|Year : 2020 | Volume
| Issue : 1 | Page : 1-7
Erectile dysfunction in diabetes mellitus: A review
Deepak K Jumani1, Omkar Patil2
1 Department of Medicine, Sir J J Group of Hospital and Grant Government Medical College, Mumbai, Maharashtra, India
2 Dr. Mohan’s Diabetes Specialities Centre, Chennai, Tamil Nadu, India
|Date of Submission||09-Oct-2018|
|Date of Decision||28-Dec-2018|
|Date of Acceptance||28-Dec-2019|
|Date of Web Publication||18-Dec-2019|
Prof. Deepak K Jumani
Department of Medicine, Sir JJ Group of Government Hospitals and Grant Medical College, 10, Shastri Nagar, Near Vibgyor High School, Link Road, Goregaon West, Mumbai - 400 104, Maharashtra.
Source of Support: None, Conflict of Interest: None
The International Diabetes Federation estimates that globally there are 425 million people with diabetes. Estimates of the prevalence of erectile dysfunction (ED) in men with diabetes range from 20% to 85% in different studies. Among men with ED, those with diabetes are likely to experience the problem 10–15 years earlier than men without diabetes. This review aims to provide an update of the epidemiology, pathophysiology and management of ED in diabetes patients in India. The proposed mechanisms of ED in diabetic patients include elevated advanced glycation end-products and increased levels of oxygen-free radicals, impaired nitric oxide (NO) synthesis, increased endothelin B receptor binding sites and ultrastructural changes, upregulated RhoA/Rho-kinase pathway, NO-dependent selective nitrergic nerve degeneration and impaired cyclic guanosine monophosphate-dependent kinase-1. Modifiable risk factors for ED include smoking, lack of physical activity, wrong diets, overweight or obesity, metabolic syndrome and excessive alcohol consumption. Therefore, the promotion of healthful lifestyles would yield great benefits in reducing the burden of ED. The treatment of diabetic ED is multimodal. The treatment of the underlying hyperglycaemia and comorbidities is of utmost importance to prevent the progression of the disease. The peripherally acting oral phosphodiesterase type 5 inhibitors are the mainstay of oral medical treatment of ED in diabetics. Vacuum erection devices are an additional a non-invasive treatment option. The local administration of vasoactive medication through urethral suppository or intracorporal injection can be effective with minimal side-effects.
Keywords: Diabetes mellitus, erectile dysfunction, phosphodiesterase type 5 inhibitors
|How to cite this article:|
Jumani DK, Patil O. Erectile dysfunction in diabetes mellitus: A review. J Diabetol 2020;11:1-7
| Introduction|| |
The International Diabetes Federation estimates that globally, there are 425 million people with diabetes. Estimates of the prevalence of erectile dysfunction (ED) in men with diabetes range from 20% to 85% when defined as consistent inability to have an erection firm enough for sexual intercourse. Among men with ED, those with diabetes are likely to have experienced the problem as much as 10–15 years earlier than men without diabetes. The prevalence estimate of ED is over 50.4% in Indian diabetic men after 40 years or older. The prevalence of ED increased with increasing age. A significant high prevalence of ED was observed in men who smoked heavily, all those who were single, had diabetes and lower urinary tract symptoms from benign prostatic hyperplasia. Obesity (body mass index ≥30kg/m2) significantly increased the risk for ED by multivariable-adjusted odds ratios.
Diabetes has been associated with sexual dysfunction both in men,,,,,, and in women.,, Diabetes is a risk factor for sexual dysfunction in men; a three times increased risk of ED was seen in diabetic compared with nondiabetic men. Among women, the evidence regarding the association between diabetes and sexual dysfunction is less conclusive,, although most studies have reported a higher prevalence of female sexual dysfunction in diabetic women as compared with nondiabetic women.,,
What is erectile dysfunction?
ED is defined as the persistent inability to achieve or maintain penile erection for successful sexual intercourse causing decreased quality of life in men., ED is detected by having male patients complete standardised questionnaires investigating their sexual function. One of the most practical questionnaires that is administered is the International Index of Erectile Function (IIEF)-5, which consists of items 5, 15, 4, 2 and 7 from the full-scale IIEF-15; a sum score of 21 or less indicates the presence of ED.
