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Background and aim Evidences suggest that androgen deficiency is associated with sudden cardiac death (SCD). Our purpose was to analyse some electrocardiographic (ECG) markers of repolarization phase in hypogonadal patients either at baseline or after testosterone replacement therapy (TRT). Patients and Methods Baseline and after 6 months of testosterone replacement therapy, 14 hypogonadal patients and 10 age-matched controls underwent a short-term ECG recordings at rest and immediately after a maximal exercise test. The following ECG parameters have been collected: QTe (the interval between the q wave the end of T wave), QTp (the interval between the q wave and the peak of T wave), and Te (the interval between the peak and the end of T wave). Results At baseline, in the hypogonadal patients, corrected QTe and QTp values were longer at rest than in the controls at rest (p < 0.05), whereas, during the recovery phase, only the QTp remained significantly longer (p < 0.05). After TRT, hypogonadal patients showed an improvement only in Te (p < 0.05). Conversely, any difference between hypogonadal patients and control subjects was found with respect to the markers of temporal dispersion of repolarization phases, except for a worse QTp → Te coherence (p = 0.001) obtained during the recovery phase. Conclusions In conclusion, at rest, hypogonadal patients suffer from a stable increase in the myocardial repolarization phase without an increase in its temporal dispersion and, hence, the SCD risk seems to be low.

Oxidative stress may be defined as an imbalance between reactive oxygen species (ROS) and the antioxidant system to counteract or detoxify these potentially damaging molecules. This phenomenon is a common feature of many human disorders, such as cardiovascular disease. Many of the risk factors, including smoking, hypertension, hypercholesterolemia, diabetes, and obesity, are associated with an increased risk of developing cardiovascular disease, involving an elevated oxidative stress burden (either due to enhanced ROS production or decreased antioxidant protection). There are many therapeutic options to treat oxidative stress-associated cardiovascular diseases. Numerous studies have focused on the utility of antioxidant supplementation. However, whether antioxidant supplementation has any preventive and/or therapeutic value in cardiovascular pathology is still a matter of debate. In this review, we provide a detailed description of oxidative stress biomarkers in several cardiovascular risk factors. We also discuss the clinical implications of the supplementation with several classes of antioxidants, and their potential role for protecting against cardiovascular risk factors.

Hormones and cytokines are known to regulate cellular functions in the testes. These biomolecules induce a broad spectrum of effects on various level of spermatogenesis, and among them is the modulation of cell junction restructuring between Sertoli cells and germ cells in the seminiferous epithelium. Cytokines and androgens are closely related, and both correct testicular development and the maintenance of spermatogenesis depend on their function. Cytokines also play a crucial role in the immune testicular system, activating and directing leucocytes across the endothelial barrier to the inflammatory site, as well as in increasing their adhesion to the vascular wall. The purpose of this review is to revise the most recent findings on molecular mechanisms that play a key role in male sexual function, focusing on three specific molecular patterns, namely, cytokines, miRNAs, and endothelial progenitor cells. Numerous reports on the interactions between the immune and endocrine systems can be found in the literature. However, there is not yet a multi-approach review of the literature underlying the role between molecular patterns and testicular and sexual function.

Background: Recent studies have supported the beneficial effects of a short abstinence period on sperm parameters. The aim of this study was to assess sperm motility, morphology and DNA fragmentation before and after swim-up of a second ejaculate obtained after a short abstinence period in normozoospermic men and oligo-astheno-teratozoospermic (OAT) patients. Material and methods: Semen analyses and swim-up preparations of two consecutive semen samples (collected within 1 h) were carried out in 30 normozoospermic and 35 OAT patients enrolled in an assisted reproductive technique (ART) program. Results: Compared to the first ejaculate, the second sample showed a higher percentage of spermatozoa with normal form (p &lt, 0.01) and lower percentage of spermatozoa with DNA fragmentation (p &lt, 0.01) in normozoospermic men, whereas a higher percentage of spermatozoa with progressive motility (p &lt, 0.001) and normal morphology (p &lt, 0.0001) was found in OAT patients. Swim-up separation showed a lower DNA fragmentation rate (p &lt, 0.05) in the second ejaculate in normozoospermic men, whereas the second ejaculate of OAT patents showed an increase in normally-shaped spermatozoa (p &lt, 0.01) and lower percentage of spermatozoa with fragmented DNA (p &lt, 0.001) compared to the first one. Conclusions: Swim-up separation of a second ejaculate collected within 1 h might be suggested for ART procedures, especially in OAT patients.

