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 and Erection: Practical Management for the Patient with Erectile Dysfunction

Although erectile dysfunction (ED) and testosterone deficiency syndrome are two independently distributed disorders, there is a degree of overlap between them. Testosterone replacement therapy, either alone or combined with other treatments such as a phosphodiesterase type 5 (PDE5) inhibitor, may therefore be useful in some men with ED. Corrective treatment of ED includes sex therapy, risk factor modification, chronic usage of PDE5 inhibitors, and testosterone replacement. Studies have shown that testosterone replacement in men with hypogonadism improves libido and erectile function in a significant proportion of cases. If corrective treatment fails or is not indicated, symptomatic treatments such as oral PDE5 inhibitors or intraurethral/intracavernous therapy are available. PDE5 inhibitors are an excellent first-line choice, although a significant proportion of men still fail to respond to monotherapy. Testosterone deficiency may be overlooked in some men with ED and, because this may be associated with lower expression of PDE5 in the penis, it could result in failure of PDE5 inhibitor therapy. Recent recommendations, therefore, suggest the need for combination therapy in some patients. In conclusion, all men presenting with ED should have their testosterone levels checked, and testosterone replacement should be considered in those with low levels. Testosterone replacement should also be considered in hypogonadal men with ED not responding to PDE5 inhibitors. If erections remain insufficient after 3 mo, a combination of testosterone and a PDE5 inhibitor may be beneficial.     

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.     

Challenges in the Diagnosis of the Right Patient for Testosterone Replacement Therapy

Diagnosis of testosterone deficiency is important to identify patients who might benefit from testosterone replacement therapy. Unfortunately, the diagnosis of hypogonadism may be a challenge for many practicing physicians, including endocrinologists and urologists. Signs and symptoms, such as sexual dysfunction, change in body composition, lethargy, and mood changes, are nonspecific and the available questionnaires are generally not useful in clinical practice. The diagnosis of testosterone deficiency is ultimately based on measurement of serum testosterone levels. However, marked variations in the reference ranges of serum testosterone levels among laboratories pose a challenge for physicians when interpreting the results. In addition, initial laboratory assessments usually determine total testosterone levels. About 1–2% of total testosterone is free and a further 30–50% is bound with low affinity to albumin; only these two components are bioavailable to the target tissues. In general, assuming the normal reference range for serum total testosterone in adult men is 300–1000 ng/dl (10–35 nmol/l), levels of < 250 ng/dl (8.7 nmol/l) suggest the patient is likely to be hypogonadal, whereas levels of > 350 ng/dl (12.7 nmol/l) suggest the symptoms may not be due to androgen deficiency. Values between 250 to 350 ng/dl warrant a repeat morning serum testosterone determination with assessment of free or bioavailable testosterone. In men with symptoms suggestive of androgen deficiency and borderline serum testosterone levels, where there are no contraindications to androgen therapy, a short therapeutic trial of testosterone may be justified.     

Androgen deficiency impairs erectile function in rats through promotion of corporal fibrosis

The aim of this study was to investigate the underlying mechanism of androgen deficiency inducing corporal fibrosis, thereby causing erectile dysfunction (ED). Forty 12‐week‐old healthy male rats were divided randomly into four groups: normal control group (Control); castration group (Castration); the other 20 rats were castrated followed by testosterone (T) (orally) each day: castration + 10mg/kg T group (Castration + 10T) and castration + 20 mg/kg T group (Castration + 20T). After 8 weeks' treatment, the main outcome measures were the following: serum levels of T; the ratios of intracavernous pressure (ICP) to mean arterial pressure (MAP); histologic changes in penile smooth muscle cells; the Smad and non‐Smad pathways; and extracellular matrix (ECM) protein deposition. Castration group showed lower level of T and ratio of ICP/MAP, reduced ratio of penile smooth muscle cells/collagen, increased extracellular matrix protein deposition, and a higher expression of the Smad and non‐Smad pathways. Castration + 10T partially preserved erectile function and histology stabilisation. However, the Castration + 20T group showed significantly better erectile function and molecular changes. Better efficacy could be expected with ART of adequate dose. Androgen deficiency induces corporal fibrosis through activation of the Smad and non‐Smad pathways, and accumulation of ECM proteins.     

