How to optimise treatment of erectile dysfunction above and beyond the beneficial effects of a phosphodiesterase type 5 inhibitor

The introduction in 1998 of the phosphodiesterase type 5 (PDE-5) inhibitors has changed the landscape of diagnosis and, in particular, the treatment of erectile dysfunction (ED). It has paved the road for a more profound insight into ED. ED and other ailments of elderly men, such as atherosclerosis, hypertension, diabetes mellitus and lower urinary tract symptoms were usually regarded as distinct diagnostic/therapeutic entities, but there is growing evidence that they are interrelated and are factors in ED. To optimise the treatment of ED, an integral approach to the health of the ageing male is required. There is an interdependence between the metabolic syndrome, ED and patterns of testosterone in ageing men. The main features of the metabolic syndrome are abdominal obesity, insulin resistance, hypertension and dyslipidaemia, significant factors in the aetiology of erectile function. The metabolic syndrome is associated with lower-than-normal testosterone levels. Testosterone is a determinant of glucose homeostasis and lipid metabolism. Testosterone is not only a factor in libido but also exerts essential effects on the anatomical and physiological substrate of penile erection. With these recent insights, the health problems of elderly men must be placed in a context that allows an integral approach. While PDE-5 inhibitors are the mainstay of treatment of men with ED, treatment of testosterone deficiency is becoming part and parcel of a new approach to both ED and the metabolic syndrome. The diagnostic work-up of ED should comprise measurement of plasma testosterone. If proven deficient, treatment with testosterone is indicated.     

A survey on relative frequency of metabolic syndrome and testosterone deficiency in men with erectile dysfunction

Purpose

Erectile dysfunction (ED) is a common male sexual dysfunction and affects the individual??s physical and psychological well-being. It has been classified as organic and psychogenic. Men with low testosterone levels have an increased risk of ED. On the other hand, direct detrimental effect of metabolic syndrome on the endothelium, smooth muscle and nerves of the vascular system of the penis is what causes ED to develop in men with metabolic syndrome. Therefore, it is supposed that a large number of men with erectile dysfunction are patients who have ED, metabolic syndrome and testosterone deficiency as a triad. The aim of this study is determining relative frequencies of metabolic syndrome and testosterone deficiency in a group of men with ED.

Methods

Men suffering from ED who were referred to a certain private urology clinic between 22.11.2009 and 22.9.2010 were evaluated for metabolic syndrome criteria; their morning free testosterone levels were measured, and then the related questionnaires were filled out.

Results

Of 241 men with ED, the relative frequency of metabolic syndrome was 41.5%, of testosterone deficiency was 36.5% and of metabolic syndrome in combination with testosterone deficiency was 19.5%.

Conclusion

The relative frequencies of metabolic syndrome and testosterone deficiency in men with ED seem to be significant, and it is the time that we should evaluate ED not as a disease but as a presentation of multiple underlying pathologies which needs medical attention to general health.     

Metabolic syndrome, testosterone deficiency and erectile dysfunction never come alone

Until a decade ago the ailments of elderly men, such as atherosclerosis, hypertension, diabetes mellitus, lower urinary tract symptoms and erectile dysfunction (ED), were regarded as distinct diagnostic/therapeutic entities but there is a growing awareness that these entities are not disparate and, to improve the health of the ageing male, require an integral approach. There is an inter-dependence between the metabolic syndrome, ED and patterns of testosterone in ageing men. The main features of the metabolic syndrome are abdominal obesity, insulin resistance, hypertension and dyslipidaemia, significant factors in the aetiology of erectile function. The metabolic syndrome is associated with lower-than-normal testosterone levels. A new concept of the role of testosterone in male physiology suggests that testosterone plays also a significant role in the development and maintenance of bone and muscle mass and is a determinant of glucose homeostasis and lipid metabolism. Testosterone is not only a factor in libido but exerts also essential effects on the anatomical and physiological substrate of penile erection. With these recent insights, the health problems of elderly men must be placed in a context that allows an integral approach. Treatment of testosterone deficiency is to become part and parcel of this approach.     