Obesity is a severe public health problem worldwide, leading to an insulin-resistant state in liver, adipose, and muscle tissue, representing a risk factor for type 2 diabetes mellitus, cardiovascular diseases, and cancer. We have shown that abdominal obesity is associated with homeostasis derangement, linked to several hormonal and paracrine factors. Data regarding potential link between GH/IGF1 axis, bone mineral density, and inflammation in obesity are lacking. Thus, aim of this study was to evaluate correlation among IGF-1, BMD, and inflammation in obese individuals. The study included 426 obese subjects, mean age 44.8 ± 14 years; BMI 34.9 ± 6.1. Exclusion criteria were chronic medical conditions, use of medications affecting bone metabolism, hormonal and nutritional status, recent weight loss, and prior bariatric surgery. Patients underwent measurements of BMD and body composition by DEXA and were evaluated for hormonal, metabolic profile, and inflammatory markers. In this population, IGF-1 was inversely correlated with abdominal FM% (p

Development of metabolically healthy adipocytes within dysfunctional adipose tissue may represent an attractive way to counteract metabolic syndrome (MetS). In an experimental animal model of high fat diet (HFD)-induced MetS, in vivo, long- and short-term tadalafil treatments were able to reduce visceral adipose tissue (VAT) accumulation and hypertriglyceridemia, and to induce the expression in VAT of the brown fat-specific marker, uncoupling protein 1 (UCP1). VAT preadipocytes (PAD), isolated from the tadalafil-treated HFD rabbits, showed: i) a multilocular morphology; ii) an increased expression of brown fat-specific genes (such as UCP1 and CIDEA); iii) improved mitochondrial structure and dynamic and reduced superoxide production; iv) improved insulin sensitivity. Similar effects were obtained after in vitro tadalafil treatment in HFD rPAD. In conclusion, tadalafil counteracted HFD-associated VAT alterations, by restoring insulin-sensitivity and prompting preadipocytes differentiation towards a metabolically healthy phenotype.

Insulin resistance is the most important underlying cause of obesity and type 2 Diabetes (T2DM), and insulin sensitizing treatments have proved effective in preventing diabetes and inducing weight loss. Obesity and T2DM are also associated with increased inflammation. Mangosteen is a tropical tree, whose fruits, widely known for their antioxidant properties, have been recently suggested having a possible further role in the treatment of obesity and T2DM. The objective of this pilot study has been to evaluate safety, compliance and efficacy of mangosteen on insulin resistance, weight management, and inflammatory status in obese female patients with insulin resistance. 22 patients were randomized 1:1 to behavioral therapy alone or behavioral therapy and mangosteen and 20 completed the 26-week study. The mangosteen group reported a significant improvement in insulin sensitivity (HOmeostatic Model Assessment-Insulin Resistance, HOMA-IR -53.22% vs -15.23%, p=.0037), and a trend decrease in inflammation markers serum levels, together with trend greater weight loss and trend increased HDL levels. No side effect attributable to treatment was reported. Given the positive preliminary results we report and the excellent safety profile, we suggest a possible role of mangosteen in the treatment of obesity, insulin resistance and inflammation.

