Obesity and Erectile Dysfunction: Title and subTitle BreakCommon Problems, Common Solution?

The introduction of sildenafil (Viagra) in 1998 unleashed a tidal wave of interest in medical treatment for erectile dysfunction (ED). Although data from the Massachusetts Male Aging Study indicated that approximately 52% of men aged 40 to 70 years experienced some degree of ED,¹ many of these men were either unaware of treatment options for the condition, averse to the invasive nature of some of the existing options, or too embarrassed to discuss the topic with a physician. The heavy direct-to-consumer marketing campaign that accompanied the release of this drug contributed to a new, open discussion in popular culture about this highly prevalent condition; ED was suddenly fair game for late night comics and national news magazine covers. By the end of 1999, Viagra was a billion-dollar drug.² From 1996 to 2000, the national rate of physician office visits during which ED was one of the reasons for the encounter increased by almost 50%.³

In 2004, the introduction of 2 new phosphodiesterase type 5 inhibitors, tadalafil (Cialis) and vardenafil (Levitra), is being accompanied by another marketing blitz aimed directly at men with ED. The advertising for these new agents is ubiquitous, with estimates of approximately $100 million being spent to market each drug in its first year; however, this time around the advertisements are even more sexually provocative.⁴ Primary care physicians and urologists can expect to be approached by their patients with a number of questions about the claims made in these advertisements. However, amid all the marketing hype surrounding these pharmacological therapies, is it possible that another, potentially more beneficial, treatment strategy for ED has been overlooked?

For many patients, ED is one manifestation of more generalized pathology. Strong epidemiological evidence links the subsequent risk of ED to the presence of well-recognized risk factors for coronary artery disease (CAD), such as increased body mass index (BMI), hypertension, hypertriglyceridemia, and hypercholesterolemia.^{1 ,5 - 7} These comorbidities are common in cohorts of men with ED.⁸ Endothelial dysfunction is likely a pathogenetic mechanism common to both of these comorbid states and ED.⁸ Some have suggested that a diagnosis of ED is a sentinel event that should prompt investigation for CAD in asymptomatic men.⁹

A reasonable inference from these findings is that ameliorating some of these risk factors might prevent the subsequent occurrence of ED. Regular physical exercise can have a modifying effect on some CAD risk factors,¹⁰ suggesting a similar hypothesis regarding the effect of increased physical activity on risk of ED later in life. Derby et al examined a cohort of men aged 40 to 70 years without ED and assessed the relationship between changes in modifiable ED risk factors and development of ED after 8 years.¹¹ They found that the adjusted odds ratio for ED was 0.3 in men who started physical activity compared with those who remained at their sedentary baseline. However, men who were overweight at baseline were at higher risk of ED even if they subsequently lost weight. Their findings suggest another intriguing hypothesis: is existing ED treatable by attention to modifiable risk factors such as sedentary lifestyle and obesity?

The study published in this issue of JAMA by Esposito et al¹² tested this hypothesis. The authors conducted a randomized controlled trial involving 110 obese men seeking care at a university weight loss clinic. Eligible participants were those who at baseline had ED as defined by a sub-scale of the International Index of Erectile Function (IIEF).¹³ Patients with comorbid conditions relatively common in the obese population, including diabetes, cardiovascular disease, and hypertension, were excluded. Men randomly assigned to the intervention group were entered into an intensive weight loss program, involving personalized dietary counseling and exercise advice and regular meetings with a nutritionist and personal trainer. Men assigned to the control group received general guidance on weight loss at each visit.

Baseline height, weight, dietary intake, and exercise activity were recorded. To elucidate the nature of the biological response to weight loss in the setting of obesity and ED, serum markers of low-grade inflammation, including interleukin 6, interleukin 8, and C-reactive protein were measured. Elevated serum concentrations of these markers have been associated with endothelial dysfunction in obese patients.^{14 - 15} Thus, a further hypothesis of this study was that weight loss in obese patients would reduce serum concentration of these markers and would provide evidence of improved endothelial function. Endothelial function was tested by measurement of blood pressure and platelet aggregation after intravenous infusion of L-arginine. The effects of L-arginine on lowering blood pressure and decreasing platelet aggregation are likely mediated via its conversion to nitric oxide, making this test a measure of endothelial function.¹⁶ The pathogenesis of ED is likely multifactorial and may not be explained by endothelial dysfunction alone; oxidative damage to smooth muscle cells of the corpora cavernosa has also been implicated.¹⁷ However, because endothelial dysfunction is part of the pathogenesis of ED, reversal or improvement in this dysfunction after weight loss would provide a possible mechanism to explain any associated improvement in IIEF score after weight loss.

After 2 years, men in the intervention group were eating healthier diets, exercising more, and had experienced more weight loss than men in the control group (men in the control group actually did not experience statistically significant change in BMI). Similar small numbers of men in both groups started therapy with a phosphodiesterase type 5 inhibitor during the study, and excluding these men from analysis did not change the findings. At follow-up, 17 men in the intervention group had a score on the IIEF indicating normal sexual function, compared with 3 men in the control group (P = .001). That almost one third of obese men reversed their ED after exercising more and losing weight is striking. In multivariate analysis, both reduction in BMI and increase in physical activity were significantly associated with changes in IIEF score. Both of these variables may represent targets for intervention by physicians counseling obese patients with ED.

The authors also found that weight loss in obese men was associated with a lowering of the serum concentrations of the inflammatory markers measured, as well as a significant improvement in endothelial function. This finding suggests that obese patients may experience an improvement in endothelial function after weight loss and increased physical activity. The benefits of weight loss and increased exercise for these obese patients are not limited to possible restoration of erectile function; cardiovascular risk reduction and reduction in risk of insulin resistance are but 2 of the myriad possible health benefits.

The findings from the study by Esposito et al are provocative but come with some caveats. The population studied may differ from obese patients typically seen in primary care clinics in that these patients did not have known CAD, diabetes, or hypertension, all commonly seen in obese patients in practice. The presence of these comorbid diseases may lessen the impact of the effect of exercise and weight loss on ED. Another limitation to the generalizability of the findings is these obese patients were seeking treatment for weight loss at a specialized clinic. Counseling overweight patients to begin and sustain effective weight-reducing behaviors can be a daunting challenge for clinicians. Some obese patients may lack the motivation demonstrated by the patients in this study. Even among these motivated patients, benefit was evident only in those who were entered into an intensive program, which may be difficult to replicate in many practices. Also, as the authors point out, it is possible that improved self-esteem related to weight loss may be a contributing factor to help explain the findings, although data to explore this possibility were not collected.

At a time in which obesity has become a public health crisis, this study provides evidence of efficacy for what perhaps should be the first-line treatment for obese patients with ED. This treatment strategy produces many benefits for the patient if it is successful and incurs no untoward risk if it is not. Unfortunately, however, this is one treatment for ED that will not be accompanied by free pens, free notepads, and its own Super Bowl commercial.