Low testosterone elevates interleukin family cytokines in a rodent model: a possible mechanism for the potentiation of vascular disease in androgen-deficient males

Background

Androgen deficiency (AD) is associated with increased risk of atherosclerosis, cardiovascular, and peripheral arterial disease. Although the biochemical and molecular mechanisms underlying this risk remain unclear, higher testosterone (TST) levels correlate to significant immunoprotective molecular and cellular responses. Our group has previously demonstrated that female sex hormones influence vascular pathogenesis via inflammatory-modulated matrix metalloproteinase (MMP) regulation. Here we investigated the role of AD and androgen replacement therapy in the modulation of these hormonally responsive pathways that could be playing a role in the development of vascular pathogenesis.

Methods

Aged orchiectomized male rats underwent TST supplementation per controlled release pellet implantation (0–150 mg). Young and aged intact groups served as controls. Serum was collected at 0–4 wk and analyzed by enzyme-linked immunosorbent assays, qualitative cytokine screening, and quantitative multiplex analyses. Human aortic smooth muscle cells were treated with 4,5α-dihydrotestosterone (DHT; 0–3000 nM) before or after interleukin 1β (IL-1β; 5 ng/mL) stimulation. Quantitative polymerase chain reaction and in-gel zymography was used to assay the effect on MMP expression and activity.

Results

Subphysiological, physiological, and supraphysiological levels of TST were achieved with 0.5, 2.5, and 35 mg TST pellet implants in vivo, respectively. Inflammatory arrays indicated that interleukin cytokines, specifically IL-2, IL-6, IL-10, IL-12, and IL-13, were elevated at subphysiological level of TST, whereas TST supplementation decreased interleukins. Supraphysiological TST resulted in a significant increase in MMP-9 and tissue inhibitor of metalloproteinase-1 (TIMP-1) in vivo. Pretreatment with IL-1β slightly increased membrane type 1-MMP (MT1-MMP) and MMP-2 expression at low to mid-level DHT exposure in vitro, although these trends were not statistically significant.

Conclusions

Here we demonstrate AD is a proinflammatory modulator and indicate that MMP-independent mechanisms may play a role downstream of AD-induced inflammatory signaling in dysfunctional vascular remodeling. Future in vivo studies will examine AD and TST supplementation in acute inflammatory response to vascular injury and in MMP-modulated vascular disease.     

Recognising late-onset hypogonadism: a difficult task for sexual health care

Late-onset hypogonadism (LOH) is a clinical and biochemical syndrome associated with advancing age and characterised by typical symptoms together with a deficiency in serum testosterone levels. Identification of LOH-related symptoms and signs is, therefore, essential for suspecting this condition. We investigated a specific association between indicative signs and symptoms of androgen deficiency and its biochemical correlates (total T below 12 and/or 8 nmol/l) in a large series (2817) of patients consulting our Sexual Dysfunction Unit. In addition, a systematic review of the literature using Medline (1969 to March 2009) was also performed. We found that although structured interviews, such as ANDROTEST or other self-reported questionnaires, might help physicians to familiarise themselves with hypogonadal symptoms and suspect LOH, LOH-related symptoms and signs are rather non-specific, as they are also characteristic of the ageing process per se. We confirmed that an accurate focused clinical history (inquiring about cryptorchidism, pituitary diseases and delayed puberty) can be very informative about the presence of LOH. In addition, sex life-related performances (libido, erection and ejaculation) and attitudes (masturbation and extra-marital affairs) might also provide insights. Clinical signs, such as testis volume, penile blood flow and the presence of the metabolic syndrome, can also raise the suspicion of LOH: an increased waist circumference increases the risk of having LOH by a factor of 3. Although a clinical evaluation is mandatory in suspecting LOH, it is our opinion that the determination of total testosterone is essential in confirming the diagnosis and/or in starting any substitutive therapy.     