Epidemiology of diabetic erectile dysfunction
The overall prevalence of ED has been reported to be 16%–25% in the general population depending on the cohort of study and the definition of ED being applied. The prevalence of ED in diabetes has been reported to be 60%–80% in many studies [Table 1]. Age is a strong determinant of occurrence of ED and epidemiological studies indicate a strong relationship between ED and advancing age. While men aged 50–59 years have a 3.6 times higher risk of developing ED as compared to those aged 18–29 years, the risk is even higher (6–7 times) among males older than 70 years. Age-related hormonal, metabolic and inflammatory, as well as increased prevalence of other risk factors for ED in the older population, may be responsible for increased prevalence. When ED occurs in younger males, it is associated with a greater increase in the risk of future cardiac events as compared to its first detection in older males. Therefore, younger men with early-onset ED may be the ideal candidates for intensive CV risk factor screening and medical interventions.
Causes of erectile dysfunction
There are various causes of ED. As the erectile function is the result of a complex interplay between vascular, neurologic, hormonal and psychological factors [Table 2].
Pathophysiology of erectile dysfunction in diabetes mellitus
Diabetes causes several changes in the neuromuscular system, all of which can contribute to ED. In men with diabetes, there is good evidence that ED is due to failure of nitric oxide (NO)-induced smooth muscle relaxation due to both autonomic neuropathy endothelium dysfunction. The endothelium which is the innermost single layer of our vascular bed and also considered to be the brain of the vascular system has an important role in vascular homeostasis. It has many sensors and mediators. It secretes numerous mediators such as NO, prostacyclin and endothelin that regulate vascular tone, platelet activity and coagulation factors but also influence vascular inflammation and cell migration.
Besides hyperglycaemia, hypertension, dyslipidaemia, obesity and smoking also causes endothelial dysfunction. Endothelial dysfunction is a single most predictor of atherosclerosis, coronary artery disease and stroke.
The dynamics of erection in men is 3-fold. First, it is the neurologically mediated arterial inflow, second, there is relaxation of the corpora spongiosa smooth muscles to allow the blood to flow in the penile vasculature, and finally, there is venous obstruction which allows the blood to remain in the penile vasculature and let the penis remain erect. Any disturbance in any of the above three stages can result in ED.
The vascular endothelium in the penile vasculature produces Endothelial NO synthase eNOS, and the neuronal tissues produce neuronal NO synthase n NOS. Both these synthases transport, the NO in the corpora spongiosa smooth muscle and convert the Guanosine triphosphate into cyclic guanosine monophosphate (cGMP), with the help of an enzyme guanylate cyclase. This cyclic GMP relaxes the smooth muscle and allows the blood to flow in. cGMP also potentiates Protein kinase G which inhibits calcium conduction and opens up potassium ion channels which further relaxes the smooth muscles. The cGMP soon hydrolyses into guanosine monophosphate GMP with the help of an enzyme Phosphodiastrase 5 which is present in the penile smooth muscles and the smooth muscle contracts and leads to detumescence. Hence for proper erection, one needs to have basically a good functional enthothelium which produce good amount of eNOS and also nNOS, we also need NO, which we all are aware is the chemical currency which initiates the erectogenic mechanism and also reduces as we age. There should be adequate guanylate cyclase activators and stimulators, cGMP in the more bioavailable form to keep the penile smooth muscle in a relaxed state, and something to block the phosphodiesterase type 5 (PDE5) like PDE5 inhibitors to sustain the erection.
Rho A/Rho-Kinase pathway is the key pathway which inhibits relaxation of the penile smooth muscle vasculature. Rho-associated protein kinase (ROCK) is a kinase which induces the formation of stress fibers and focal adhesions by phosphorylating myosin light chain. Due to this phosphorylation, the actin binding of myosin II and contractility increases. Protein kinase C and ROCK are involved in regulating calcium ion intake and these calcium ions, in turn, stimulate a myosin light chain kinase forcing contraction. Hence, inhibition of these pathways will help in relaxation of the cavernous smooth muscle and produce a sustained erection.
