The word “diabesity” was originally used by Ethan Sims in the 1970s in the context of studies of experimental human obesity. More recently the term has been used to describe the co-existence of type 2 diabetes and obesity (Haslam, 2012). Erectile dysfunction (ED) is one of the most under-diagnosed complications in men with diabetes. It is expected to affect more than 300 million men by the year 2025 (Rajendran and Cummings, 2012), with the diabesity pandemic being a major contributing factor. The prevalence of ED in men with diabetes averages about 35%, varying from 6–52%. This is far higher than the average of about 20% in men without diabetes (Rajendran and Cummings, 2012). The risk of ED is increased approximately 1.5- to three-fold in obese men (Chitaley et al, 2009) and three-fold with an HbA1c level >65 mmol/mol (8.1%; Al-Hunayan et al, 2007).
Better understanding of the biochemical pathways underlying the mechanisms of ED has led to the development of a number of successful therapeutic options in recent years. In this article, we discuss the management of ED in the context of diabesity.
Pathophysiology
Changes within corpus cavernosum
There are several abnormalities in either the availability or effectiveness of several key chemical mediators involved in smooth muscle relaxation and constriction in the corpus cavernosum of men with diabetes. Both parasympathetic nerve and endothelium-dependent smooth muscle relaxation are affected in men with ED and diabetes (Cummings, 2004). Reduced nitric oxide (NO) synthase levels and increased superoxide radicals leads to oxidative stress and free radical damage of endothelium (Shin et al, 2011).&
Other abnormalities demonstrated include: reduced acetylcholine-mediated muscle relaxation; reduced vasoactive intestinal polypeptide (smooth muscle relaxant) activity; reduced noradrenaline (smooth muscle contraction) levels (Cummings, 2004); increased endothelin-1 (smooth muscle contraction) levels (Francavilla et al, 1997); and accumulation of advanced glycation end products that result from non-enzymatic reactions between glucose and lipids, proteins or nucleic acids (Wen et al, 2002), apart from structural abnormalities such as fibrosis of the penile arteries and corpus cavernosum and reduced amounts of cavernous nerve fibres of unmyelinated axons with collagen, factors that impair smooth muscle relaxation and vasodilatation (Cummings, 2004).
Neural and vascular factors
Diabetic neuropathy and microvascular blood supply are closely linked. Neuropathy, especially autonomic neuropathy, has been linked to the development of ED and the principal abnormality seems to be the parasympathetic nervous system, responsible for achieving tumescence (Cummings, 2004), with dysfunction of the penile nerves preceding neuropathy in the other peripheral nerves in some men with diabetes (Bleustein et al, 2002). There appears to be no impairment of the sympathetic nervous system.
The penis is a highly vascular organ and diabetes may be associated with diffuse atherosclerosis or isolated disease of the external iliac artery, both of which may contribute to the development of ED. Up to 95% of men with diabetes and ED show impaired penile blood flow (Cummings, 2004). It has been shown that significant ED is associated with diabetic retinopathy severity that is independent of age, duration of diabetes and cardiovascular risk factors (Henis et al, 2011), and that ED in men with diabetes is associated with proteinuria, which is a marker for diabetic nephropathy (Yamasaki et al, 2004). Other abnormalities in vascular function, in particular NO-mediated vasodilatation, have been described earlier.
Hormonal factors
Hypogonadism is defined as a clinical condition comprising both symptoms with or without signs and biochemical evidence of testosterone deficiency (Jones, 2007). It is now clear that penile erection and blood flow is associated with circulating testosterone levels and that testosterone controls several mechanisms that lead to erection and detumescence (Corona and Maggi, 2010). Testosterone also appears to mainly regulate the timing of the erectile process as a function of sexual desire (Corona and Maggi, 2010).
The link between obesity, diabetes, hypogonadism and ED has become better recognised in the last decade (Jones, 2007; Corona and Maggi, 2010; Wang et al, 2011) with several cross-sectional studies showing that the prevalence of biochemical and symptomatic hypogonadism in men with diabetes ranges from 33% to 42% (Corona and Maggi, 2010). This justifies the need for hypogonadism screening in this population.
