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.     

The dark side of testosterone deficiency: II. Type 2 diabetes and insulin resistance

A considerable body of evidence exists suggesting a link among reduced testosterone plasma levels, type 2 diabetes (T2D), and insulin resistance (IR). Hypogonadal men are at higher risk for T2D. Here we evaluate the relationships between testosterone, metabolic syndrome (MetS), T2D, and IR and discuss the relationships among androgen deficiency and these factors, especially as it ultimately relates to the development of cardiovascular disease and erectile dysfunction (ED). Thus, a comprehensive literature search was carried out using PubMed, and relevant articles pertinent to androgen deficiency, T2D, IR, MetS, and ED were reviewed and discussed. Low testosterone precedes elevated fasting insulin, glucose, and hemoglobin A1c (HbA1C) values and may even predict the onset of diabetes. Treatment of prostate cancer patients with surgical or medical castration exacerbates IR and glycemic control, strengthening the link between testosterone deficiency and onset of T2D and IR. Androgen therapy of hypogonadal men improves insulin sensitivity, fasting glucose, and HbA1c levels. We suggest that androgen deficiency is associated with IR, T2D, MetS, and with increased deposition of visceral fat, which serves as an endocrine organ, producing inflammatory cytokines and thus promoting endothelial dysfunction and vascular disease.     

Clinical and metabolic evaluation of subjects with erectile dysfunction: a review with a proposal flowchart

Erectile function is a haemodynamic phenomenon depending on the integrity of neurological, vascular, endocrinological, tissue (corpora cavernosa), psychological and relational factors; changes in any one of these components may lead to erectile dysfunction (ED). ED and its comorbid conditions share common risk factors such as endothelial dysfunction, atherosclerosis and metabolic and hormonal abnormalities. Furthermore, although cross-sectional studies have shown a clear age-dependent association between ED, diabetes mellitus, hypertension, metabolic syndrome (MetS) and cardiovascular diseases, longitudinal evidence has recently emphasized that ED could be an early marker of these conditions. Recently, the European Association of Urology and American Urology Association provided consensus guidelines for the management of ED patients. However, the metabolic aspect of ED is rather neglected or not sufficiently treated. In this study, more emphasis will be placed on the presence of ED comorbid metabolic factors. The primary and secondary goals of therapy, according to current guidelines and to prevent their clinical evolution, will also be provided. We review the concepts of metabolic diseases related to ED and their treatment. Criteria for the diagnosis and treatment of hypogonadism, metabolic and vascular disease related to ED were analysed. ED can mark the starting point for the evaluation and prevention of significant severe diseases (such as diabetes, MetS, dyslipidaemia, arteriosclerosis, hypertension, ischaemic cardiopathy, neuropathy, etc.) hitherto unknown by the patients. Most widely used criteria for the diagnosis and treatment of these diseases were reported. We suggest a clinical approach which allows the identification of metabolic and others systemic pathologies contributing to the development of ED. This approach may constitute an improvement in disease prognosis and either induce a spontaneous reduction of ED or facilitate its specific therapy.     

Original evaluation of endothelial dysfunction in men with erectile dysfunction and metabolic syndrome

We have recently demonstrated the diagnostic value of a new immunophenotype of blood endothelial progenitor cells (EPCs=CD45neg/CD34pos/CD144pos) and endothelial microparticles (EMPs=CD45neg/CD144pos/AnnexinVpos) in patients with arterial erectile dysfunction (ED) according to severity of cavernous arterial insufficiency evaluated through penile Doppler. The aim of this study was to evaluate both EPCs and EMPs in patients with arterial ED and metabolic syndrome (MetS), comparing these patients with another group of patients without MetS and ED and a third group with MetS but without ED. For this study 50 patients with arterial ED and MetS were selected (age: 55.0±3.0 years; range: 47-60). A group of age-matched (age: 54.0±2.0 years; range: 44-60) patients without arterial ED and MetS (n=30), and another group of age-matched (age: 57.0±4.0 years; range: 40-62) patients with MetS but without ED (n=20) represented the control groups. EPCs and EMPs were significantly higher in patients compared with other groups (P<0.01). Both EPCs and EMPs correlated positively with the age, body mass index, and score of international index of ED (version five items) and with the following cavernous artery indices: peak systolic velocity, acceleration time and intima-media thickness. Among control groups patients with MetS but without ED showed serum concentrations of EPCs and EMPs significantly higher (P<0.05) compared with patients without MetS and ED. Patients with arterial ED and MetS have higher EPCs and EMPs compared with patients with MetS but without ED and patients without MetS and ED.     

