest and the lowest value the remaining four values were averaged. Light touch thresholds were determined using Semmes-Weinstein hairs placed on the top of the distal phalanx of the right big toe. The lowest force detected by the patient was recorded. Axon reflex vasodilation was measured with a laser Doppler device (Perimed PF4, Stockholm) after intradermal injection with capsaicin (0.05μg in 10μL) into the right lateral calf. The difference between the basal blood flow and the maximum blood flow after injection was recorded as the rise in flux units. Axon reflex sweating was measured using an evaporimeter (Servomed, Stockholm, Sweden) after intradermal injection with nicotine (0.8μg in 0.2mL) into the right lateral calf; the peak sweat rate was recorded. In case of reduced axon-reflex vasodilatation, sweat glands were stimulated directly by intradermal injection with methacholine (4 μg in 0.1mL), to establish a neurogenic deficit. Sural and peroneal nerve conduction studies (SAPs) were carried out on a Medelec Sapphire machine, by the same examiner using standard techniques. An abnormal result was defined as ≥2 sd above the mean of age-matched controls. The results from all assessments were analysed using the chi-square test, unless stated otherwise.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

The MED and nonMED groups were matched for their baseline characteristics, in that differences for the known risk factors for neuropathy were not statistically significant (Table 1); other differences were either marginal or not likely to be of clinical significance with respect to MED in this group of patients.

Symptoms were generally more common in the MED group, but statistically significant only for neuropathic pain in the distal lower limb (MED 53%; nonMED, two of 11, P<0.05). Autonomic symptoms were also more common in the MED patients, but only gastroparesis was statistically different (MED 43%, nonMED 0, P<0.05). Using the Dyck criteria, MED patients had evidence of more severe clinical neuropathy (62% in stages 2 or 3 vs three of 11 in the nonMED group, P<0.05; Table 1).

The results of quantitative sensory and autonomic testing are also shown in Table 1. Axon reflex vasodilatation and warm perception threshold were most commonly abnormal in diabetics with MED. They were followed by vibration threshold, light touch threshold, cool perception threshold and axon-reflex sweating. On the nerve conduction studies, SAPs were more commonly abnormal in the MED group. Warm perception threshold abnormalities were only marginally more common in the MED group, but axon reflex vasodilatation was significantly (P<0.001) more often abnormal in the MED group.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Neurogenic MED may result from abnormalities of sensory and/or autonomic fibres [5]. In the present study, tests of sensory small nerve fibre function were most commonly abnormal in the lower limbs in diabetics. Axon-reflex vasodilatation and the warm detection threshold were abnormal in most cases, with the former being the best discriminator between diabetics with and without MED. Fowler et al. [13] found abnormal warm thresholds in all their diabetic patients with neurogenic MED; however, they did not study matched nonMED diabetics. Further studies, with more nonMED patients and with a prospective design, are warranted. There may thus be subpopulations of unmyelinated fibres, nociceptors mediating axon-reflex vasodilatation and those mediating warm sensation, that are affected differentially in the course of diabetes mellitus. The associated symptoms of neuropathic pain and gastroparesis in the present MED patients appear to support this view. It has been shown that unmyelinated fibres are reduced in the vagus nerve in patients with diabetic gastroparesis [20]. The relationship of the present findings in the lower limbs to sexual dysfunction is indirect, but there may be underlying common mechanisms, as discussed below.

Small sensory and sympathetic fibres are dependent on nerve growth factor (NGF), which is produced by the target organ, e.g. skin keratinocytes and blood vessels. In our previous study, skin NGF depletion in diabetic patients with mild neuropathy correlated with reduced axon-reflex vasodilatation [19]. These findings may thus reflect a failure of neurotrophic support, leading to selective fibre dysfunction and the pattern of clinical presentation. Burgers et al. [21] showed in rats that treatment with NGF can facilitate pelvic nerve regeneration after ablation of the cavernosal nerve, with improvement of erectile function. Milner et al. [22] reported that NGF treatment leads to an increase in substance P and calcitonin-gene related peptide (CGRP) in the nerve fibres supplying the urogenital tract in rats. Both peptides are present in NGF-dependent neurons, mediate the axon-reflex vasodilatation response to capsaicin, and play a role in the physiology of erection [5,23]. Substance P is mainly found in nerve fibres around the corpuscular receptors of the human glans penis [24] and CGRP is important for penile erectile response in monkeys [25]. Efferent fibres and their neuroeffector agents are also depleted in penile tissue of diabetics with MED, i.e. VIP-ergic, cholinergic and noradrenergic nerves [26,27]. Whether NGF or other related growth factors can be beneficial in diabetic erectile dysfunction remains to be shown in man.

In the present study, a higher proportion of patients reported MED and neuropathic pain than in published prevalence studies in diabetics, as patients were recruited from a MED clinic, a general diabetic clinic, and referrals to a neurologist for treatment of neuropathic pain. In any case, the method of assessment of MED, by either history or nocturnal penile tumescence studies, results in wide variations of its reported prevalence in diabetics. Klein et al. [28] found that the prevalence of self-reported MED in 365 diabetic patients was age-dependent, ranging from 1.1% (21 to 30 years) to 47.1% (≥43 years). In a European population study of 3250 randomly selected patients with IDDM, the prevalence of MED, using similar questions in the assessment as in this study, was 2–85% in the different countries [29]. The authors claimed cultural differences in personal attitudes towards these questions as responsible for these variations. A British study using questionnaires found 35% of 541 diabetic patients suffered from MED; at the follow-up after 5 years, 28% of the patients had developed MED [30,31].

Vardi et al. [14] found the prevalence of neuropathy to be 38% in diabetics with MED. Again, the higher prevalence in the present study may be explained by the use of a larger set of quantitative tests in the evaluation of patients, and thereby the detection of more subclinical cases of neuropathy, and also by the recruitment methods. However, the methods of recruitment and the severity of neuropathy cannot alone account for the marked difference in the proportion of patients who show abnormalities on individual sensory small nerve fibre tests.

In conclusion, tests of sensory small nerve fibre function were most commonly abnormal in the lower limbs in diabetics. There appeared to be preferential involvement of unmyelinated sensory fibres that mediate axon-reflex vasodilatation in diabetic patients with erectile dysfunction. This test may be the best discriminator of neurological involvement in diabetic erectile dysfunction and may help monitor the effect of new treatments, such as nerve growth factors.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

This work was supported by the Medical Research Council, UK and Amgen, Inc., USA.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References