Obesity, low testosterone levels and erectile dysfunction

Obesity is an important risk factor for many common diseases including cardiovascular disease (CVD), type 2 diabetes, cancer and erectile dysfunction (ED). Adipose tissues produce a number of adipokines and cytokines, which affect endothelial and metabolic function resulting in insulin resistance and the metabolic syndrome (risks factors for CVD). Both ED and metabolic syndrome improve with a reduction in body mass index (BMI). The relationships among obesity, metabolic syndrome, ED, sex hormone-binding globulin (SHBG) and serum total and free testosterone levels are complex and often confusing to the physician. It is known that BMI is inversely proportional to serum total testosterone concentrations; low serum SHBG levels in obesity contribute to the low serum total testosterone. Recent studies show that BMI is also inversely proportional to free testosterone concentration. The characteristic low serum testosterone concentrations observed in obese men are also present in men with the metabolic syndrome and type 2 diabetes mellitus. A small proportion of men with ED have hypogonadism; however, the proportion increases if these men are obese with manifestations of the metabolic syndrome or type 2 diabetes mellitus. ED is a common symptom in patients with type 2 diabetes who also have low testosterone levels. This review describes the relationships between low serum testosterone concentrations and ED in obese patients and those with metabolic syndrome and type 2 diabetes mellitus.     

Prevalence of late-onset hypogonadism in men with type 2 diabetes mellitus

Late-onset hypogonadism (LOH) or age-associated testosterone deficiency syndrome is defined as a clinical and biochemical syndrome associated with advancing age and characterised by symptoms and a deficiency in serum testosterone levels. This condition may result in significant detriment in the quality of life and adversely affect the function of multiple organ systems. It has been suggested that sex steroid hormones may play a causal role in the development of insulin resistance and type II diabetes. This comparative study was aimed at determining the prevalence of LOH in diabetic men with erectile dysfunction and investigating the effect of testosterone replacement therapy on erectile function and on glycaemic control.     

Testosterone deficiency and risk factors in the metabolic syndrome: implications for erectile dysfunction

The most common cause of erectile dysfunction (ED) is penile vascular insufficiency. This is usually part of a generalized endothelial dysfunction and is related to several conditions, including type 2 diabetes mellitus, hypertension, hyperlipidemia, and obesity. These conditions underlie the pathophysiology of metabolic syndrome (MetS). Hypogonadism, or testosterone deficiency (TD), is an integral component of the pathology underlying endothelial dysfunction and MetS, with insulin resistance (IR) at its core. Testosterone replacement therapy for TD has been shown to ameliorate some of the components of the MetS, improve IR, and may serve as treatment for decreasing cardiovascular and ED risk.     

Testosterone Associations with Erectile Dysfunction,Diabetes, and the Metabolic Syndrome

Hypogonadism and erectile dysfunction are common disorders seen in patients presenting to urology clinics. Increasing evidence indicates that both disorders have important associations with the metabolic syndrome, type 2 diabetes, and cardiovascular disease, all conditions with an increased morbidity and mortality. A low testosterone level is positively associated with the presence and severity of atherosclerosis. The early recognition of these clinical conditions is important to allow treatment and hence reduce cardiovascular risk. Recent publication of guidelines to aid the diagnosis of hypogonadism and a better understanding of how to interpret biochemical tests of androgen deficiency are helping to clarify which patients require testosterone substitution. Symptoms of hypogonadism are not specific and can be especially confounding in men with chronic diseases such as diabetes. Furthermore, convincing evidence shows that testosterone replacement, in addition to improving well-being and symptoms of hypogonadism, may have other vascular and metabolic benefits. Erectile dysfunction is associated with both diabetes and atherosclerosis. Men who fail to respond to phosphodiesterase type 5 inhibitors are more likely to have low testosterone levels and testosterone replacement improves the response. Testosterone substitution also can improve glycaemic control, insulin resistance, and waist circumference in hypogonadal men with type 2 diabetes and cardiac ischaemia in angina. The role of testosterone in these conditions requires further investigation; however, the identification of hypogonadism in its own right requires treatment. Larger studies are underway to investigate the additional potential benefits of testosterone therapy in men with diabetes and metabolic syndrome.     