Diabetic neuropathy is the most common diabetic complication, affecting 10%–90% of people with diabetes, depending on the diagnostic criteria and the age and duration of DM. Some studies showed an earlier development of DN in men, compared to women. Neuropathy is a very important pathogenetic factor in the development of ED. Because DN affects all levels of the neural system, disturbances could happen at all levels in the complex process of erection from the central initiation to the penis. In the literature, much more attention is paid to the vascular aspects of ED compared to the neural ones.
Clinical features and investigations in erectile dysfunction
Clinical features of ED include many key features in the history and also include some physical signs on examination. There are no formal tests to diagnose ED. Some blood tests are generally done to exclude underlying disease [Table 3].
Treatment of Erectile dysfunction
Life style modification
The only meta-analysis regarding exercise and ED showed that moderate and high physical activity was associated with a lower risk of ED, with odds ratios at 0.63 (95% confidence interval [CI]: 0.43–0.93) and 0.42 (95% CI: 0.22–0.82), respectively. Several prospective investigations indicate that physical activity has a beneficial effect on prevention and/or improvements of ED.,,
Both cross-sectional and prospective epidemiologic studies suggest that overweight, obesity and metabolic syndrome are associated with an increased risk of ED. In particular, the largest population from the Health Professionals Follow-up Study in the United States, including 31,724 men free of ED at baseline, showed a 40% increased risk of developing ED with obesity. Prospective studies, of variable duration from 5 to 25 years of follow-up reported that overweight or obese men had an increased probability (70%–96% higher) of developing ED compared with normal weight men.
Dietary patterns with a high content of whole grain foods and legumes and vegetables and fruits, and that limit red meat, full-fat dairy products and food and beverages high in added sugars are associated with a reduced risk of ED.
Only few studies assessed the role or the effect of diet on ED. Esposito et al. studied 65 men with the metabolic syndrome and ED; 35 of them were assigned to the intervention diet and 30 to the control diet. After 2 years’ follow-up, IIEF score (IIEF Score) increased up to 22 in 13 men who were assigned to the intervention diet and in two men in control diet group (P = 0.015).
Both the direct use of tobacco and second-hand exposure seem a consolidated risk factor for ED.,
Harte and Meston investigated the association between smoking cessation and indices of physiological and subjective sexual health in men: smoking cessation significantly enhanced both physiological and self-reported indices of sexual health in long-term male smokers, irrespective of baseline erectile impairment. In a prospective study, Pourmand et al. reported a beneficial effect on erectile function in men who ceased smoking. After 1 year, the ED status improved in ≥25% of ex-smokers but none of the current smokers; moreover, men who stopped smoking continued to have a significantly better ED status with long-term follow-up.
The moderate consumption of alcohol may exert a protective effect on ED in both the general population and in diabetic men. In a recent study aimed at describing the incidence or remission and bio-psychosocial predictors of ED in 810 randomly selected Australian men aged 35–80 years, low-alcohol consumption was a predictor of ED. The data from a population-based cross-sectional study of men’s health to assess the association between usual alcohol consumption and ED in Australia revealed that among current drinkers (n = 51 374), the odds were lowest for consumption between 1 and 20 standard drinks per week. On further adjustment for cardiovascular disease or cigarette smoking, age-adjusted odds of ED were reduced by 25%–30% among alcohol drinkers. In general, the overall findings are suggestive of alcohol consumption of a moderate quantity conferring the highest protection.
Strict glycaemic control is the cornerstone in the treatment of diabetes mellitus (DM) and prevention of its complications like DED. Poor control increases the risk for ED 2–5-fold compared to good control., Lu et al. concluded in a study including 792 subjects 83.6% with ED and 43.2% with severe ED that better glycaemic control probably would reduce the prevalence of ED and its severity among the younger men with T2D, while age is the major determinant for ED risk for the older group. Cho et al. showed a weak relationship between HBA1c level and diabetes-related ED when using a multiple logistic regression analysis to identify risk factors for all types of ED. However, in the same study, classifying the patients based on the level of ED showed the connection between the severity of ED with HBA1c was significant (P < 0.001).
The advent of effective oral therapies has transformed the management of ED. These should be offered as first-line therapy to men with diabetes and ED and other treatment options should be reserved for those in whom oral therapy is contraindicated or ineffective.