Hypoandrogen-metabolic (HAM) syndrome: an important men's health issue

Hypoandrogenaemia (hypogonadism, hypotestosteronaemia) may be a common accompanying factor in men with the metabolic syndrome and together they may be considered as a specific entity, the hypoandrogen-metabolic (HAM) syndrome. Both hypoandrogenaemia and the metabolic syndrome are common and their prevalence increases with age. Hypoandrogenaemia may be an aetiological factor in the development of the metabolic syndrome and both share similar co-morbid factors. Obesity, low androgen levels and the metabolic syndrome are common findings in Western middle-aged and elderly men and place them at an increased risk for type 2 diabetes, cardiovascular and coronary heart disease. In the absence of contraindications, men with HAM and symptoms of androgen deficiency may be managed by testosterone replacement therapy along with weight reduction and other measures to normalise glucose, insulin, lipid and blood pressure control.     

Inflammation, metabolic syndrome, erectile dysfunction, and coronary artery disease: common links

OBJECTIVE: Erectile dysfunction (ED) may be the early clinical manifestation of a generalized vascular disease and carries an independent risk for cardiovascular events. Low-grade subclinical inflammation affects endothelial function and is involved in all stages of the atherosclerotic process. This review identifies potential pathophysiologic links among low-grade inflammation, ED, metabolic syndrome, and coronary artery disease (CAD) and presents the clinical implications in terms of ED diagnosis, assessment of patient risk, and therapy. METHODS: A comprehensive evaluation was performed for available published data in full-length papers that were identified in MedLine up to July 2007. RESULTS: Studies support an association between metabolic syndrome, ED, and increased inflammatory state. Increased circulating levels of inflammatory and endothelial-prothrombotic compounds are related to the presence and severity of ED. Specific inflammatory biomarkers and their combination appear to have the potential to aid ED diagnosis or exclusion. ED and CAD may confer a similar unfavorable impact on the inflammatory and prothrombotic state, whereas ED adds an incremental activation on top of CAD; these findings have important implications for cardiovascular risk. Lifestyle and risk factor modification, as well as pharmacologic therapy, are associated with anti-inflammatory effects. CONCLUSIONS: Low-grade systemic inflammation could be an important element of the association between metabolic syndrome, ED, and CAD. Its individualized assessment may be a valuable tool for ED diagnosis, risk assessment, and rationalized therapeutic approach especially in patients with ED who have metabolic syndrome and carry an intermediate risk for future cardiovascular events.     

Exploring new treatment options for polycystic ovary syndrome: Review of a novel antidiabetic agent SGLT2 inhibitor

Polycystic ovary syndrome(PCOS) is the most common endocrinopathy in women of reproductive age associated with long-term metabolic and cardiovascular consequences. A plethora of symptoms and their severity differentiate on an individual level, giving the syndrome numerous phenotypes. Due to menstrual cycle abnormalities, women suffer from irregular menstrual bleeding, difficulty in conception, and infertility. Furthermore, the risk of pregnancy complications such as gestational diabetes mellitus, hypertensive disorders of pregnancy, and preterm birth are higher in women with PCOS than in the general population. Often, women with PCOS have comorbidities such as dyslipidemia, obesity, glucose intolerance or diabetes type 2, non-alcoholic fatty liver disease, and metabolic syndrome, which all influence the treatment plan. Historic insulinsensitizing agents, although good for some of the metabolic derangements, do not offer long-term cardiovascular benefits; therefore, new treatment options are of paramount importance. Sodium-glucose co-transporter-2(SGLT-2) inhibitors, a new class of antidiabetic agents with beneficial cardiovascular, bodyweight, and antihyperglycemic effects, although not approved for the treatment of PCOS, might be an attractive therapeutic addition in the PCOS armamentarium. Namely, recent studies with SGLT-2 inhibitors showed promising improvements in anthropometric parameters and body composition in patients with PCOS. It is important to further explore the SGLT-2 inhibitors potential as an early therapeutic option because of the PCOS-related risk of metabolic, reproductive, and psychological consequences.     