Clinical awareness and diagnosis of male hypogonadism

Male hypogonadism is an underdiagnosed clinical condition. The reasons for this include a lack of clinical awareness, non-specific symptoms and until recently no coherent guidance on how to interpret the biochemical tests. Hypogonadism is defined as a clinical syndrome, which consists of symptoms with or without signs associated with biochemical evidence of testosterone deficiency. Recent international guidelines have helped physicians to make a diagnosis and improved testosterone formulations allow more physiological testosterone replacement. Testosterone levels are not always assessed in men with fatigue or with bone fractures but are more likely to be assessed but again not always in men with symptoms of loss of libido or erectile dysfunction. There is also increasing evidence that low testosterone levels are an independent risk factor for the metabolic syndrome and type 2 diabetes and that there is a high prevalence of hypogonadism in these conditions. All of these are important triggers to the clinician to consider the diagnosis. There is now evidence that testosterone is not only a sex hormone, it has important beneficial effects on metabolism, the cardiovascular system, the brain as well as muscle and bone.     

Erectile dysfunction, testosterone deficiency, metabolic syndrome and prostatic disease in Taiwan

The purpose of this article is to review the current status and associations between erectile dysfunction (ED), testosterone deficiency (hypogonadism), the metabolic syndrome (MS) and prostatic disease in Taiwan. The prevalence of ED among Taiwanese men older than 40 years was 17.7%, and self-reported ED was lower than International Index of Erectile Function (IIEF)-5 defined ED. Phosphodiesterase type 5 (PDE-5) inhibitors are the first line treatment, but intracavernosal injection and penile prosthesis still have their place. The serum total testosterone (TT) level showed a decline with age, and is one of the major factors that reduces quality of life (QoL). Testosterone deficiency and hypogonadism are associated with ED, which can be improved by testosterone replacement. The MS was reported to have a prevalence of 14–16% in Taiwanese men, and was associated with an increase in all-cause and cardiovascular disease (CVD) mortality. It was also reported to be associated with hypogonadism and ED. The incidence of prostate cancer (PCa) has been rapidly increasing, and its management has also been changing in Taiwan. In conclusion, we need to pay more attention to men's health in Taiwan.     

Testosterone in men's health: a new role for an old hormone

Testosterone is an anabolic hormone with a wide range of beneficial effects on men's health. A considerable body of evidence suggests that testosterone (T) deficiency contributes to the onset and/or progression of type 2 diabetes mellitus (T2D), insulin resistance (IR), metabolic syndrome (MetS), cardiovascular disease (CVD), and erectile dysfunction (ED). Low testosterone precedes elevated fasting insulin, glucose, and hemoglobin A1c (HbA1C) values and may even predict the onset of diabetes. Low testosterone also produces adverse effects on cardiovascular health. Androgen deficiency is associated with increased levels of total cholesterol, low density lipoprotein (LDL), increased production of pro-inflammatory factors, increased thickness of the arterial wall, and contributes to endothelial dysfunction. Testosterone therapy of hypogonadal men improves insulin sensitivity, fasting glucose, and hemoglobin A1c levels. Testosterone supplementation restores arterial vaso-reactivity, reduces pro-inflammatory cytokines, total cholesterol, and triglyceride levels and improves endothelial function and high density lipoprotein (HDL) levels. The therapeutic role of testosterone in men's health, however, remains a hotly debated issue for a number of reasons, including the purported risk of prostate cancer. In view of the emerging evidence suggesting that androgen deficiency is a risk factor for MetS, T2D, IR, CVD, and ED, androgen replacement therapy in hypogonadal men may potentially reduce the risk for these pathologies.     

Metabolic risk factors as a connecting link for men''s health issues

According to the World Health Organization (WHO), the estimated life expectancy of men in Russia is 58.9 years, which is 13 years less than that of Russian women. Complications from cardiovascular disease (CVD) account for 37% of the male mortality rate. Of the European countries, Russia seems to hold the lead in the CVD-related death rate among men. This primarily results from both the social and economic situation and from a tardy recognition and correction of risk factors. Currently, about 200 behavioral, biological and environmental risk factors have been identified, but the following six are well recognized as contributing most significantly to the development of CVD: hypertension, hypercholesterolemia, smoking, obesity, alcohol abuse, sedentary lifestyle. Overall, these risk factors all further the progression towards myocardial infarction, as well as towards other non-infectious diseases. Furthermore, these risk factors tend to combine in a single individual. In 1988, G. Reaven, an American endocrinologist, propounded the theory that hypertension, dyslipidemia, and impaired glucose tolerance have a common cause in hyperinsulinemia/insulin resistance, which is a connecting link for all of these disorders.