Phosphodiesterase 5 inhibitor
This is an enzyme found in smooth muscle, platelet and corpus cavernosum. During tumescence, there is increase in intracellular concentration of NO, which produces smooth muscle relaxation through the second messenger cGMP. This is broken down in turn to PDE5. Hence, PDE5 inhibitor can enhance erections under conditions of sexual stimulation.
Available phosphodiesterase type 5 inhibitors
This was the first PDE5 inhibitor and early small trials showed it to be a highly effective treatment for ED in men with or without diabetes.
Sildenafil is the most studied PDE-5i with an enormous database. It has been successfully used in doses 25, 50 and 100mg in the general population as well as in difficult-to-treat subgroups, particularly in DED. In one of the first trials, a multicentre, randomised, double-blind, placebo-controlled study (RCT) 268 men with DED were randomised to sildenafil in a flexible escalating dose or placebo for 12 weeks. In the active arm, 56% of the patients had an improvement of erections compared to 10% on placebo.
Sildenafil has also been shown to be effective versus placebo in DM1 patients. Significant improvements in the ability to achieve erections evaluated by IIEF (35.7% vs. 19.9%) and to maintain erections (68.4% vs. 26.5%), improved erections with treatment (Global Assessment Question [GAQ] 66.6% vs. 28.6%) and successful attempts at intercourse (63% vs. 33%) were reported.
Vardenafil is a powerful PDE5 inhibitor whose efficacy and tolerability at doses 5, 10 and 20mg were shown in RCTs including large populations of men with ED, and men presenting difficult-to-treat groups such as DM and after prostatectomy. The reliability of vardenafil was determined in a retrospective analysis of two clinical studies showing an increased probability for penetration, maintenance of erection and higher general satisfaction compared to placebo. Most of the patients who responded to the first dose of vardenafil reported success during the whole 12-week treatment period. In one open study with 398 non-preselected men, the efficacy and tolerability of vardenafil used at the initial dose of 10mg and titrated to 5 or 20mg were investigated. At the end of the 10-week therapeutic period, an improvement in EF domain of IIEF from 13.9 to 25.9 points, successful penetration (SEP2) in 89%, maintenance of erection (SEP3) in 78% and general satisfaction of the treatment (GAQ) in 92% were reported.
Avanafil was recently approved by the US Food and Drug Administration (2012) and European Medicine Agency (2013) for the management of ED. It was studied in over 1 300 patients during clinical trials, including patients with DM and those who had undergone radical prostatectomy, and was found to be more effective than placebo in all men who were randomised to the drug. The medication was studied with on-demand dosing as 50, 100 or 200mg that may occur after food and/or alcohol. Avanafil has a very quick onset of action and higher specificity for PDE5 versus other phosphodiesterase subtypes.
In a 12-week, multicenter RCT 390 men with DED were randomised 1:1:1 to receive avanafil 100 or 200mg, or placebo. Compared with placebo IIEF-EF domain, SEP2 and SEP 3 improved with both doses avanafil – 100mg (P ≤ 0.002) and 200mg (P < 0.001). The authors concluded that avanafil was safe and effective for treating ED in men with diabetes and was effective as early as 15min and more than 6h after dosing. The adverse events seen with avanafil were similar to those seen with other PDE-5 inhibitors.
Tadalafil is an effective drug for treatment of ED of different severity and etiology. Tadalafil 10 and 20mg on demand resulted in 56 and 64% improvement of the erections compared to 25% in the placebo arm in a study with 191 diabetic men. Based on the significant benefit of low dose daily tadalafil, the FDA approved this regimen in 2008.,
In a meta-analysis of 12 RCTs with tadalafil included 637 men of mean age 57 years with DM and meant baseline IIEF 12.6. The use of tadalafil 10 or 20mg leads to an improvement of 7.4 points versus 0.9 points in the placebo group. In men with DM, 53% of the sexual attempts were successful versus 22% in the placebo group. Baseline IIEF showed a negative correlation with HbA1c, but the response to tadalafil treatment was not related to the glycaemic control, type of treatment or previous use of sildenafil.
