The effect of sildenafil citrate (viagratm) on the frequency, duration, and degree of nocturnal penile tumescence in diabetic neuropathic men

Int J Diabetes & Metabolism (2009) 17:45- 52 The effect of Sildenafil citrate (ViagraTM) on the frequency, duration, and degree of
nocturnal penile tumescence in diabetic neuropathic men
Department of Physiology, Faculty of Medicine, Umm-al-Qura University, Makkah, Saudi Arabia ____________________________________________________________________________________________________
Abstract
The present study deals with the effects of sildenafil citrate (Viagra) on the nocturnal sleep related erectile dysfunctions in
diabetic neuropathic men. In this investigation 50 type 1 and 50 type 2 diabetic patients with and without an objective
evidence of neuropathy, aged between 15 to 60 years with a duration of diabetes distributed over 1-20 years were included
along with their age matched non diabetic controls. Subjects were evaluated for nocturnal penile tumescence (NPT) and
rigidity testing and the effect of oral administration of 100 mg. of sildenafil citrate (Viagra) was noted on the above-
mentioned parameters. Both types of diabetic neuropathic patients exhibited a highly significant decrease in all nocturnal
tumescence parameters including frequency, duration, and degree. However, both type 1 and type 2 patients without
neuropathy showed a non-significant difference in the above-mentioned parameters than their respective control subjects,
thus suggesting that impotence and altered nocturnal erectile responses are likely to be associated with an increased frequency
to autonomic neuropathy in these patients irrespective of their type of diabetes. Treatment with oral administration of 100 mg.
of sildenafil in both type 1 and type 2 diabetic neuropathic patients indicated significant increase (P<0.0001) in all the
parameters of NTP and rigidity testing, however this difference was not significant in both types of diabetic patients without
neuropathy before and after oral administration of sildenafil and when compared with their respective control subjects thus
suggesting that oral administration of sildenafil citrate improves the quality of nocturnal erection in both type 1 and type 2
neuropathic group of patients. We thus conclude that sildenafil citrate is an effective first-line therapy for erectile dysfunction
in diabetic men with impotence of neuropathic etiology. These results will improve our insight into the management of sexual
disorders as part of diabetic care, and suggest guidelines for the prescription of Viagra in diabetic neuropathic patients.

Key words: Sildenafil, nocturnal penile tumescence, diabetes, neuropathy
Introduction
Direct evidence for a neuropathic etiology of diabetic Erectile dysfunction (ED) etiology in diabetes is erectile dysfunction comes from studies that show structural multifactorial, including neuropathy, vascular disease, changes in autonomic nerve fibers supplying the corpora endocrine disorders, psychogenic factors, and anti-diabetes cavernosa.6 The patient may complain of the insidious onset and gradual progression (over 6 months to 2 years) of inability to attain and/or maintain an adequate erection as Diabetic autonomic neuropathy (DAN) is one of the most well as loss of morning erections although libido remains severe and common complications of diabetes. Major normal. Testicular anesthesia, presence of a neurogenic clinical manifestations of DAN include resting tachycardia, bladder, and delayed bulbocavernous reflex response orthostatic hypotension, constipation, loss of penile erection latency are indirect evidence for a neuropathic etiology of and/or retrograde ejaculation and ED. In men, DAN may the patient's complaints. Absence of nocturnal tumescence cause ED with an incidence estimated to be between 35 and as measured by penile strain gauge monitoring is helpful in 75%.2,3,4,5 A complete workup for erectile dysfunction in establishing the organic nature of the impotence.7,8,9,10 It is diabetic neuropathic men may include measurement of now established that sexual dysfunction is a common nocturnal penile tumescence tests to assess penile, pelvic, complication of diabetic autonomic neuropathy in both men and spinal nerve function and measurement of penile and and in women.11 Despite the general agreement of previous investigators that the prevalence of impotence in diabetic men approximates 50 per cent, there is controversy surrounding the etiology of this problem.12, 13 Many clinicians have used the nocturnal penile tumescence (NPT) study to assist in the differential diagnosis of Correspondence to: Dr. Syed T Ali, Department of Physiology, psychogenic from organogenic sexual dysfunction. The Faculty of Medicine, Umm-Al-Qura University, P.O. Box 7607 foundation of the test rests on the observations of regularly occurring erection cycles during sleep in healthy, sexually functional men,14 and