INTRODUCTION:

Sexual dysfunction (SD) in men with diabetes is one of the chronic complications which is characterized by erectile dysfunction. Erectile dysfunction is the inability to develop and maintain an erection for satisfactory sexual intercourse or activity in the absence of an ejaculatory disorder such as premature ejaculation. Erectile dysfunction is the preferred term rather than the more commonly used term of impotence. There are no universally agreed on criteria for how consistent the problem has to be and for what duration it needs to be present to fulfill the definition. A period of persistence for longer than 3 months has been suggested as a reasonable clinical guideline¹.Erectile dysfunction was self-reported and the condition was classified as mild, moderate, or complete. The combined prevalence of minimal, moderate, and complete erectile dysfunction was 52%. The study demonstrated that erectile dysfunction is increasingly prevalent with age. At age 40, there is an approximately 40% prevalence rate, increasing to almost 70% in men at age 70. The prevalence of moderate erectile dysfunction increases from 17% to approximately 34% the prevalence of complete erectile dysfunction increases from 5% to 15% as age increases from 40 to 70 years.²

Diabetes is known to cause multiple medical³, psychological⁴, and sexual⁵ dysfunctions. Impaired sexual function in men is a well-documented complication of diabetes. Several studies have shown that men with diabetes are at increased risk for erectile dysfunction, that it occurs at an earlier age^6–10, and that it is related to longer duration of diabetes, poor metabolic control, and the presence and number of diabetic complications¹¹.

According to the Canadian Diabetes Association (CDA), erectile dysfunction (ED) is common for men who have diabetes. Fifty percent of men with diabetes will suffer from ED within 10 years of diagnosis.¹²

Heart disease and diabetes are often linked together because coronary artery damage is a complication of diabetes as well. Coronary artery disease can affect sexual function on its own, but erectile dysfunction is nine times as likely in men who suffer with both coronary artery disease (CAD) and diabetes, than men who have diabetes without the addition of CAD. Erectile dysfunction is so prevalent in both coronary artery disease and diabetes, that it could be considered a risk factor for both. If a man is suffering from ED, his doctor should suggest screening for CAD and diabetes.¹³

Epidemiology:

Erectile dysfunction is a commonly encountered clinical problem, with a particularly strong correlation with increasing age. Other factors associated with an increased prevalence of ED include smoking, heart disease, and diabetes. With regard to diabetics specifically, rates of ED are approximately three-fold that of the general population. ED may also be the presenting symptom for DM and may predict later neurologic sequelae.

ED has been reported to occurs in >50% of men with DM worldwide^14-17. ED is usually present within 10 years of diagnosis of DM. The incidence of ED was reported to be higher to each decade of life for men with DM than men without DM and up to 12% 0f men who present with were have previously undiagnosed DM. ED occurs at a younger age in men with type 1 DM than in the general population, and the incidence of insulin resistance is higher in men with ED.¹⁸

In health professionals Follow-Up study Cohort reported by Bacon et al, men with DM had an age-adjusted RR 1.32% for having ED compared with their non diabetic counterparts. Furthermore, men with type 2 DM had increasingly greater risk of ED with increase duration since diagnosis, particularly men whose DM was diagnosed >20 years previously. Fedele et al reperted a 35.8% prevalence rate for ED in cross-sectional study, ranging from 4.6% for men 20 to 29 years age to 45.5% for men 60 to 69 years age. Fedele et al also reported crude incidence rate of 68 cases per 1000 persons-years in a subset of 1010 men without ED at baseline who were followed perspectively for 2.8 years.¹⁸The prevalence of ED differs across subsets of patients with coronary artery disease (CAD) and is an early marker of vascular disease.In patients with estabilished CAD. ED may precede the clinical diagnosis of CAD by an average of 2 to3 years. Furthermore, several studies suggested that, phosphodiesterase type-5 (PDE-5) inhibitors can improve endothelial function in addition to saving the patient’s life. ED is present in almost all men with DM- related neuropathy and it is correlated with glycemic control(based on measurement of glycosylated hemoglobin (A1C) levels.¹⁹

DM is a major component of the metabolic syndrome,and results of several studies revealed that high percentage of men with ED also had metabolic syndrome²⁰.Esposito et al.reported a 26.7% prevalence of ED in patients with metabolic syndrome compared with 13.0% control group. In addition to ED,the presence of DM at baseline was significantly associated with all aspects of sexual dysfunction, including sexual drive, ejaculatory function, and sexual satisfaction(all, P<0.0001).²¹

Physiology of penile erection:

Stimuli that can lead to penile erection include tactile stimuli to the penis and genitalia which will produce a reflex erection, while erotic stimuli, whether visual, auditory, olfactory or imaginative also produce penile erection by a mechanism which involves the paraventricular nucleus and medial preoptic area of the hypothalamus.²² A third mechanism is involved in the production of nocturnal erections that occur in all men during REM sleep.²³ While the exact central pathways involved in these processes are unclear, descending pathways from the hypothalamus ultimately lead to increased parasympathetic and decreased sympathetic neural activity within the penis²⁴.The parasympathetic nerves release a number of neurotransmitters within the penile tissue, of which the most important is nitric oxide (NO).²⁵ However, the neural release of NO is supplemented by release from the vascular endothelium and this leads to relaxation of the smooth muscle in the penile arteries and in the spongy tissue of the corpora cavernosal.²⁶ As a result of this, there is arterial dilatation, cavernosal relaxation and increased pooling of blood within the trabecular spaces of the corpora.²⁷ As a consequence, the veins which normally carry blood out of the penis are compressed against the tunica albuginea, leading to reduced venous outflow, and this so-called ‘veno-occlusive’ mechanism results in the rigid penile erection.^28-29

Pathophysiology of ED:

The pathophysiology of ED in DM is multifactorial, consisting of vascular and neurologic insults. There is impaired relaxation of the corpus cavernosal smooth muscle in diabetics in response to neuronal- and endothelial-derived nitric oxide, which may be due to the accumulation of glycosylation products. DM may cause ED through a number of pathophysiological changes, including neuropathy, endothelial dysfunction, cavernosal smooth muscle structural/functional changes, hormonal changes and psychological effects.³⁰Diabetic neuropathy may be linked to selective neurodegeneration that results in decreased neuronal nitric oxide (NO) synthase activity and diminished NO associated with impaired nitrergic relaxation in the corpus cavarnosum.In addition, oxidative damage through the formation of oxygen free radicals may contribute to the neurodegeneration, suggesting that it is an NO-dependent process.^31-32

Endothelial dysfunction is a major cause of Diabetic ED.³³Hyperglycemia reduces activity of endothelial NO synthase, diminishes the effect of released NO,and decreases oxygen free radicals, including advanced glycosylation end products (AGEs).³⁴The ultrastructural changes in the endothelium result in increased penile vasoconstriction due to increased levels of endothelin-1(ET-1) and upregulation of endothelin receptors (ETA and ETB) in the corpus cavarnosum.³⁵ ET-1 induced vasoconstriction is linked to the RhoA/Rho- kinase pathway that mediates ED through decreased production of NO in the corpus cavarnosa.^36-37

Structural changes include reduction in smooth muscle content, increased collagen deposition, thickening of basal lamina and loss of endothelial cells.³⁸ Several studies have consistently found a reduction in the relaxation responses mediated by endothelial and neurogenic NO in the corpus cavarnosum.³⁹These findings may be explained by the presence of AGEs, which decrease compliance in the corpora cavarnosa and impair smooth muscle relaxation by generating free radicals or reactive oxygen species that reacts with NO.^40-41

Obesity and age are associated with low testosterone levels in men with DM. Hypogonadism has been associated with metabolic syndrome and insulin resistance. Psychological effects are another important factor in Pathophysiology of DM- associated ED. Depression, anxiety, and stress are common factors in the diabetic men that may be associated with ED through an excessive sympathetic outflow that results in inhibition of erection.⁴²

Ejaculatory dysfunction:

Beyond erectile difficulties, diabetics may also be bothered by other sexual disorders, such as lack of ejaculate (anejaculation or retrograde ejaculation) or premature ejaculation. Successful antegrade ejaculation depends on the coordination of three neurologic events: seminal emission, bladder neck closure, and contraction of the muscles of the pelvic floor (e.g. bulbocavernous, ischiocavernous, etc.).^43-44

Diagnosis:

The diagnosis of ED is based on the patient’s sexual and medical histories, as well as the results of validated questionnaires such as the International Index of Erectile Function (IIEF).⁴⁵Several medications have been associated with ED and these agents need to be identified through the patient’s medical history. Physical examination is focused on signs of cardiovascular disease and associated neuropathy,where as penile examination is focused on identification of other co morbidities such as peyronie disease. Laboratory examinations are limited to testosterone and prolactin levels which may independently contribute to ED. These abnormalities occur significantly more often in men with DM than in the general ED population (all, P<0.0001) and they have implications for treatment. Specialized examinations are not necessary for most diabetic men with ED.^46.47

Useful and simple way to distinguish between physiological and psychological impotence is to determine whether the patient ever has an erection. If never, the problem is likely to be physiological; if sometimes, it could be physiological or psychological. The current diagnostic and statistical manual of mental diseases has included a listing for impotence.⁴⁸

Duplex ultrasound:

Duplex ultrasound is used to evaluate blood flow, venous leak, signs of atherosclerosis, and scarring or calcification of erectile tissue. Injecting prostaglandin, a hormone-like stimulator produced in the body, induces erection. Ultrasound is then used to see vascular dilation and measure penile blood pressure.