The most common adverse effects related to PDE5 inhibitors are headache, dyspepsia and flushing. Headache and flushing might be expected, as the inhibitors are vasodilators. The dyspepsia is usually mild and may be due relaxation of the cardiac sphincters of the stomach. The abnormal vision is experienced by about 6% of men taking sildenafil; this may be because the drug has some activity against PDE6, which is a retinal enzyme. Back pain and muscle cramps are an adverse effects mostly seen with tadalafil.
Recent studies have shown many pleiotropic beneficial effects of PDE-5 inhibitors in patients with CAD, hypertension, heart failure, pulmonary arterial hypertension, DM and Raynaud’s phenomenon.
Other treatment options
Intracavernosal injection therapy
The technique of intracavernosal self-injection therapy using phentolamine was first described in 1983 by Brindley. Alprostadil is supplied in self-injection pen device, which is easy to use. Since 1983, ICI has become a staple therapeutic option and high success rates have been reported. The efficacy rate is approximately 70%, with reported sexual activity in 94% and satisfaction rates are high. However, dropout rates of 41%–68% have been reported, with most dropouts occurring within the first 2–3 months. Complications with intracavernous alprostadil include penile pain, prolonged erections, priapism and fibrosis. Drug combinations such as alprostadil plus papaverine, a nonspecific PDE inhibitor resulting in increased levels of cAMP and/or cGMP, and alprostadil plus phentolamine, a competitive antagonist of alpha-1 and alpha-2 adrenoreceptors, may increase efficacy by up to 90%.
Transurethral alprostadil (medicated urethral system for erection)
Medicated urethral system for erection (MUSE) (alprostadil) is a single-use, medicated transurethral system for the delivery of alprostadil to the male urethra. Alprostadil is suspended in polyethylene glycol 1450 (as excipient) and is formed into a medicated pellet that resides in the tip of a translucent hollow applicator. MUSE is administered by inserting the applicator stem into the urethra after urination. The pellet containing alprostadil is delivered by depressing the applicator button. The components of the delivery system are constructed of medical grade polypropylene. The active ingredient in MUSE is alprostadil, which is chemically identical to the naturally occurring eicosanoid, prostaglandin E1 (PGE1).
MUSE is a transurethral delivery system available in 4 dosage strengths: 125 mcg, 250 mcg, 500 mcg and 1000 mcg. MUSE should be administered as needed to achieve an erection. The onset of effect is within 5–10min after administration. The duration of effect is approximately 30–60min. However, the actual duration will vary from patient to patient.
Topical alprostadil cream
Alprostadil is also available as cream, which is applied around the urethral meatus. It contains dodecyl 2-N, N-dimethylaminopropionate, a novel penetration enhancer to allow the prostaglandin reach the erectile tissue.
Vacuum devices become widely available in 1970s. They consist of a translucent tube, which is placed over the penis, and an attached vacuum pump. The air is pumped out of the tube, and negative pressure draws blood into erectile tissue, producing tumescence. A construction band is then slipped off to remain firmly around the base of penis so as to maintain the erection, and the tube is removed.
It was reported that vacuum/constriction devices (VCDs) achieved satisfactory erections in more than 70% of diabetic men. Recently, Sun et al. reported that combined use of sildenafil and VCD for 3 months significantly enhances erectile function, and that is well tolerated by DM patients not responding to first-line sildenafil 100mg alone. Problems with VCDs include pain from the constriction ring, lack of spontaneity, decrease in the quality of orgasm and ejaculatory discomfort. In addition, up to 30% of patients discontinue use as the result of inadequate rigidity, penile pain and failure to ejaculate and the appearance of the penis while using the device.
In spite of recent advances in the management of ED, some men will not be able to use the above-mentioned treatment options. There will therefore always be a limited role of surgery. The surgical options include the insertion of penile prosthesis, corrective surgery for associated Peyronie disease or post injection corporal fibrosis and venous and arterial surgery.
When pharmacotherapy fails, surgical implantation of a penile prosthesis may be considered. Penile implants provide a predictable and reliable erection and have the highest satisfaction rate among both patients and their partners of all the available treatments for waning erections.
In summary, ED is an important but often neglected complication of diabetes. Physicians should include taking a history of the sexual health while taking the history of their parents. Early diagnosis and prompt treatment of ED can be very rewarding to both the patient and the physician.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4]