Hypogonadism with low testosterone and normal gonadotrophins (mixed hypogonadism) are more commonly described in the context of diabesity, as visceral obesity and metabolic syndrome directly impact on testosterone levels and vice versa (Jones, 2007; Wang et al, 2011). A number of mechanisms have been suggested, including: low circulating levels of plasma sex hormone-binding globulin causing low total testosterone, which leads to increased insulin resistance; and increased aromatase activity resulting in increased conversion of testosterone to oestrogen in visceral adipose tissue thereby decreasing testosterone levels and insulin resistance in type 2 diabetes per se, leading to reduced insulin action in the hypothalamus (Jones, 2007; Corona and Maggi, 2010; Wang et al, 2011).
Other endocrine disorders such as hyperprolactinaemia, hypothyroidism, hyper-thyroidism or growth hormone deficiency can be concurrently present in men with ED and diabesity, with thyroid abnormalities more commonly observed in diabetes, although there is no significant difference in the circulating levels of these hormones when compared with the general population (Cummings, 2004).
Other factors
There is evidence that sedentary lifestyle, smoking and alcohol consumption are linked to the occurrence of ED, with increased physical activity conferring some protection upon development of ED (Rajendran and Cummings, 2012).
A number of drugs that have been used to treat diabetes or its complications have been associated with the development of ED, although the aetiological process is unclear.
The prevalence of psychological or psychiatric disease can be up to 40% causing performance anxiety, although it is not possible to implicate this as the primary aetiological precipitant of ED, as generally organic disease predominates (Cummings, 2004). There are a number of other factors which have been described in men with ED and diabetes (see Table 1).
The risk of cardiovascular disease
The emerging evidence shows that ED may be the early clinical manifestation of generalised vascular disease and is an independent risk for cardiovascular events (Shin et al, 2011). ED precedes clinically evident coronary artery disease (CAD) and can predict future cardiovascular events, with the severity of ED correlating to the extent of CAD.
There are two hypotheses linking ED, cardiovascular disease (CVD) and diabetes (Araña Rosaínz Mde et al, 2011; Shin et al, 2011). One hypothesis implicates endothelial dysfunction and chronic inflammation that can be caused by various vascular insults including diabetes. The other theory is the artery size hypothesis, with the same plaque burden having greater effect on blood flow in penile arteries (due to smaller diameter) compared to coronary arteries. This would explain why ED manifests earlier than CVD. In summary, the onset of ED could be a potential screening tool for silent CAD in men with diabesity.
Clinical examination and investigations
Broadly, the assessment and treatment of ED is similar in men with or without diabesity, but there are some specific therapeutic approaches which are important in the context of diabesity. It is important to assess for any underlying microvascular or macrovascular complications, especially silent CAD, due to its well-described association with ED and diabetes. The second Princeton consensus guidelines (Table 2) are very useful in assessing the cardiovascular risk of a patient in relation to considering treatment for ED (Jackson et al, 2006). The international index of erectile function (IIEF), or its more recent abridged 5-item version, is a useful questionnaire tool that can be used as a guide to detect ED and monitor response to treatment (Rosen et al, 1999).
Investigations available in clinical practice for men with ED and diabesity are shown in Box 1. In our own practice, we limit investigations to hormonal blood tests, although we acknowledge that the yield of unrecognised endocrine abnormalities (apart from hypogonadism) is low. Screening for hypogonadism is important as concurrent treatment with both testosterone replacement therapy and phosphodiesterase-5 (PDE5) inhibitors may be of benefit (Jones et al, 2007).
Pharmacotherapy
Lifestyle modification and glycaemic control
Weight loss, increased physical activity, stopping smoking and limiting alcohol consumption are important lifestyle changes that need to be reinforced in people with ED and diabesity. Table 3 summarises the studies that suggest that weight loss may be beneficial in improving ED in diabesity (Dallal et al, 2008; Wing et al, 2010; Khoo et al, 2011). Psychosexual counselling (such as sensate focusing) is important in men with an overt psychological or psychiatric aetiology to their ED. While drug therapy improves glycaemic control when ED develops concomitantly with acute deterioration in glycaemic control, there is no evidence of enhanced erectile performance when glycaemic control is improved in patients with chronic hyperglycaemia and ED (Cummings, 2004). Also, in our experience despite drugs being associated with development of ED, restoration of potency is only successful in those patients when a clear temporal relationship between the commencement of the drug (within 2 weeks) and the development of ED has been established and the drug withdrawn. This may not be always possible due to other therapeutic reasons.
Figure 1 is a simple algorithm that we suggest to guide physicians in treating ED and diabesity. For a summary of treatment options, see Table 4.