abnormally diminished or absent sense or pin prick sensation in the feet or hands, or there sleep-related erection cycles in organically sexually was history of neuropathic pain, foot ulcer, or symptoms diagnosis) including postural hypotension, intermittent Measurements of NPT thus provide an objective and diarrhea especially nocturnally, epigastria fullness, bladder quantitative method for evaluating changes in erectile dysfunction, diminished sweating in the legs, gustatory pattern. Furthermore, assessment of NPT is useful for the sweating and hypoglycemic unawareness. The criteria for differentiation of organic/neuropathic from psychogenic the presence of symptomatic autonomic neuropathy were two or more severe or three or more mild/moderate features. One interesting new breakthrough in the treatment of Impotence was determined according to the method of erectile dysfunction using oral drugs lies in the substance Bancroft and Bell30 as the inability to achieve or maintain an sildenafil (Viagra). Sildenafil is an oral selective inhibitor of erection sufficient for satisfactory sexual performance and type 5 cGMP-specific phosphodiesterase enzyme (PDE-5) was further assessed using the International Index of that is the predominant isozyme in the corpus cavernosum Erectile Function (IIEF)-5: a multidimensional scale for that degradates cGMP. The sildenafil-dependent PDE-5 assessment of erectile dysfunction as described previously.31 inhibition results in an increase of cGMP together with a The IIEF is a multidimensional, self-administered consequent decrease of intracellular ca2+, finally resulting in questionnaire (15-questions) addresses the relevant domains penile smooth muscle relaxation and vasodilatation.18, of male sexual function (that is, erectile function, orgasmic 19,20,21,22 Until now, the efficacy of sildenafil on erectile function, sexual desire, intercourse satisfaction, and overall function has been assessed by self-filled questionnaires satisfaction). The IIEF demonstrates the sensitivity and concerning sexual activity or visual erotic stimulation23 or specificity for detecting treatment-related changes in by visual erotic stimulation and simultaneous penile rigidity patients with erectile dysfunction. Men were considered monitoring.24 These types of studies provide results candidates for this study when they had complained of concerning psychogenic and/or reflexive erections, which erectile dysfunction with diabetic neuropathy for 6 or more are dependent at least in part on the psychological pattern of Diabetic treatment was recorded as diet alone, oral Sleep-related erections represents a valid clinical model hypoglycemic agent or insulin. Inquiry was made of other useful to investigate the effects of sildenafil on penile drug therapy, angina pectoris, previous myocardial physiology for the continuous monitoring of sleep-related infarction or cardiac failure, intermittent claudication, erections by means of a device, providing quantitative and thyroid dysfunction, previous sympathectomy or other qualitative parameters of penile erections.25,26 Moreover, abnormality that might predispose to organic impotence nocturnal erections are poorly or not affected by external such as neurological disease or previous injury. factors for example embarrassment, state anxiety, which To assess the efficacy and safety of oral sildenafil citrate can interfere with penile erections when studied on awake (ViagraTM-Pfizer, USA) in the treatment of erectile dysfunctions in both type 1 and type 2 diabetic men with nocturnal penile erections constitutes a useful tool to and without neuropathy and in age-matched non diabetic evaluate the pure effects of sildenafil on erectile function. controls, subjects home and clinical practice centers in the local vicinities, were randomized to receive sildenafil citrate While many studies have demonstrated abnormal findings (100 mg), but not more than once daily, for 12 months. Self- from NPT studies in sexually dysfunctional diabetic men, reported ability to achieve and maintain an erection for measurement of NPT with special reference to diabetic sexual intercourse according to the International Index of neuropathy is limited. The current study has been Erectile Function and adverse events were recorded undertaken to determine relationship between sildenafil according to the method described previously.31 citrate therapy and changes in sleep-related erections in Nocturnal penile tumescence and rigidity testing were done in a sleep laboratory setting simultaneously using Materials and Methods