Penile nerves function:

Tests such as the bulbocavernosus reflex test are used to determine if there is sufficient nerve sensation in the penis. The physician squeezes the glans (head) of the penis, which immediately causes the anus to contract if nerve function is normal. A physician measures the latency between squeeze and contraction by observing the anal sphincter or by feeling it with a gloved finger inserted past the anus.⁴⁹

Nocturnal penile tumescence (NPT):

It is normal for a man to have five to six erections during sleep, especially during rapid eye movement (REM). Their absence may indicate a problem with nerve function or blood supply in the penis. There are two methods for measuring changes in penile rigidity and circumference during nocturnal erection: snap gauge and strain gauge. A significant proportion of men who have no sexual dysfunction nonetheless do not have regular nocturnal erections.

Penile biothesiometry:

This test uses electromagnetic vibration to evaluate sensitivity and nerve function in the glans and shaft of the penis.

Dynamic Infusion Cavernosometry (DICC):

DICC technique in which fluid is pumped into the penis at a known rate and pressure. It gives a measurement of the vascular pressure in the corpus cavernosum during an erection.

Corpus Cavernosometry:

Cavernosography measurement of the vascular pressure in the corpus cavernosum. Saline is infused under pressure into the corpus cavernosum with a butterfly needle, and the flow rate needed to maintain an erection indicates the degree of venous leakage. The leaking veins responsible may be visualized by infusing a mixture of saline and x ray contrast medium and performing a cavernosogram. Digital Subtraction Angiography: In DSA, the images are acquired digitally.

Magnetic resonance angiography (MRA):

This is similar to magnetic resonance imaging. Magnetic resonance angiography uses magnetic fields and radio waves to provide detailed images of the blood vessels. Doctors may inject a "contrast agent" into the patient's bloodstream that causes vascular tissues to stand out against other tissues. The contrast agent provides for enhanced information regarding blood supply and vascular anomalies.^{50, 51}

Treatment:

The improved glycemic control is beneficial for diabetic men with ED. In some men primary causes of ED may be irreversible, or ED may persist after treatment. In such patients therapies the etiology should be considered for proper evaluation and management of erectile dysfunction in men with diabetes (Figure 1).

Treatment of ED with phosphodiesterase type 5 inhibitors (PDE5i):

The treatment of ED in general was revolutionized by the availability of sildenafil (Viagra), followed by tadalafil (Cialis) and vardenafil (Levitra). Each of these medications has been prospectively examined in a variety of populations, including diabetics (Table1). The three medications work by a similar pathway. Sexual stimulation provokes the release of nitric oxide (NO), leading to increased cellular concentrations of cyclic guanosine monophosphate (cGMP) and subsequent penile smooth muscle relaxation. This process is reversed by the conversion of cGMP to guanosine monophosphate, which is mediated by phosphodiesterase type 5 (PDE5) the predominant functional PDE type found in the penis.

Table 1: Comparison of PDE5 inhibitors for the treatment of ED in the general patient population and patients with type 1 and 2 diabetes mellitus

Drug	Duration of Study (weeks)	No. of Randomized patients	No. of patients with Type 1 and Type 2 DM	No. (%) of patients completing study	Duration of ED	Duration of diabetes mellitus, Type 1	Duration of diabetes mellitus, Type 2
Sildenafil⁷⁰	24	532	268	252 (94%)	> 6 months	> 5 years	> 2 years
Tadalafil⁷¹	24	179	216	NR	3 months	NR	NR
Vardenafil^72,73	24	590	452	NR	6 months	NR	NR

NR-Not Reported

Multi-center, randomized, double-blind, placebo-controlled study

Table 2: Clinical studies of erectile dysfunction in men with diabetes mellitus

Study

Design

Description

Outcome measures

University of Ghent(2005-2007)⁷⁴

NCT00134329

Observational,

Perspective

300 DM patients

( Male-Age older than 18 years)

IEF (International Index of Erectile Function) questionnaire and Part 2 is an additional questionnaire.