Aims An increased rate of cerebrovascular complications in patients with metabolic syndrome (MetS) has been reported. Previous studies demonstrated an association between glycemic variability (GV) and cerebrovascular reactivity (CRV) in MetS, thus suggesting a putative role of GV on cerebrovascular events. Although the pathophysiological mechanism linking GV to damage is still to be elucidated, evidence suggests oxidative stress plays a crucial role. Since functional variants in glutathione S-transferases (GST) genes modulate the cellular detoxification processes, the aim of this study was to elucidate the involvement of GSTs in MetS and investigating the correlation with GV, arterial stiffness, and sympatho-vagal (SV) balance. Methods A hundred metabolic syndrome patients without diabetes underwent GST gene polymorphism analysis and a sub-sample 36 patients were randomly selected to investigate the correlation between GST gene polymorphisms and GV, and sympatho-vagal (SV) balance and arterial stiffness. Results GSTM1 showed a significant association with several GV, arterial stiffness, and SV balance indexes. In particular, the GSTM1 deletion positively correlates with lower values of these indexes when compared to the presence of the gene. Conclusions Therefore, we suggested a global influence of GSTM1 deletion on the GV, arterial stiffness, and SV balance pathways in MetS patients, probably also interacting with AMP-activated protein kinase (AMPK) regulation. Our novel findings indicate GSTM1 could be a risk locus in MetS development and shed light novel scenarios on the role of glucose fluctuations in neurological impairments.

There is a widely acknowledged association between insulin resistance and obesity/type 2 diabetes (T2DM), and insulin sensitizing treatments have proved effective in preventing diabetes and inducing weight loss. Obesity and T2DM are also associated with increased inflammation. Mangosteen is a tropical tree, whose fruits—known for their antioxidant properties—have been recently suggested having a possible further role in the treatment of obesity and T2DM. The objective of this pilot study has been to evaluate safety and efficacy of treatment with mangosteen extract on insulin resistance, weight management, and inflammatory status in obese female patients with insulin resistance. Twenty-two patients were randomized 1:1 to behavioral therapy alone or behavioral therapy and mangosteen and 20 completed the 26-week study. The mangosteen group reported a significant improvement in insulin sensitivity (homeostatic model assessment-insulin resistance, HOMA-IR −53.22% vs. −15.23%, p = 0.004), and no side effect attributable to treatment was reported. Given the positive preliminary results we report and the excellent safety profile, we suggest a possible supplementary role of mangosteen extracts in the treatment of obesity, insulin resistance, and inflammation.

The aim of this study was to evaluate the safety and efficacy of a new intragastric balloon (Elipse™ Balloon, Allurion Technologies, Natick, MA USA) not needing endoscopy. The balloon was swallowed under fluoroscopy in 38 consecutive patients (F/M 28/10, mean age 46.4 ± 10.6 years, mean weight 109.7 ± 21.9 kg, and mean body mass index (BMI) 38.6 ± 6.7 kg/m2). After 4 months, the balloon spontaneously emptied and it was excreted through the digestive tract without upper endoscopy. There were no complications during balloon passage. After 16 weeks, the mean weight loss was 12.7 kg, mean percent excess weight loss was 26%, and mean BMI reduction was 4.2 kg/m2. Total body weight loss was 11.6%. There was a significant reduction in major co-morbidities related to metabolic syndrome: blood pressure (p

Men with erectile dysfunction (ED) considered challenging-to-treat with PDE-5 inhibitors (PDE5i) include patients with severe neurological damage (e.g., due to radical prostatectomy), diabetes and severe vascular disease. Another factor that may limit PDE5i efficacy is the age-related decline of testosterone (T), occurring in 3 - 35% of older men depending on different cut-offs chosen. T regulation of PDE5 expression has been accepted as one of the major mechanisms controlling vasodilator mechanisms in penile tissue.We reviewed data regarding the use of T as a salvage therapy in PDE5i nonresponders.Guidelines recommend that hypogonadal men with ED should commence therapy with PDE5i due to time course effects of T on erection that needs 6 - 12 weeks to occur. The possibility to 'salvage' some patients with low T not responding to PDE5i alone by adding T therapy should consider correct cut-off values, plasma T levels attained and androgen receptor (AR) polymorphism. Meta-analyses suggest that T treatment plus PDE5i yielded more effective results in noncontrolled versus controlled studies. We recommend T assay in all men with ED not responsive to PDE5i. Before commencing T treatment, side effects and consequent higher mortality in older frail men have to be avoided.