Androgens, visceral obesity and the risks for cardiovascular disease and diabetes mellitus

Given that there is a sex difference in cardiovascular disease, testosterone has long been regarded as the culprit for this difference. This position is no longer tenable. In epidemiological studies low plasma testosterone levels predict cardiovascular disease and diabetes mellitus, often clustered in the metabolic syndrome. Acute deprivation of testosterone, as in men treated for prostate cancer, leads to impairment of the risk factors for diabetes mellitus and cardiovascular disease. Testosterone administration to hypogonadal men decreases fat mass, increases lean body mass and leads to a reduction in plasma cholesterol, triglycerides and low-density lipoprotein (LDL)-cholesterol levels.Further studies are needed to investigate whether maintaining plasma testosterone levels in the mid-normal range improves the risk for cardiovascular disease and diabetes mellitus.     

Laparoscopic treatment of metabolic syndrome in patients with type 2 diabetes mellitus

Background  Metabolic syndrome refers to risk factors for cardiovascular disease. Hyperglycemia is a critical component contributing to the predictive power of the syndrome. This study aimed to evaluate the results from the laparoscopic interposition of an ileum segment into the proximal jejunum for the treatment of metabolic syndrome in patients with type 2 diabetes mellitus and a body mass index (BMI) lower than 35. Methods  Laparoscopic procedures were performed for 60 patients (24 women and 36 men) with a mean age of 51.7 ± 6.4 years (range, 27–66 years) and a mean BMI of 30.1 ± 2.7 (range, 23.6–34.4). All the patients had a diagnosis of type 2 diabetes mellitus (T2DM) given at least 3 years previously and evidence of stable treatment using oral hypoglycemic agents, insulin, or both for at least 12 months. The mean duration of type 2 diabetes mellitus was 9.6 ± 4.6 years (range, 3–22 years). Metabolic syndrome was diagnosed for all 60 patients. Arterial hypertension was diagnosed for 70% of the patients (mean number of drugs, 1.6) and hypertriglyceridemia for 70%. High-density lipoprotein was altered in 51.7% of the patients and the abdominal circumference in 68.3%. Two techniques were performed: ileal interposition (II) into the proximal jejunum and sleeve gastrectomy (II-SG) or ileal interposition associated with a diverted sleeve gastrectomy (II-DSG). Results  The II-SG procedure was performed for 32 patients and the II-DSG procedure for 28 patients. The mean postoperative follow-up period was 7.4 months (range, 3–19 months). The mean BMI was 23.8 ± 4.1 kg/m², and 52 patients (86.7%) achieved adequate glycemic control. Hypertriglyceridemia was normalized for 81.7% of the patients. An high-density lipoprotein level higher than 40 for the men and higher than 50 for the women was achieved by 90.3% of the patients. The abdominal circumference reached was less than 102 cm for the men and 88 cm for the women. Arterial hypertension was controlled in 90.5% of the patients. For the control of metabolic syndrome, II-DSG was the more effective procedure. Conclusions  Laparoscopic II-SG and II-DSG seem to be promising procedures for the control of the metabolic syndrome and type 2 diabetes mellitus. A longer follow-up period is needed.     

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.     

Vascular dysfunction in diabetes: The endothelial progenitor cells as new therapeutic strategy

The vascular endothelium is a critical determinant of dia- betes-associated vascular complications, and improving endothelial function is an important target for therapy. Diabetes mellitus contributes to endothelial cell injury and dysfunction. Endothelial progenitor cells (EPCs) play a critical role in maintaining endothelial function and might affect the progression of vascular disease. EPCs are essential to blood vessel formation, can differentiate into mature endothelial cells, and promote the repair of damaged endothelium. In diabetes, the circulating EPC count is low and their functionality is impaired. The me- chanisms that underlie this reduced count and impaired functionality are poorly understood. Knowledge of the status of EPCs is critical for assessing the health of the vascular system, and interventions that increase the number of EPCs and restore their angiogenic activity in diabetes may prove to be particularly beneficial. The pre-sent review outlines current thinking on EPCs’ therapeutic potential in endothelial dysfunction in diabetes, as well as evidence-based perspectives regarding their use for vascular regenerative medicine.     