For experimental purposes and for the studies of diabetic according to the methods described previously.32 In brief, neuropathy, after approval from the local ethical committee, RigiScan was applied to the patients in a standard fashion at 50 type 1 and 50 type 2 diabetic male patients with and the beginning of the test session. Loops were placed around without evidence of neuropathy and 50 age-matched non- the base and subcoronal regions of the penis near but not diabetic male controls were selected. Every male aged overlapping the mercury strain gauges to measure penile between 20 to 65 years with duration of 1 to 25 years of the dimensions at a similar location. Loop positions were checked after each nocturnal penile tumescence event and locations were kept constant. Sleep staging and nocturnal The presence of diabetic complications was assessed by a penile tumescence were graphed every thirty seconds. review of the medical record. Neuropathy was present if the Degree of nocturnal penile tumescence was defined as records indicated absence of ankle jerk, decreased vibration increase in penile circumference over the flaccid state, The effect of Sildenafil citrate (ViagraTM) on the frequency, duration, and degree of nocturnal penile tumescence in diabetic neuropathic men measured in millimeters at the base. Maximum episodes maximum tumescence of the base lead, change in were defined as deviations from the baseline recording of 80 tumescence at the base, total area under the curve of the tip -100% of greatest circumference estimated to be full by lead rigidity, and total area under the curve of bases lead direct observation. Frequency was defined as the mean number of total or maximum tumescence episodes per night. Duration was defined as the mean time per night spent in Four men with normal nocturnal tracings were rejected for tumescence. Although no clear consensus exists on which study because they were proven to have psychological measured parameters are best to monitor, we chose what impotence. Of the remaining men who qualified, 2 declined appeared to be the best, overall measures of tumescence and the study, 1 withdrew during the study and 1 was deleted rigidity: average maximum rigidity of the tip lead, average from the study by for not following the protocol. TREATMENT
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Figure 1: Frequency of penile tumescence (No. of episodes/night) before and after oral administration of sildenafil citrate (
100 mg dose) in type 1 (IDDM) and type 2 (NIDDM) diabetic males (with and without neuropathy) and in age matched non-
diabetic controls. Values are means ± S.D
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Figure 2: Frequency of penile tumescence (Episodes maximum tumescence) before and after oral administration of sildenafil
citrate (100 mg dose) in type 1 (IDDM) and type 2 (NIDDM) diabetic males (with and without neuropathy) and in age
matched non-diabetic controls. Values are means ± S.D
and episodes maximum tumescence before and after the oral The sleep and penile tumescence variables were compared administration of 100 mg of oral dose of sildenafil citrate in by the Student’s t-test for the significant differences 50 type 1 and 50 type 2 diabetic men (with and without between the means of treated/untreated neuropathic and neuropathy) and in 50 age-matched non-diabetic controls non-neuropathic men. In all instances probability (p<0.05) are shown in Figures 1 and 2. In both the parameters, sildenafil-treated diabetic neuropathic patients showed a highly significant increase of about 72% and 71%, The data for the measured values of frequency of nocturnal respectively compared with the values obtained from erectile episodes including number of episodes per night TREATMENT
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Figure 3: Duration of penile tumescence (Total tumescence-min) before and after oral administration of sildenafil citrate
(100 mg dose) in type 1 (IDDM) and type 2 (NIDDM) diabetic males (with and without neuropathy) and in age matched non-
diabetic controls. Values are means ± S.D.
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Figure 4: Duration of penile tumescence (Tumescence /sleep time-%) before and after oral administration of sildenafil citrate
(100 mg dose) in type 1 (IDDM) and type 2 (NIDDM) diabetic males (with and without neuropathy) and in age matched non-
diabetic controls. Values are means ± S.D.
The effect of Sildenafil citrate (ViagraTM) on the frequency, duration, and degree of nocturnal penile tumescence in diabetic neuropathic men TREATMENT
AFTER TREATMENT
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Figure 5: Degree of penile tumescence (Mean increase circumference-mm) before and after oral administration of sildenafil
citrate (100 mg dose) in type 1 (IDDM) and type 2 (NIDDM) diabetic males (with and without neuropathy) and in age
matched non-diabetic controls. Values are means ± S.D.
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Figure 6: Degree of penile tumescence (Maximum increase circumference-mm) before and after oral administration of
sildenafil citrate (100 mg dose) in type 1 (IDDM) and type 2 (NIDDM) diabetic males (with and without neuropathy) and in
age matched non-diabetic controls. Values are means ± S.D.