Background: Persistence is commonly considered a key factor for the successful management of osteoporosis and fragility fractures. Denosumab is the first biologic agent developed for the treatment of osteoporosis with satisfying data regarding the persistence with this therapy. Aim: The purpose of this multicenter observational real practice study was to evaluate the persistence with denosumab treatment in post-menopausal women affected by osteoporosis. Material/subjects and methods: Women were recruited in four specialized centers for the management of osteoporosis in North, Center and South of Italy. We included women with a diagnosis of post-menopausal osteoporosis, aged >50 years, able to obtain a prescription according to the Italian reimbursement criteria in force during the study period for anti-osteoporotic pharmacological treatment. They initiated a treatment with subcutaneous denosumab (Prolia ® ) 60 mg/every 6 months between November 2011 and May 2016. Women who had received aromatase inhibitors were excluded. Patients were assessed at baseline and every 6 months for all treatment length. Persistence data were evaluated for a total of 36 months. Results: Eight hundred seventy women were enrolled; mean aged 70 years, with a mean body mass index of 24.8 ± 4.1 kg/m 2 . At the Dual-energy X-ray absorptiometry assessment, the mean lumbar spine T-score was −2.76 ± 1.14 standard deviations (SD) and the mean femoral neck T-score was −2.49 ± 0.80 SD. During the study, the total persistence was 91.4%. Total dropouts were 75 (8.6%), higher within the initial 6-month period of treatment. Conclusions: Persistence to denosumab treatment in our observational real practice study was very high. These results suggest that factors such as frequency of visits, pharmacological schedule, and opportunity to call the doctor might play an important role in the persistence and adherence to treatment to obtain maximum therapeutic effect and avoid further fragility fractures. Background: Persistence is commonly considered a key factor for the successful management of osteoporosis and fragility fractures. Denosumab is the first biologic agent developed for the treatment of osteoporosis with satisfying data regarding the persistence with this therapy. Aim: The purpose of this multicenter observational real practice study was to evaluate the persistence with denosumab treatment in post-menopausal women affected by osteoporosis. Material/subjects and methods: Women were recruited in four specialized centers for the management of osteoporosis in North, Center and South of Italy. We included women with a diagnosis of post-menopausal osteoporosis, aged >50 years, able to obtain a prescription according to the Italian reimbursement criteria in force during the study period for anti-osteoporotic pharmacological treatment. They initiated a treatment with subcutaneous denosumab (Prolia®) 60 mg/every 6 months between November 2011 and May 2016. Women who had received aromatase inhibitors were excluded. Patients were assessed at baseline and every 6 months for all treatment length. Persistence data were evaluated for a total of 36 months. Results: Eight hundred seventy women were enrolled; mean aged 70 years, with a mean body mass index of 24.8 ± 4.1 kg/m2. At the Dual-energy X-ray absorptiometry assessment, the mean lumbar spine T-score was −2.76 ± 1.14 standard deviations (SD) and the mean femoral neck T-score was −2.49 ± 0.80 SD. During the study, the total persistence was 91.4%. Total dropouts were 75 (8.6%), higher within the initial 6-month period of treatment. Conclusions: Persistence to denosumab treatment in our observational real practice study was very high. These results suggest that factors such as frequency of visits, pharmacological schedule, and opportunity to call the doctor might play an important role in the persistence and adherence to treatment to obtain maximum therapeutic effect and avoid further fragility fractures.

Objective The formation of reactive oxygen species (ROS) contributes to the pathogenesis and progression of several diseases. Polyphenols have been shown to be beneficial against ROS. The aim of this study was to evaluate the effects of a natural antioxidant ice cream on oxidative stress, vascular function, and physical performance. Methods In this controlled, single-blind, crossover study, 14 healthy individuals were randomized to consume 100 g of either antioxidant ice cream containing dark cocoa powder and hazelnut and green tea extracts or milk chocolate ice cream (control ice cream). Participants were studied at baseline and 2 h after ingesting ice cream. Serum polyphenols, antioxidant status (ferric-reducing ability of plasma [FRAP]), nitric oxide (NOx) bioavailability, markers of oxidative stress (determination of reactive oxygen metabolites [d-ROMs] and hydrogen peroxide [H 2 O 2 ]), endothelium function (flow-mediated dilation [FMD] and reactive hyperemia index [RHI]), and exercise tolerance (stress test) were assessed, and the double product was measured. Results Serum polyphenols ( P P P P P P 2 O 2 , P P Conclusions To our knowledge, this is the first study to demonstrate that a natural ice cream rich in polyphenols acutely improved vascular function and physical performance in healthy individuals through a reduction in oxidative stress.