Screening for metabolic syndrome and testosterone deficiency in patients with erectile dysfunction: results from the first UK prospective study

Study Type – Diagnostic (exploratory cohort)
Level of Evidence 2b

OBJECTIVE

To screen patients with erectile dysfunction (ED) for the presence of metabolic syndrome (MetS), testosterone deficiency and cardiovascular (CV) risk factors, in a secondary referral centre in the UK, as men with ED have a high incidence of CV risk factors that might amount to MetS, with obesity, increased risk of coronary heart disease and type II diabetes; testosterone deficiency has also been associated with both ED and MetS.

PATIENTS AND METHODS

We assessed 124 men presenting with ED between March 2007 and August 2008. Data were collected prospectively for patient demographics, risk factors associated with MetS, and hypogonadism. MetS was assessed using the National Cholesterol Education Program Adult Treatment Panel III Criteria 2005 (based on three or more of five criteria: waist circumference, high triglycerides, low levels of high‐density lipoprotein cholesterol, hypertension and impaired glucose tolerance).

RESULTS

The mean (range) age of the men was 50 (16–76) years; 50 of 124 (40%) patients had MetS and 27% had hypogonadism. The latter was also associated with a low testicular volume and decreased libido. Ninety‐seven patients (82%) were either overweight or obese, and 64 (52%) were current or ex‐smokers.

CONCLUSIONS

Our audit confirms a high incidence of MetS and hypogonadism in patients with ED in the UK. We recommend routine screening for CV risk factors, MetS and testosterone deficiency in all patients in the UK with ED.     

Circulating endothelial progenitor cells and endothelial microparticles in patients with arterial erectile dysfunction and metabolic syndrome

Blood endothelial progenitor cells (EPC) and microparticles (EMP) have been proposed as markers of endothelial dysfunction. The aim of this study was to evaluate both EPCs and EMPs in patients with arterial erectile dysfunction (ED) and metabolic syndrome (MetS). To accomplish this, 100 patients (ages 45-60 years) with ED and MetS (Adult Treatment Panel III [ATP III] 1999 criteria) and 17 healthy men (ages 44-57 years) were selected. EPC (CD45(neg)/CD34(pos)/CD144(pos)) and EMP (CD45(neg)/CD144(pos)/Annexin V(pos)) blood concentrations were evaluated by flow cytometry, before and after administration of tadalafil (20 mg) on demand for 3 months. Before treatment, EPCs and EMPs were significantly higher in patients compared with healthy men. EPCs increased significantly after tadalafil administration, whereas EMPs did not differ significantly. EPCs correlated positively or negatively with body mass index and with some cavernous artery indices, both before and after tadalafil administration. EMPs showed only positive correlations with body mass index and some cavernous artery indices, both before and after tadalafil administration. Patients with arterial ED and MetS have higher EPCs and EMPs compared with healthy men; hence, these cells may be regarded as markers of cavernous artery dysfunction. Tadalafil administration increased EPCs but not EMPs, suggesting that this compound may play a role in the endothelial repair response.     

Endothelial dysfunction as a predictor of cardiovascular disease in type 1 diabetes

Macro and microvascular disease are the main cause of morbi-mortality in type 1 diabetes(T1DM).Although there is a clear association between endothelial dysfunction and atherosclerosis in type 2 diabetes,a cause-effect relationship is less clear in T1 DM.Although endothelial dysfunction(ED) precedes atherosclerosis,it is not clear weather,in recent onset T1 DM,it may progress to clinical macrovascular disease.Moreover,endothelial dysfunction may either be reversed spontaneously or in response to intensive glycemic control,long-term exercise training and use of statins.Acute,long-term and post-prandial hyperglycemia as well as duration of diabetes and microalbuminuria are all conditions associated with ED in T1 DM.The pathogenesis of endothelial dysfunction is closely related to oxidative-stress.NAD(P)H oxidase over activity induces excessive superoxide production inside the mitochondrial oxidative chain of endothelial cells,thus reducing nitric oxide bioavailability and resulting in peroxynitrite formation,a potent oxidant agent.Moreover,oxidative stress also uncouples endothelial nitric oxide synthase,which becomes dysfunctional,inducing formation of superoxide.Other important mechanisms are the activation of both the polyol and protein kinase C pathways as well as the presence of advanced glycation end-products.Future studies are needed to evaluate the potential clinical applicability of endothelial dysfunction as a marker for early vascular complications in T1 DM.     