Testosterone replacement therapy in hypogonadal men
Testosterone replacement can be successful in hypogonadal men, with some recipients often noticing dramatic improvement within days of commencing treatment. This can be either intramuscular testosterone (given every 3 weeks with standard testosterone or every 3 months with longer-acting preparations) or topical testosterone in the form of gels or creams. The method is largely a lifestyle choice as topical therapy involves avoiding contact with water and other people for a short time after application whereas parenteral therapy can sometimes be quite painful.
Other routes such as buccal or subcutaneous implants are rarely used. Nearly 60% of men with ED who previously failed to respond to PDE5 inhibitors and are now diagnosed as hypogonadal respond to PDE5 inhibitors alongside testosterone replacement therapy (Jones, 2007; Corona and Maggi, 2010; Wang et al, 2011).
Oral >agents
Oral PDE5 inhibitors have revolutionised the management of ED and sublingual apomorphine and oral yohimbine are now rarely used. PDE5 inhibitors facilitate erections through prolonging the availability of cyclic guanosine monophosphate that promotes smooth muscle relaxation within the corpus cavernosum. Currently there are four commercial forms of PDE5 inhibitors available: sildenafil, vardenafil, tadalafil and avanafil.
Though it is difficult to reliably interpret any clinical differences in effectiveness between these agents, tadalafil has the added advantage in that it can be administered daily without timing the PDE5 inhibitor to sexual activity. In general, between three and four out of five patients will respond, a response rate that is slightly less than that of the general population with ED. They are cost-effective and generally well tolerated. Selected CAD patients with stable disease who are not on nitrate therapy can take PDE5 inhibitors. Though some studies have shown beneficial effects on endothelial dysfunction and fewer cardiovascular events (Phé and Rouprêt, 2012), more robust randomised controlled trials are needed to establish the long term cardio-protective effects of PDE5 inhibitors.
There are very few published studies assessing the use of over-the-counter herbal or Chinese traditional medicines such as panax ginseng, butea superba and yohimbine and even they are not considered robust. Many of these natural products contain either potent inhibitors of PDE5 (Chen, 2009) or pharmacological doses of PDE5 inhibitors such as sildenafil or tadalafil (Fleshner et al, 2005). This is clearly a concern when marketed freely because they have a potentially fatal interaction with nitrates.
Second- and third-line options
Intracavernosal injections with papaverine and phentolamine have been used to treat ED since the 1980s, but both drugs can cause priapism (erections lasting greater than 6 hours) and other side effects. As such, their use has been superseded by a licensed intracavernosal preparation of prostaglandin E1 (alprostadil) that can be self-administered directly into the corpus cavernosum. It is the most potent treatment available (approximately nine out of 10 injections in the general population resulted in successful erections) with a lower incidence of priapism and there is no significant difference in response between men with and without diabetes. Other side effects include local pain and tingling, bruising, fibrosis, scarring and occasional infection.
The application of alprostadil in the form of a pellet into the urethra has been associated with a 65.9% success rate in achieving erections suitable for sexual intercourse in the general population, with similar success rates in the subgroup of men with diabetes. Side effects include penile pain, minor urethral trauma and dizziness, although priapism has not been reported.
Though vacuum devices provide a safe alternative strategy to pharmacological therapy, they require a moderate degree of manual dexterity and are usually only suitable for men in stable relationships with nearly one-third of men discontinuing it due to bruising, discomfort and ejaculatory failure.
Penile prostheses may be considered in men who have failed to respond to less invasive measures. Corrective surgery may be considered in men with primary penile abnormalities such as Peyronie’s disease and venous ligation may be undertaken in men with established venous leaks (Cummings, 2004).
Future treatment options
Newer agents such as topical nitrates or combinations of aminophylline, isosorbide dinitrate and co-dergocrine, oral L-arginine, bremelanotide, and intracavernosal vasoactive intestinal polypeptide continue to be explored.
Though controversial, gene therapy and umbilical stem cell therapy may become available in the future for refractory cases (Bivalacqua et al, 2003; Cummings, 2004; Bahk et al, 2010).
Conclusion
In summary, effective intervention is now available for the vast majority of men with diabesity who present with ED. Lifestyle modification such as weight loss, increased physical activity and smoking cessation are beneficial in preserving erectile function.
Hypogonadism in men with ED and diabesity is now increasingly recognised and assessment should also include focus on silent CVD and this may influence treatment options. The advent of PDE5 inhibitors has revolutionised the management of ED but it important for healthcare professionals to adopt a more holistic approach to this under-diagnosed complication of diabesity.