Phosphodiesterase type-5 inhibitor administration in diabetic men with erectile dysfunction (ED) is associated with reduced waist circumference. We evaluated potential effects of daily tadalafil administration on body composition and investigated its possible mechanism(s) of action in C2C12 skeletal muscle cells in vitro. Forty-three men on stable caloric intake (mean age 48.5 ± 7; BMI 25.5 ± 0.9 kg/m2) complaining mild ED and/or low urinary tract symptoms (LUTS) were randomly assigned to receive tadalafil (TAD) 5 mg/daily (once-a-day=OAD-TAD; n = 23) or 20 mg on-demand (on-demand=OD-TAD; n = 20) for 2 months. Primary outcomes were variations of body composition measured by Dual-energy X-ray absorptiometry; secondary outcomes were ED/LUTS questionnaire scores along with hormone (testosterone, estradiol, insulin) and endothelial function (Endopat2000) variations. OAD-TAD increased abdominal lean mass (p

Le malattie cardiovascolari (CVD) rappresentano le piu importanti cause di morbilita e mortalita nei paesi industrializzati. Recentemente e emersa una correlazione tra deficit androgenico e CVD, come anche un’associazione con aumentati livelli di glucosio, con un assetto lipidico pro-aterogenico, un pattern citochinico pro-infiammatorio, nonche con un incremento dello spessore miointimale, e con la presenza di disfunzione endoteliale. La terapia sostitutiva con testosterone in presenza di comorbidita dimostra un ottimo profilo di sicurezza.

Introduction It is controversial whether or not testing the length of the androgen receptor polymorphism in clinical practice is useful for correct diagnosis and treatment of hypogonadism. Aim To describe the molecular and clinical implications of testing the length of the androgen receptor polymorphism for treatment of hypogonadism in both male and female subjects. Methods A systematic Medline search was conducted using several terms related to and including the terms “androgen receptor,” “CAG‐repeat polymorphism,” “male hypogonadism,” “female hypogonadism,” and “neurodegenerative disease.” Main Outcome Measures Clinical evidence that demonstrates the importance of CAG repeat number investigation in male and female hypogonadism. Results A thorough review of the clinical utility of CAG repeat polymorphism investigation in men and women with hypogonadism is presented. Conclusions The role of AR CAG repeat number investigation in hypogonadism (male and female) is not yet established in the clinical practice. In both sexes, a role during clinical management of hormonal replacement therapies may be hypothesized, but the CAG repeat number's relationship with the presence or absence of hypogonadal symptoms remains unclear. Pharmacogenomic investigations of the AR polymorphism may be a future option to tailor testosterone titration individually and to better identify subjects as potentially more or less responsive to treatments; also, investigation may be important to individually predict beneficial and side effects in special subpopulations, specifically, obese men and postmenopausal women. Francomano D, Greco EA, Lenzi A, and Aversa A. CAG repeat testing of androgen receptor polymorphism: Is this necessary for the best clinical management of hypogonadism? J Sex Med 2013;10:2373–2381.

To elucidate whether adrenergic overtone is involved in the pathophysiology of men with lifelong (LL) premature ejaculation (PE), we investigated differences in reactive hyperemia index (RHI) responses by using peripheral arterial tonometry (PAT). 20 men with LL-PE (18–40 years) were enrolled in an 8-week, double-blind, placebo-controlled, crossover study and compared with 10 age-matched controls without LL-PE. Primary endpoints were PAT modifications induced by vardenafil 10 mg on demand. Secondary endpoints were the improvement in intravaginal ejaculatory latency time (IELT) as measured by the stopwatch technique and variations in anxiety scores at Stai-X1 for state-anxiety and Stai-X2 for trait-anxiety. At baseline, men with LL-PE showed higher RHI variation (P < 0.001), Stai-X1 and Stai X2 scores (P < 0.0001, resp.), and prolactin levels (P < 0.05) compared with controls. Vardenafil treatment markedly reduced RHI variation in men with LL-PE (P < 0.01) when compared with placebo. Mean changes in geometric IELT were higher after taking vardenafil (0.6 ± 0.3 versus 4.5 ± 1.1 min, P < 0.01) when compared with placebo. STAI-X1 and STAI-X2 scores fell within the normal range after treatment with vardenafil (P < 0.01). Vardenafil was an effective treatment in men with LL-PE; improvements of IELT may be due to increased NO production which is able to reduce adrenergic overactivity and anxiety levels.