1) Documentation of the prevalence of erectile dysfunction in the diabetic convention.

2) Relation of erectile dysfunction with metabolic parameters and sex steroids.

Toho University School of Medicine-Department of Urology⁷⁵

randomized, placebo-controlled, double-blind, parallel-group comparison

ITT-DM population

(Intent to treat)

Patients received vardenafil 10 mg, 20 mg, or placebo, and were instructed to start sexual activity 1 hour after dosing.

Retrospective analysis, Vardenafil improved successful intercourse rates compared with placebo in DM patient.

0-15 minutes (P = 0.0268), 15-30 minutes (P = 0.0094) through > 120 minutes were all higher in vardenafil-treated patients

SK Chemicals Co.,Ltd.(2007-2008)⁷⁶

NCT00705861

Randomized, Double Blind, Parallel Assignment, Safety/Efficacy Study

112 DM patients

(Male- 19 Years and older)

Placebo substitute of SK3530.

Drug: SK3530

(100 mg)

(IIEF) Questionnaire

1)Erectile Function domain score.(1,2,3,4,5)

2)Sexual Encounter Profile(SEP)Q2 and Q3, 3) Life Satisfaction Checklist,

4) Global Efficacy Assessment Question(GEAQ)

University of Pavia (2009-2010)⁷⁷

NCT01049750

Observational, cohort, cross-sectional

250 Type-2 DM patients

(Male- 18 Years to 80 Years)

IEF (International Index of Erectile Function), SAS of Zung (self-rating anxiety state) and SDS of Zung (self-rating depression scale)questionnaires.

1) Evaluation of diabetic neuropathy in patients with erectile dysfunction

2) Insulin-sensitivity index

3) Glycemic control

PDE5i act at this step to maintain elevated levels of cGMP and continued smooth muscle relaxation.⁵² Since the release of NO is a neurologically-mediated event, neuropathology may impede this step and, theoretically, make diabetics less sensitive to the effects of PDE5i. This is indeed borne out clinically; as diabetics have a poorer response overall to PDE5i than men with ED of other causes.⁵³A prospective, multi-center, randomized, double-blinded (RCDB) trial of vardenafil in diabetics was carried out by Goldstein, et al. The study consisted of 430 men with chronic ED, a hemoglobin A1c (HbA1c) of <12%, and without other serious confounding causes of ED (e.g. radical pelvic surgery, spinal cord injury, etc.).⁵⁴ Additionally, patients were excluded if they had unstable coronary disease or other contraindications to PDE5i use. In the different clinical trials, the patients were evaluated using the erectile function (EF) domain of the 15 question validated International Index of Erectile Function (IIEF), 2 diary questions regarding the patient’s ability to penetrate and have successful intercourse, and a global assessment question (GAQ) about whether or not the treatment had improved their erections. There were statistically and clinically significant improvements in all of the evaluated endpoints, with most of the improvements demonstrating a dose-relation (Table 2). With 20 mg of vardenafil, the EF score was 19 (out of a total possible of 25) and 54% of men were able to complete intercourse, with an overall responder rate (as measured by the GAQ) of 72%.⁵⁵The effect was attenuated in patients with severe underlying ED but improvement remained significant. There was no correlation noted between different strata of HgA1c levels. The drug was well-tolerated with few patients discontinuing the study due to adverse side-effects. A similar RCDB trial of tadalafil in diabetics was performed by Saenz de Tejada, et al. A total of 191 patients completed this study; evaluated parameters were very similar to the vardenafil study above. Exclusion criteria were also similar to the vardenafil study, except that patients with hypertension and hypercholesterolemia were also excluded in the tadalafil study. As in the vardenafil study, statistically and clinically significant improvements were noted in all of the evaluated parameters for men using tadalafil, regardless of severity of underlying DM or level of HgA1c, with an overall responder rate (as assessed by GAQ) of 64% by those using 20 mg. The drug was also well-tolerated with few discontinuations.⁵⁶ A unique study from Denmark attempted to assess the “real-life” use of sildenafil in diabetics in terms of how many patients wanted to try an agent, how many were eligible to do so, and how efficacious the medicine. Examining a diabetes outpatient clinic population of 326 men, 192 (59%) self-reported ED and 187 of these were over 40 years old. Of these 187 patients, 79 (42%) were excluded because of medical or pharmacologic contraindications to sildenafil use. A further 63 patients either declined to participate in the study or did not respond. This left 45 patients for the study (23% of those patients with self-reported ED). Of these, 10 dropped out due to lack of sexual partner and 2 others without recorded reason. Sixty-one percent of the remaining patients self-titrated to a maximum dose of 100 mg. of the 33 patients remaining, 36% noted consistent improvement, 27% noted variable improvement, and 36% felt they had no improvement; overall, 54% felt that the medicine had met their expectations. If we consider that 18 patients total felt that the medicine met their expectations and that the starting pool was 187 patients with self-reported ED, this leaves less than 10% of patients with a satisfactory outcome, thus pointing out that PDE5i, while efficacious under normal study conditions, do not represent a panacea.⁵⁷