Recently, papers on the link between the metabolic syndrome (MS), erectile dysfunction (ED) and androgen deficiency have been increasingly published. Thus, low testosterone blood levels, apart from being associated with ED and decreased libido, are also associated with insulin resistance, central obesity, and the impairment of lipid metabolism. Thus, in patients with hypogonadism, compared to individuals with obesity or with normal body weight, a marked, significant, insulin resistance/hyperinsulinemia has been established. However, among men with ED and the MS, in contrast to patients with ED without the MS, their total testosterone levels appear to be four times as low as their free testosterone levels. A step-by-step regression analysis has shown that the metabolic risk factors predominate over other major risk factors of ED progression.

Androgen replacement therapy can be a reasonable first-line treatment for patients with hypogonadism combined with sexual dysfunction and the MS. Clinical studies have demonstrated that long-term testosterone injections improve the metabolic profile, namely by also decreasing triglyceride and LDL cholesterol levels, body weight, waist circumference and glucose metabolism parameters.

Thus, the metabolic risk factors act as a connecting link between the pathogenesis of CVD and androgen deficiency. To prevent complications from these conditions, the development of an interdisciplinary work-up for the comprehensive diagnosis and therapy of the MS, hypogonadism and sexual dysfunction should be considered.     

Dramatic improvement of penile venous leakage upon testosterone administration. A case report and review of literature

The main effect of testosterone was long-time assumed to be on sexual interest and, indirectly, on erectile function. Newer insights demonstrate that testosterone deficiency impairs the anatomical, ultrastructural, biological and physiological/functional substrate of penile erection, which can be, at least in part, restored by normalization of plasma testosterone levels. This is a report on a 56-year-old man suffering from diabetes mellitus type II and metabolic syndrome, who had complaints of a severe erectile dysfunction because of venous leakage, confirmed by pharmaco-cavernosography. He was also testosterone deficient (1.8 ng ml(-1)). Upon testosterone administration his erectile function improved dramatically. Repeated cavernosography no longer showed venous leakage.     

Lifestyle modifications and erectile dysfunction: what can be expected?

Erectile dysfunction (ED) is a common medical disorder whose prevalence is increasing worldwide. Modifiable risk factors for ED include smoking, lack of physical activity, wrong diets, overweight or obesity, metabolic syndrome, and excessive alcohol consumption. Quite interestingly, all these metabolic conditions are strongly associated with a pro-inflammatory state that results in endothelial dysfunction by decreasing the availability of nitric oxide (NO), which is the driving force of the blood genital flow. Lifestyle and nutrition have been recognized as central factors influencing both vascular NO production, testosterone levels, and erectile function. Moreover, it has also been suggested that lifestyle habits that decrease low-grade clinical inflammation may have a role in the improvement of erectile function. In clinical trials, lifestyle modifications were effective in ameliorating ED or restoring absent ED in people with obesity or metabolic syndrome. Therefore, promotion of healthful lifestyles would yield great benefits in reducing the burden of sexual dysfunction. Efforts, in order to implement educative strategies for healthy lifestyle, should be addressed.     

Hypogonadism and metabolic syndrome: implications for testosterone therapy

PURPOSE: Metabolic syndrome, characterized by central obesity, insulin resistance, dyslipidemia and hypertension, is highly prevalent in the United States. When left untreated, it significantly increases the risk of diabetes mellitus and cardiovascular disease. It has been suggested that hypogonadism may be an additional component of metabolic syndrome. This has potential implications for the treatment of metabolic syndrome with testosterone. We reviewed the available literature on metabolic syndrome and hypogonadism with a particular focus on testosterone therapy. MATERIALS AND METHODS: A comprehensive MEDLINE review of the world literature from 1988 to 2004 on hypogonadism, testosterone and metabolic syndrome was performed. RESULTS: Observational data suggest that metabolic syndrome is strongly associated with hypogonadism in men. Multiple interventional studies have shown that exogenous testosterone has a favorable impact on body mass, insulin secretion and sensitivity, lipid profile and blood pressure, which are the parameters most often disturbed in metabolic syndrome. CONCLUSIONS: Hypogonadism is likely a fundamental component of metabolic syndrome. Testosterone therapy may not only treat hypogonadism, but may also have tremendous potential to slow or halt the progression from metabolic syndrome to overt diabetes or cardiovascular disease via beneficial effects on insulin regulation, lipid profile and blood pressure. Furthermore, the use of testosterone to treat metabolic syndrome may also lead to the prevention of urological complications commonly associated with these chronic disease states, such as neurogenic bladder and erectile dysfunction. Physicians must be mindful to evaluate hypogonadism in all men diagnosed with metabolic syndrome as well as metabolic syndrome in all men diagnosed with hypogonadism. Future research in the form of randomized clinical trials should focus on further defining the role of testosterone for metabolic syndrome.     