Osteocalcin (OSCA) seems to act as a negative regulator of energy metabolism and insulin sensitivity. Evidence from male rodents suggests that OSCA may also regulate testosterone (T) synthesis. Using a cross-sectional design, we evaluated OSCA, 25(OH) vitamin D, T, 17β-estradiol (E2), homeostasis model assessment of insulin resistance (HOMA-IR), and body composition in 86 obese (mean BMI = 34) male subjects (18–69 yr old). Independently from BMI, an inverse relationship between trunk fat percentage and plasma T (r2=−0.26,P<0.01) and between HOMA-IR and OSCA levels (r2=−0.22,P<0.005) was found. OSCA levels, as well as vitamin D, decreased significantly for higher BMI with significant differences above 35 (P<0.01). A direct correlation between T and bone mineral density at lumbar (BMDL) and neck (BMDH) (P<0.001,r2=−0.20;P<0.001,r2=−0.24) was found, independently from age. An inverse correlation between E2 levels, BMDL, and BMDH (P<0.001,r2=−0.20;P<0.001,r2=−0.19) was observed. These data provide new evidences that a relationship between trunk fat mass, insulin sensitivity, OSCA and T synthesis occurs. This new relationship with skeletal health has relevant implications for the aging male, suggesting OSCA as a novel marker of metabolic and gonadal health status.

Phosphodiesterase type-5 inhibitor (PDE5i) tadalafil administration in men with erectile dysfunction is associated with increased testosterone/estradiol ratio, leading to hypothesize a potential increased effect of androgen action on target tissues. We aimed to characterize, in a cellular model system in vitro, the potential modulation of aromatase and sex steroid hormone receptors upon exposure to tadalafil (TAD).Human osteoblast-like cells SAOS-2 were chosen as an in vitro model system since osteoblasts are target of steroid hormones. Cells were tested for viability upon TAD exposure, which increased cell proliferation. Then, cells were treated with/without TAD for several times to evaluate potential modulation in PDE5, aromatase (ARO), androgen (AR) and estrogen (ER) receptor expression.Osteoblasts express significant levels of both PDE5 mRNA and protein. Exposure of cells to increasing concentrations of TAD (10(-8)-10(-7) M) decreased PDE5 mRNA and protein expression. Also, TAD inhibited ARO mRNA and protein expression leading to an increase in testosterone levels in the supernatants. Interestingly, TAD increased total AR mRNA and protein expression and decreased ERα, with an increased ratio of AR/ER, suggesting preferential androgenic vs estrogenic pathway activation.Our results demonstrate for the first time that TAD decreases ARO expression and increases AR protein expression in human SAOS-2, strongly suggesting a new control of steroid hormones pathway by PDE5i. These findings might represent the first evidence of translational actions of PDE5i on AR, which leads to hypothesize a growing relevance of this molecule in men with prostate cancer long-term treated with TAD for sexual rehabilitation.

Men affected by multiple sclerosis often experience neurogenic overactive bladder (OAB), lower urinary tract symptoms and erectile dysfunction (ED). The aim of the study was to investigate modifications of urinary and sexual functions after administration of daily tadalafil (TAD) 5 mg. Twenty men were enrolled in a single-blind, 4-week prospective study while 10 men without treatment served as controls. Primary outcomes were changes from baseline of International Prostate Symptom (IPSS), OAB questionnaire (OAB-q-short form) and International Index of Erectile Function (IIEF-5) scores. To evaluate the influence of bladder filling on somatic reflexes, we studied variations of the H-reflex evoked by electrical stimuli applied to the tibial nerve at the popliteal fossa and recorded from the soleus muscle. Also testosterone/estradiol (T/E) ratio was measured before and after treatment. In TAD group, an improvement in IPSS (p