Treatment of ED with other modalities:

Intracavernosal alprostadil injection therapy in diabetics was evaluated in a large, multicenter trial by Heaton, et al. Over 300 men entered the trial, 83% completing the titration period and proceeding to home use. Of those patients using the medication at home, 79% required 30 micrograms/dose or less, and 72% remained satisfied with the initial dose during the follow up period (6 months). There were only 2 instances of priapism (sustained erection of greater than 6 hours unaccompanied by sexual stimuli) neither of which required intervention, 1 patient developed a penile nodule, and 24% of patients reported penile pain; the pain led to patient drop-out in 5% of the treatment group.⁵⁸ A smaller, more recent study with longer followup (10 years) found that diabetic patients tended to shift towards decreased frequency of use but preferred stronger agents (mixtures of alprostadil with other vasodilators such as papavarine and Phentolamine), with type 1 diabetics stabilizing their doses within 5 years and type 2 diabetics stabilizing within 9-10 years. In patients for whom injections do not work, often a result of veno-occlusive dysfunction.⁵⁹

Vacuum Erection Devices (VED):

There is a paucity of data specifically evaluating the use of VED in diabetics but the drop-out rate for patients is generally quite high, even for patients who are able to achieve a rigid erection with the device.⁶⁰ One subset analysis found that despite a good response (i.e. rigid erection) using VED, only 50% of those couples found the treatment to be satisfactory. This may be due to the “unnaturalness” of the devices, as well as the fact that they may have several local side effects, including glans petechia, a feeling of having a cold penis, and abnormal sensation of ejaculation. ⁶¹

Penile Prosthetics:

When there is lack of efficacy or dissatisfaction with other modalities, penile prostheses are often the best alternative for erectile dysfunction in diabetics. Unlike the other modalities, prosthesis surgery is irreversible in that the corporal tissue is permanently altered such that physiologic erections are no longer possible. If the prosthesis has to be removed, there will be complete ED.⁶²While a variety of exotic materials, flaps , and grafts have been used, most contemporary prostheses are hydraulic or semi-rigid. Of all modalities for management of ED, prostheses have the highest satisfaction rates, with 2 large studies demonstrating greater than 95% satisfaction.^63-64Although some studies suggest that elevated HbA1c levels may predict a higher rate of infections in diabetics having penile prosthesis surgery, more recent studies refute this. A large study from Wilson, et al demonstrated that neither diabetic status nor preoperative HgA1c were risk factors for prosthesis infection. A more recent study also finds that elevated HbA1c is not a risk factor for infection but notes that shortterm poor glucose control (as defined by morning fast glucose levels >200 ng/ml) is, although that data is hampered by very low numbers of patients within that set.^65,66

Electroejaculation:

In diabetes, sympathetic nervous system derangement may cause retrograde ejaculation (i.e. ejaculate is present but transmitted to the bladder and expelled with voiding) or, if more severe, lack of seminal emission entirely.⁶⁷ Either of these conditions will impact fertility, but they may be disturbing to the patient from an aesthetic point of view, as well. From a fertility standpoint, post-ejaculate urine may be treated and then used for artificial insemination. Strategies to overcome retrograde ejaculation generally focus on attempts to coapt the bladder neck. Electroejaculation has been used with limited success, and a variety of pharmacologic agents have also been used, including anticholinergics, antihistamines, and alpha-adrenergics ^.68-69

CONCLUSION:

Sexual Dysfunction in men with diabetes deserves further research.PDE-5 inhibitors are considered first- line treatment, although the efficacy of these agents is lower in men with DM than in the general ED population. When these agents fail Intracavernosal injections, penile prosthesis implantation and proper counseling can be considered in the treatment. However, given that diabetes is the cause of this diabetes complication, the focus should be on the metabolic syndrome as such, as well as on its individual constituent parts.

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Received on 15.12.2010 Modified on 22.12.2010

Research J. Pharm. and Tech. 4(5): May 2011; Page 677-684