Androgen deficiency in aging and metabolically challenged men

Androgen deficiency in aging men is common, and the potential sequelae are numerous. In addition to low libido, erectile dysfunction, decreased bone density, depressed mood, and decline in cognition, studies suggest strong correlations between low testosterone, obesity, and the metabolic syndrome. Because causation and its directionality remain uncertain, the functional and cardiovascular risks associated with androgen deficiency have led to intense investigation of testosterone replacement therapy in older men. Although promising, evidence for definitive benefit or detriment is not conclusive, and treatment of late-onset hypogonadism is complicated.     

Erectile dysfunction as a predictor of the metabolic syndrome in aging men: results from the Massachusetts Male Aging Study

PURPOSE: The metabolic syndrome, characterized by central obesity, insulin dysregulation, abnormal lipids and borderline hypertension, is a precursor state for cardiovascular disease. We determined whether erectile dysfunction is predictive of the metabolic syndrome. MATERIALS AND METHODS: Data were obtained from the Massachusetts Male Aging Study, a population based prospective cohort observed at 3 points during approximately 15 years (T(1)-1987 to 1989, T(2)-1995 to 1997, T(3)-2002 to 2004). The metabolic syndrome was defined by using a modification of the Adult Treatment Panel III guidelines. The association between erectile dysfunction and the metabolic syndrome was assessed using relative risks and 95% confidence intervals estimated using Poisson regression models. RESULTS: Analysis was conducted of 928 men without the metabolic syndrome at T(1). There were 293 men with incident metabolic syndrome, of which 56 had erectile dysfunction at baseline. Body mass index and the presence of 1 or 2 conditions constituting the metabolic syndrome definition were the strongest predictors of the metabolic syndrome. The association of erectile dysfunction with the metabolic syndrome (unadjusted RR 1.35, 95% CI 1.01-1.81) was modified by body mass index, with a stronger effect of erectile dysfunction in men with body mass index less than 25 (adjusted RR 2.09, 95% CI 1.09-4.02), and no erectile dysfunction and metabolic syndrome association in men with body mass index 25 or greater (adjusted RR 1.06, 95% CI 0.76-1.50). CONCLUSIONS: Erectile dysfunction was predictive of the metabolic syndrome only in men with body mass index less than 25. This finding suggests that erectile dysfunction may provide a warning sign and an opportunity for early intervention in men otherwise considered at lower risk for the metabolic syndrome and subsequent cardiovascular disease.     

The dark side of testosterone deficiency: I. Metabolic syndrome and erectile dysfunction

The metabolic syndrome (MetS) is considered the most important public health threat of the 21st century. This syndrome is characterized by a cluster of cardiovascular risk factors including increased central abdominal obesity, elevated triglycerides, reduced high-density lipoprotein, high blood pressure, increased fasting glucose, and hyperinsulinemia. These factors increase the risk of cardiovascular disease (CVD) and/or type 2 diabetes. Although the etiology of this syndrome is thought to stem from obesity and physical inactivity, the extent of interactions of the individual MetS components with one another remains poorly defined. Obesity, diabetes, hypogonadism, and specific hormone and metabolic profiles have been implicated in the pathophysiology of CVD. The evolving role of androgens in MetS and CVD is of paramount importance. Reduced androgen levels associated with hypogonadism or androgen deprivation therapy increase cardiovascular risk factors and produce marked adverse effects on cardiovascular function. MetS has been associated with hypogonadism and erectile dysfunction (ED), and MetS may be considered a risk factor for ED. It is suggested that MetS, diabetes, and CVD will increase in the upcoming decades. Thus, it is critically important to develop a better understanding of how obesity, diabetes and hypogonadism contribute to androgen deficiency and the various pathophysiologic states of vascular disease. In this review we discuss the current literature pertaining to androgen deficiency, MetS, and ED, because the relationship of these factors is of scientific and clinical importance. Specifically, we will focus on exploring the relationships between hypogonadism, obesity, MetS, and ED.     