Aims: Osteogenesis imperfecta (OI) is a rare inherited disorder causing low bone density and increased fragility. Bisphosphonates (BP) are a treatment of choice for OI. Few studies have investigated the long-term effects of BP in OI patients. Thus, aim of our study was to follow up adults affected by OI to evaluate changes in metabolic, clinical situation and safety of long-term neridronic acid therapy, BP authorized for OI treatment. Study design: Longitudinal observational study. Place and duration of the Study: Department of Experimental Medicine, Section of Medical Pathophysiology, Endocrinology and Nutrition. Year: 2004 - October 2010. Methodology: 68 patients underwent clinical examination, laboratory endocrine/ metabolic, pro-inflammatory cytokines screening, ECG at baseline and every 3 months and bone mineral density evaluation, by DEXA, once a year. Results: Skeletal evaluation showed a significant increase of BMD through follow up. Patients were evaluated for metabolic and cardiovascular risk factors, which were unmodified by long-term therapy. Conclusion: Long-term neridronic acid treatment increases bone density, does not alter metabolic parameters indicating that this therapy can be considered safe and a valid therapeutic option for OI patients.

The application of digital pulse amplitude by fingertip peripheral arterial tonometry (PAT) device in patients with erectile dysfunction (ED) has never been performed. We investigated the diagnostic value of reactive hyperaemia (RH) and augmentation index (AI) as evaluated using PAT in men with ED of any origin. A total of 40 patients underwent diagnostic investigation for ED, including dynamic penile duplex ultrasound (PDU) and PAT device. Moreover, 30 patients without ED served as controls. According to PDU cutoff at 35 cm/sec, patients were divided into vascular (n = 30) and nonvascular (n = 10) ED aetiology. Moreover, controls with (n = 10) or without (n = 20) vascular risk factors (VRFs) were studied in a separate analysis. Average RH-PAT was not different in men with or without ED (P = 0.56) independently of VRFs. The AI was higher in men with ED compared with the controls (P < 0.0001) as well as when controlled for the presence or absence of VRFs (P < 0.0001). An inverse relationship between AI and PSV was also found (r² = -0.72, P < 0.0001). In conclusion, an increased AI but not an impaired RH-PAT is present in men with vascular ED independently of VRFs and may represent an early detection of vascular impairment that may precede endothelial dysfunction in populations at low risk for developing vascular ED.

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.

Background The high consumption of nickel (Ni)-containing products raised concerns about their potential hazardous effects on human health. Ni is the most frequent cause of contact allergy (about 17% of women and 3% of men). Ni is present in most of green foods but the content may vary considerably from place to place due to the difference in Ni content of the soil. Several studies have investigated the relationship between Ni intake by food and onset of systemic symptoms. …

Obesity is a widespread emergency in industrialised countries, and its incidence is expected to increase over the time. The presence of endocrine comorbidities in obese men is often neglected. Many studies have demonstrated that in severely obese patients a state of secondary ‘panhypopituitarism’ may occur, along with multiple endocrine peripheral defects, i.e. hypogonadism, sexual disturbances, vitamin D deficiency, osteoporosis and thyroid and growth hormone secretion disturbances. The recognition and appropriate treatment of these obesity-associated conditions is important to make the patient aware that weight loss and the achievement of the right body composition target is possible. Testosterone replacement therapy (TRT) in obese hypogonadal men is still a matter of debate because it is poorly understood whether obesity precedes or is rather the cause of reduced testicular function. The aim of this chapter will be to describe the pathophysiology of testicular dysfunctions occurring in obese men and the possibility to commence TRT in order to correct hypogonadism along with lifestyle modifications. Evidence-based medicine is growing up, and the most recent studies (controlled and uncontrolled) regarding efficacy and safety of TRT in obese men will be discussed.