中国肝移植受者代谢病管理专家共识（2019版）

为了进一步规范中国肝移植受者代谢病管理,在《中国肝移植受者代谢病管理专家共识（2015版）》基础上,参考近年来国内外相关行业协会发布的诊疗规范和共识,结合我国肝移植临床诊治实践经验,更新为《中国肝移植受者代谢病管理专家共识（2019版）》。此版共识除了介绍糖尿病、高血压病和血脂异常相关内容,还新增高尿酸血症和肥胖症相关内容,旨在更全面地指导肝移植受者代谢病的规范化管理。     

Antioxidant treatment associated with sildenafil reduces monocyte activation and markers of endothelial damage in patients with diabetic erectile dysfunction: a double-blind, placebo-controlled study

OBJECTIVE: To investigate the synergic effect of propionyl L-carnitine (PLC) plus sildenafil in reducing monocyte oxidative activity and endothelial dysfunction markers in diabetic patients with erectile dysfunction (ED). METHODS: Thirty-two type 2 diabetic patients with ED (according to the International Index of Erectile Function-5 [IIEF-5]) were randomized to receive PLC (2 g/d) alone (n=8) or combined with sildenafil (50 mg/d twice weekly) (n=8), sildenafil alone (50 mg/d twice weekly) (n=8), or placebo (n=8) in a double-blind, fixed-dose study. Monocyte oxidative activity (stimulation index [SI]), intercellular adhesion molecule-1 [ICAM-1], P-selectin, advanced glycation end product (AGE) levels, Doppler sonography (recording peak systolic velocity [PSV]; end diastolic velocity [EDV]; systolic wave time [SWT]; resistive index [RI]), and IIEF score were evaluated before and after 12 wk of treatment; IIEF-5 was evaluated again 4 wk posttreatment. RESULTS: SI was reduced by treatment with PLC alone or combined with sildenafil (p<0.05). In patients treated with PLC plus sildenafil, a decrease in ICAM-1, P-selectin, and EDV values was observed compared with patients treated with sildenafil alone (p<0.05, p<0.01, p<0.001, respectively). IIEF-5 improved in all patients treated with PLC plus sildenafil or sildenafil alone (p<0.03, p<0.05, respectively). Four weeks posttreatment, patients treated with PLC plus sildenafil maintained the improvement of the IIEF-5 compared with patients on sildenafil alone (p=0.05). In patients on PLC treatment (with or without sildenafil), SI was correlated with IIEF-5 (p<0.001), glycemia with STW (p<0.03), and AGEs with IIEF-5 (p<0.01). CONCLUSION: PLC plus sildenafil was more effective in reducing SI and endothelial dysfunction markers in patients with type 2 diabetes and ED.     

Metabolic syndrome,hypertension, and diabetes mellitus after gastric banding: The role of aging and of duration of obesity

BackgroundBariatric surgery leads to resolution of arterial hypertension and diabetes mellitus; isolated reports indicate that response to bariatric surgery is lower in aged patients. The aim of this study was to evaluate the role of age and of duration of obesity on the frequency of co-morbidities in morbid obesity, as well as on improvement of co-morbidities.MethodsA total of 837 consecutive patients with known duration of obesity, undergoing gastric banding, were considered for this study; they were divided into quartiles of age and of duration of obesity. Presence of co-morbidities (diabetes mellitus, arterial hypertension, metabolic syndrome), metabolic variables (cholesterol and HDL-C, triglycerides, blood glucose), anthropometric variables, and loss of weight during 24 months were considered.ResultsOlder patients had a higher frequency of co-morbidities; duration of obesity only affected frequency of co-morbidities, but not response to surgery. At logistic regression, duration of obesity had a moderate independent effect on the frequency of diabetes. Older patients lost less weight than younger patients, but diabetes mellitus and arterial hypertension improved to the same extent in patients of different ages, and metabolic syndrome disappeared more in older patients, associated with a greater decrease of blood glucose. Frequency of removal of gastric banding and loss to follow-up were not different in different quartiles of age or in different quartiles of duration of obesity.ConclusionOlder patients, despite lower weight loss, have a response to bariatric surgery that is similar to that of younger patients; age and duration of obesity should not be considered as limits to indications to bariatric surgery.