Getting Urology involved in the treatment of men with erectile dysfunction,the metabolic syndrome and hypogonadism

Urologists play a significant role in the diagnosis and treatment of male erectile dysfunction (ED). But the context of diagnosing and treating ED has profoundly changed over the past decade, in that it is no longer viewed as an independent entity. Rather it is recognized that in many (but not all) patients, there is a close association with the so called “metabolic syndrome” and on occasions with hypogonadism. In order to treat men with ED appropriately in this context, it is important for the urologist to become familiar with the intricacies of the metabolic syndrome and also with the diagnosis and treatment of male hypogonadism.While understanding of the metabolic syndrome involves the urologist in the understanding the management of hypertension, dyslipidaemia and diabetes, (most of which will be have changed considerably since he first learnt about them at medical school), an understanding of testosterone metabolism is much closer to home. Urologists are trained to use testosterone withdrawal as a treatment for prostate cancer, and it is only a short intellectual step to believing that there is an association between testosterone replacement and the development of prostate cancer. However, while the evidence for the former is considerable, the evidence to support the latter relationship is lacking.There is increasing evidence that there is a role for the responsible treatment of elderly men who are hypogonadal with testosterone while at the same exercising due caution in relation to any potentially harmful effects of testosterone administration on the prostate and the hematopoietic system. To this end a number of sets of guidelines for diagnosing and treating elderly men with testosterone deficiency have been developed.     

Hormonal erectile dysfunction. Evaluation and management

The clinical diagnosis of hypogonadism in the adult is difficult to establish on the basis of a history and physical examination and universally requires biochemical investigations. A serum testosterone determination is justified in men complaining of erectile dysfunction with or without alterations in sexual desire. Among the causes of erectile dysfunction, hypotestosteronemia rates are low. The prevalence of erectile dysfunction particularly is common at a period in life when alterations occur in male hormonal environment. The treatment of hypogonadal erectile dysfunction, regardless of age, is readily available, safe, and effective. The positive impact of treatment on the overall quality of life can be significant. The presence of erectile dysfunction in an aging man (> 55 years) does not imply the presence of hypogonadism, and, even if the two conditions are present, the indications for treatment require good clinical judgment. Persistent low testosterone levels may have significant detrimental effects in other organ systems; therefore, a timely diagnosis of androgen deficiency and appropriate treatment may have significant effects outside the narrow field of sexual performance.     

Metabolic syndrome and hormone profile in patients with erectile dysfunction

ObjectivesTo demonstrate the existence of relation between metabolic syndrome and erectile dysfunction and to analyze the hormone profile of these patients regarding a healthy population group.Material and methodsA case-control study was designed with 65 men divided into 2 groups according to presence or non-presence of erectile dysfunction. Group A was made up of 37 men with erectile dysfunction and group B by 28 healthy men without erectile dysfunction. Ages ranged from 40 to 65 years. The presence of metabolic syndrome according to the ATPIII definition, performance of physical exercise, smoking habit, body mass index and complete hormone profile including testosterone -total, free and bioavailability, were studied.ResultsGreater presence of metabolic syndrome was detected among men of Group A (72.9%) versus those of group B (17.8%) (p = 0.0001). Among the parameters that make up the metabolic syndrome, there are differences between both groups in systolic and diastolic blood pressure, fast blood sugar and abdominal circumference, all these differences being significant. After performing multivariate analysis between the metabolic syndrome and erectile dysfunction adjusted for age, BMI, International Index for Erectile Function (IIEF), physical exercise and smoking habit, we have observed an independent significant relation between the metabolic syndrome and erectile dysfunction. We have not found differences between both groups in any hormone parameter.ConclusionA relationship is found between metabolic syndrome and erectile dysfunction. Thus, it seems recommendable to perform the metabolic profile and cardiovascular risk study in these patients.