Treating erectile dysfunction by endothelial rehabilitation with phosphodiesterase 5 inhibitors

A large body of evidence has accumulated demonstrating that a common pathway in conditions such as hypertension, atherosclerosis, hypercholesterolemia, diabetes mellitus, and erectile dysfunction (ED) is endothelial dysfunction. Although a complete pharmacological cure for ED is currently unavailable, the phosphodiesterase 5 (PDE5) inhibitors sildenafil, vardenafil, and tadalafil are efficacious oral therapy for ED. Results from recent studies suggest that regular treatment with a PDE5 inhibitor may lead to enhanced erectile function (EF) beyond that observed with on-demand usage, possibly through improvement of endothelial function. Such an effect may be viewed as rehabilitation of damaged erectile tissue. The present review focuses on several recent studies which provide evidence for the beneficial effect of regular PDE5 inhibitor administration on the improvement of EF by rehabilitation of vascular endothelium.     

Hypogonadism, ED, metabolic syndrome and obesity: a pathological link supporting cardiovascular diseases

Hypogonadism, erectile dysfunction (ED), visceral adiposity, insulin resistance and metabolic syndrome (MetS) often coexist in the same subjects. This cluster of abnormalities is associated with an increased risk of diabetes and cardiovascular diseases (CVD), affecting not only quality of life but also life expectancy. Longitudinal studies have also demonstrated that ED and male hypogonadism could be considered surrogate markers of incident CVD and MetS. However, how androgens signal fat depots and lessen them is still a matter of active research and whether or not low testosterone could play a pathogenetic role in CVD is still under debate. Hence, pathogenetic mechanisms linking hypogonadism with obesity and insulin resistance appear to be complex and often multi-directional. Visceral obesity can probably be considered a relevant cause of hypogonadism but at the same time, hypogonadism could be a cause of obesity and insulin resistance, consequently establishing a vicious cycle. To provide a critical analysis of these issues, a comprehensive literary search was carried out to discuss the relationship between insulin resistance ED, visceral adiposity, MetS and hypogonadism focusing on their possible involvement in the development of CVD.     

Dysfunction of the endothelial-platelet pathway in patients with erectile dysfunction before and after daily treatment with tadalafil

Platelet activation results from the exposure of receptors on the surface of the platelet to specific structures on the vessel wall. The aim of this study was to assess the serum concentrations of apoptotic endothelial microparticles (EMPa) and the vitronectin receptor (VR) in patients with erectile dysfunction (ED) before and after treatment with tadalafil. This study included 50 patients with arterial ED. EMPa and VR levels were measured by using flow cytometry. The CD45(neg)-CD144(pos)-annexin V(Pos) events were defined as EMPa, and the CD51(pos)-CD61(pos) events were defined as VR. Patients with ED were evaluated before and after daily treatment with 5 mg tadalafil for 90 days. Patients with arterial ED had serum concentrations of EMPa and VR significantly higher than the control group at baseline. After tadalafil, the serum concentrations of EMPa and VR of the patients with arterial ED were significantly lower than before treatment, but significantly higher than controls. Patients with arterial ED expressed higher levels of both EMPa that are associated with dysfunction of the arterial endothelial pathway and VR-expressing platelet-endothelial elements. Chronic treatment with tadalafil reduced endothelial apoptosis in these patients and also reduced VR expression.     

内皮损伤与勃起功能障碍研究进展

内皮在维护血管稳态、调节血管紧张度及血流、预防血管内血栓形成等方面起重要作用。血管内皮是阴茎勃起过程中的重要角色,ED多数情况下存在不同程度的内皮功能障碍,内皮损伤是ED的重要病理基础。不良生活方式、心血管疾病、氧自由基、炎症因子等均可导致内皮损伤。血管内皮具有自我修复机制,内皮损伤是损伤因素与修复因素失衡的结果。本文就内皮损伤机制、内皮损伤后的修复、内皮损伤与ED关系等方面的进展作一综述。     

Endothelial dysfunction and erectile dysfunction in the aging man

Penile erection is a vascular event that requires an intact endothelium to occur. A dysfunctional endothelium is an early marker for the development of atherosclerotic changes and can also contribute to the occurrence of acute cardiovascular events. The pathogenesis of both endothelial and erectile dysfunction (ED) is intimately linked through decreased expression and activation of endothelial nitric oxide (NO) synthase, and the subsequent blunted physiological actions of NO naturally occurring with aging. It is now well-understood that ED is a symptom of underlying disease rather than a disease itself; for this reason in the near future both general practitioners, internal medicine practitioners and many specialists will have to interplay with sexual medicine. Aging in the man is also associated with several changes in arterial structure and function, part of them related to the decline of circulating levels of steroids, that is, testosterone and estradiol. These changes may be responsible, in part, for the lack of efficacy of ED treatments. The recent discovery that chronic administration of phosphodiesterase type 5 inhibitors may improve erectile and endothelial responsiveness of men previously non-responsive to on-demand regimes, and the knowledge that testosterone is one of the main modulators of the expression of penile phosphodiesterase type 5 isoenzyme, opens a new scenario in the treatment of men with ED and co-morbidities. The aim of this review is to discuss the pathophysiology of endothelial dysfunction and its relationship with ED in the aging male, and to suggest possible strategies to improve arterial function with regard to sexual dysfunctions.     