Similarly as shown in Figures 3 and 4, both types of sildenafil-treated diabetic neuropathy patients showed a circumference (mm) in controls and in both type 1 and type significant increase (p< 0.0001) in the values of the duration diabetic 2 subjects (with and without neuropathy) is of penile tumescence including total tumescence (min), and presented in Figures 5 and 6. The values of the tumescence/sleep time (%) when compared with their mean/maximum increase in the penile circumference measured from type 1 and type 2 neuropathic sildenafil- treated patients compared with the values obtained from A comparison of the measured values of the degree of untreated patients showed a consistent and highly penile tumescence including mean increase in significant increase of about 60% and 63%, respectively (p<0.0001). In all the cases however, values of the that peripheral neurovascular pathology is involved in frequency, duration and degree of nocturnal erectile pathogenesis of erectile impotence. Diabetic patients who episodes were not significant in both type 1 and type 2 met the criteria for neuropathy in this study did have patients without neuropathy before and after oral significantly diminished penile blood pressure (unpublished administration of sildenafil, and when compared with their observation). The assessment of sleep architecture suggests, respective controls of the same age groups. in addition, that abnormal autonomic nervous processes may also contribute to diabetic erectile dysfunctions. Discussion
The association between diabetes mellitus and erectile There is growing evidence that a central autonomic impotence is well known but information about prevalence dysregulation not involving peripheral autonomic pathology and the nature of this relationship remains unclear. may be associated with severe erectile impotence, sexual disturbances and diminished NPT.39 In our results, a In recent years, nocturnal penile tumescence (NPT) significant decrease in NPT parameters in diabetic monitoring has been increasingly employed as a neuropathic men is in conformity with previous physiological test of organic impotence. Diabetic patients with erectile disorders have shown significantly less NPT NPT recording may provide a sensitive indicator of psychogenically impotent and control individuals.33 physiologic changes in erectile capacity during the course of diabetes, which had been previously ignored due to the There are no controlled studies that have included psychosexual, sleep and NPT measures in a clinically well- defined diabetic group of men who are otherwise healthy The observation that the moderately dysfunctional diabetic and are not selected because of sexual problems. It is thus patients (non-neuropathic) had less NPT decrement than the evident that there is an extensive clinical literature available neuropathic group suggests, however, that the relationship on the erectile disorders of diabetic men but still there is a between erectile failure rates and NPT measures is not a lack of controlled investigation on nocturnal studies on close one. Psychological and interpersonal factors, in diabetic neuropathy that have taken into account the effect addition to physiological capacity are likely to play an of concurrent illnesses and medication on sexual function. i The aim of the present study therefore includes the Conclusions from this study on a carefully selected group of comparison of sleep recordings and NPT parameters patients should be used with caution. The results, between both type 1 and type 2 diabetics (with and without unconfounded by the effect unrelated medical disorders, neuropathy) according to well-defined criteria of erectile clearly demonstrate that diabetic neuropathy has a broad impotence.31 The differential diagnosis and clinical effect on male sexuality and that, physiologically, is management of these complications by the use of oral administration of sildenafil citrate (Viagra) was determined. Viagra is used as quality drug for the management of men This finding has diagnostic relevance as NPT monitoring is with erectile dysfunction. This is a breakthrough compared being increasingly employed for the objective assessment of to previously available treatments, such as intracavernosal impotence of neuropathic origin. The diagnostic utility of and intraurethral prostaglandin therapies, vacuum devices or NPT method is based on the notion that in psychogenic impotence sleep erections are normal while in neuropathic The present study demonstrated that both type 1 and type 2 correspondence to the patient’s deficient waking erectile diabetic men with established autonomic neuropathy function. The present results suggest that impaired NPT showed decreased penile sensitivity compared to non- may reflect subtle erectile deficiencies that are nevertheless, neuropathic type 1 and type 2 diabetics and age-matched compatible with regular coital activity. However, care non-diabetic healthy control subjects. The abnormally should be exercised in the interpretation of abnormal NPT diminished frequency, duration and degree of tumescence finding for the differential diagnosis of diabetic erectile episodes during sleep paralleled the erectile difficulties reported by both type of diabetic neuropathic patients. To judge objective sexual capability, we used nocturnal It seems reasonable to speculate that widespread NPT penile tumescence and rigidity monitoring and, instead of decrement in these patients reflect the sub-clinical using exogenous testosterone, which can suppress the impairment that placed the poorly controlled diabetic hypothalamic pituitary axis, we used sildenafil citrate patients at risk for eventual erectile difficulties. (ViagraTM, 100 mg. oral dose) in a population of both type 1 and type 2 diabetics (with and without neuropathy). The association of diabetic complications and sexual Sildenafil citrate is an orally active and selective inhibitor of problems is in agreement with previous reports.30,36,37,38 The PDE5. When sexual stimulation causes local release of markedly impaired NPT activity in diabetic patients with nitric oxide, sildenafil enhances the effect of nitric oxide on symptomatic neuropathy or retinopathy supports the notion corpus cavernosus by increasing the levels of cGMP in this The effect of Sildenafil citrate (ViagraTM) on the frequency, duration, and degree of nocturnal penile tumescence in diabetic neuropathic men tissue. Sildenafil is rapidly absorbed following oral 9. Fazio L, Brock G. Erectile dysfunction: Management administration, has an onset of action within 25 to 60 minutes after dosing24 and a plasma half-life of 10. Zippe CD, Pahlajani G. Vacuum erection devices to treat erectile dysfunction and early penile rehabilitation following radical prostatectomy. 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