Endothelium-specific gene and stem cell-based therapy for erectile dysfunction

Erectile dysfunction （ED） commonly results from endothelial dysfunction of the systemic vasculature. Although phosphodiesterase type 5 （PDE-5） inhibitors are effective at treating most cases of ED, they must be taken routinely and are ineffectual for a meaningful number of men. In recent years gene and stem cell-based therapies targeted at the penile endothelium have been gaining momentum in preclinical studies. These early studies reveal that gene and stem cell-based therapies may be both enduring and efficacious, and may eventually lead to a cure for ED. The following review will highlight our current understanding of endothelial-specific gene and stem cell-based therapies performed to date in a number of experimental animal models.     

勃起功能障碍与代谢综合征研究进展

勃起功能障碍(ED)和代谢综合征(MS)都与心血管疾病有着密切的关系,随着研究的深入,人们开始寻找两者之间存在的直接关联并取得了较大进展。MS与ED之间存在密切关系:MS患者的ED发病率明显高于非MS患者,与MS相关的性腺功能减退也会促进ED的发生,而针对MS的饮食和体育锻炼治疗可以有效逆转ED的进程。进一步研究还发现,内皮细胞损伤及血浆炎症反应标志物水平增高等因素可能是MS与ED之间密切联系的机制所在。本文对近年来关于ED与MS关系的研究结果进行归纳阐述,以期为今后MS患者的ED诊疗及进一步开展相关研究提供参考。     

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.     

内皮细胞凋亡与勃起功能障碍的研究进展

勃起功能障碍(ED)是泌尿男科最常见的疾病之一,严重影响患者的生活质量,引起ED的因素包括衰老、糖尿病、高血压、高脂血症以及不良生活方式等,其确切机制尚未完全明确。目前随着对ED研究的不断深入,其中阴茎海绵体内皮细胞凋亡与ED的关系倍受关注,内皮细胞凋亡增加可引起NOS活性降低导致NO合成受阻,从而影响阴茎勃起,不同病因引起的ED其内皮细胞凋亡的机制不同。本文就阴茎海绵体内皮细胞凋亡在ED中的作用作一综述,对ED与内皮细胞凋亡机制的深入了解将为新药研制及其他治疗措施提供新的思路。     

Pathogenetic aspects of erectile dysfunction in patients with the metabolic syndrome

BackgroundAlthough it is well known that the metabolic syndrome is a common cause of erectile dysfunction (ED) the pathogenesis of the latter in this group of patients is poorly understood. The present study aimed to improve our knowledge in this area.MethodsThe study included 385 men with ED (control group) who underwent a full evaluation, including laboratory and ultrasound assessment of endothelial function.ResultsThe full complex evaluation showed that arteriogenic impairment in the cavernosal circulation was the primary pathogenic factor for ED in patients with the metabolic syndrome. The ultrasound-assisted measurement of postocclusive changes in the diameter of the cavernosal arteries, which reflects the local endothelial function, was the most valuable method in the diagnosis of this form of ED. In addition, a considerable number of patients with the metabolic syndrome demonstrated both hormonal and neurological disorders which also contribute to the pathogenesis of ED in this cohort of men.ConclusionThe pathogenesis of ED in patients with the metabolic syndrome is multifactorial in nature: ED is primarily caused by arteriogenic disorders which are combined with neuropathic disorders in almost every second patient and with hormonal factors in every third one. In addition, psychomotor status has an impact on the development of ED in patients with metabolic syndrome.     

A Systematic Review of the Association Between Erectile Dysfunction and Cardiovascular Disease

Context

Erectile dysfunction (ED) is considered a vascular impairment that shares many risk factors with cardiovascular disease (CVD). A correlation between ED and CVD has been hypothesized, and ED has been proposed as an early marker of symptomatic CVD.

Objective

To analyze the relationship between ED and CVD, evaluating the pathophysiologic links between these conditions, and to identify which patients would benefit from cardiologic assessment when presenting with ED.

Evidence acquisition

A systematic literature review searching Medline, Embase, and Web of Science databases was performed. The search strategy included the terms erectile dysfunction, cardiovascular disease, coronary artery disease, risk factors, pathophysiology, atherosclerosis, low androgen levels, inflammation, screening, and phosphodiesterase type 5 inhibitors alone or in combination. We limited our search to studies published between January 2005 and May 2013.

Evidence synthesis

Several studies reported an association between ED and CVD. The link between these conditions might reside in the interaction between androgens, chronic inflammation, and cardiovascular risk factors that determines endothelial dysfunction and atherosclerosis, resulting in disorders of penile and coronary circulation. Because penile artery size is smaller compared with coronary arteries, the same level of endothelial dysfunction causes a more significant reduction of blood flow in erectile tissues compared with that in coronary circulation. Thus ED could be an indicator of systemic endothelial dysfunction. From a clinical standpoint, because ED may precede CVD, it can be used as an early marker to identify men at higher risk of CVD events. ED patients at high risk of CVD should undergo detailed cardiologic assessment and receive intensive treatment of risk factors.

Conclusions

ED and CVD should be regarded as two different manifestations of the same systemic disorder. ED usually precedes CVD onset, and it might be considered an early marker of symptomatic CVD.     

mpaired flow-mediated vasodilatation in Asian Indians with erectile dysfunction

Endothelial dysfunction is the postulated link between coronary artery disease （CAD） and erectile dysfunction （ED）. Brachial artery flow-mediated vasodilatation （FMD） is a non-invasive surrogate marker for endothelial function assessment. Despite Asian Indians representing a considerable global CAD burden, data on FMD and ED in these patients are lacking. Of the 225 patients undergoing coronary angiography, 72% had ED （assessed using the International Index of Erectile Function （IIEF-5） questionnaire）; ED was moderate to severe in 61% of the patients. ED patients had a higher incidence of severe and diffuse angiographic CAD, a greater number of coronary vessels involved and a lower mean brachial artery FMD （6.40%±4.60% vs. 9.10%±4.87%, P〈0.001） compared to non-ED patients. A progressive reduction in FMD was noted with increasing severity of ED. Impaired FMD （ ≤ 5.5%） was twice as common in ED patients （52% vs. 24% without ED）. Patients with impaired FMD had higher ED prevalence （85% vs. 62%） and lower mean I IEF-5 scores compared to those with normal FMD. Impaired FMD was a significant ED predictor independent of other risk factors （odds ratio, 2.33; 95% confidence interval： 0.59-9.23; P=0.03）. An inverse correlation between FMD and ED severity was observed （r=-0.22; P=0.004）. ED is common among Asian Indians with angiographically documented CAD. Patients with ED have impaired FMD independent of other risk factors, suggesting that endothelial dysfunction is the underlying pathophysiology. Urologists and cardiologists need to be aware of the association between ED, CAD and endothelial dysfunction.     

Lipoprotein‐associated phospholipase A2 levels are associated with erectile dysfunction in patients without known coronary artery disease

Endothelial dysfunction and microvascular damage play a crucial role in the pathogenesis of erectile dysfunction (ED). Lp‐PLA2 is a calcium‐independent member of the phospholipase A2 family and hydrolyses oxidised phospholipids on low‐density lipoprotein (LDL) particles that plays a pivotal role in ox‐LDL‐induced endothelial dysfunction. The purpose of the current study was to determine the association between Lp‐PLA2 levels and ED in patients without known coronary artery disease (CAD). All patients were evaluated for ED and divided into two groups: 88 patients suffering from ED for >1 year were enrolled as an experimental group and 88 patients without ED were enrolled as a control group in this study. Diagnosis of ED was based on the International Index of Erectile Function Score‐5. Levels of Lp‐PLA2 were measured in serum by colorimetric assay. The relationship between Lp‐PLA2 levels and ED in patients was evaluated statistically. The mean age of patients with ED group was 59.4 ± 11.32 and 55.8 ± 9.67 in the control group. Plasma Lp‐PLA2 levels were significantly higher in ED than in the control group (220.3 ± 66.90 and 174.8 ± 58.83 pg ml^?1, respectively, P < 0.001). The Lp‐PLA2 levels were negatively correlated with score of ED (r = ?0.482, P < 0.05). In logistic regression analysis, enhanced plasma Lp‐PLA2 levels result in approximately 1.2‐fold increase in ED [1.22 (1.25–2.76)]. In this study, serum Lp‐PLA2 levels were found to be associated with endothelial dysfunction predictive of ED. Serum Lp‐PLA2 level appears to be a specific predictor of ED, and it may be used in early prediction of ED in the male population.