Modifications of cardiovascular and metabolic parameters during testosterone (T) replacement and withdrawal have never been investigated in severely obese hypogonadal men. Twenty-four severely obese (mean BMI 42; mean age 54.5) hypogonadal men (mean T = 245 ± 52 ng/dL) were enrolled in an observational, parallel-arm, open-label, 54-week study of hypocaloric diet plus physical activity (DPE; n = 12) or DPE plus T injections (DPE + T; n = 12), followed by 24 weeks of DPE alone. Primary endpoints were variations from baseline of cardiovascular (cardiac performance, blood pressure, endothelial function, carotid intima-media thickness, CIMT; epicardial fat thickness, EF) and body composition (fat/lean mass) parameters. Secondary endpoints were variations from baseline of hormonal (T and GH) and metabolic (oral glucose tolerance test, lipids, fibrinogen) parameters. At 54 weeks, DPE + T showed improvements in EF, ejection fraction, diastolic function, CIMT and endothelial function (p

Objective To investigate the possible effects of testosterone undecanoate (TU) injections in a population of obese (mean age 57) hypogonadal men with lower urinary tract symptoms (LUTS) in a long-term observational study. Methods Twenty obese hypogonadal men with metabolic syndrome were treated with TU injections every 12 weeks for 60 months; also 20 matched subjects in whom TU was unaccepted or contraindicated were used as controls. LUTS severity and the impact of TU injections were assessed by differences in International Prostate Symptom Score (IPSS), maximum urinary flow (Qmax) rate in milliliters, post-void residual (PVR) volume, and prostate size every 12 months in a 5-year controlled study. Results TU injections did not produce differences in IPSS, Qmax, PVR, and prostate size in both groups. No modification in prostate-specific antigen (PSA) and hematocrit levels was also found between the 2 groups. Interestingly, controls showed increased incidence of prostatitis than TU-treated men (10% vs 30%, P Conclusion We showed that 5 years of TU treatment did not change IPSS, PVR, Qmax, or prostate size in obese hypogonadal men with metabolic syndrome and moderate LUTS at baseline. Therefore, long-term TU replacement therapy is a safe and effective treatment for reverting hypogonadal features related to metabolic syndrome and does not impact negatively on LUTS and prostate volume.

Metabolic and hormonal modifications after long-term testosterone (T) treatment have never been investigated. 20 hypogonadal men (mean T = 241 ng/dL–8.3 nmol/L) with metabolic syndrome (MS, mean age 58) were treated with T-undecanoate injections every 12 weeks for 60 months. 20 matched subjects in whom T was unaccepted or contraindicated served as controls. Primary endpoints were variations from baseline of metabolic and hormonal parameters. In T-group, significant reductions in waist circumference (−9.6±3.8 cm,P<0.0001), body weight (−15±2.8 Kg,P<0.0001), and glycosylated hemoglobin (−1.6 ± 0.5%,P<0.0001) occurred, along with improvements in insulin sensitivity (HOMA-I;−2.8 ± 0.6,P<0.0001), lipid profile (total/HDL-cholesterol ratio−2.9±1.5,P<0.0001), systolic and diastolic blood pressure (−23±10and−16±8mm Hg,P<0.0001, resp.), and neck and lumbar T-scores (+0.5±0.15 gr/cm2,P<0.0001;+0.7±0.8,P<0.0001, resp.). Also, serum vitamin D (+14.0±1.3 ng/mL,P<0.01), TSH (− 0.9±0.3 mUI/mL,P<0.01), GH (0.74±0.2 ng/mL,P<0.0001), and IGF1 (105±11 ng/mL,P<0.01) levels changed in T-group but not in controls. Normalization of T levels in men with MS improved obesity, glycemic control, blood pressure, lipid profile, and bone mineral density compared with controls. Amelioration in hormonal parameters, that is, vitamin D, growth hormone, and thyrotropin plasma levels, were reported.

Several chronic metabolic alterations are present in obese subjects. While it is well known about the detrimental effect of abdominal adipose tissue on chronic metabolic clinical condition, less is known on the role of lean mass in obese subjects. Thus, the aim of our study was to evaluate the potential correlation of muscle mass, metabolic condition and inflammation status in obese individuals.The study included 426 obese subjects (86 men and 340 female; mean age 44.8 ± 14 years; BMI: 34.9 ± 6.1 kg/m(2)). Exclusion criteria were chronic medical conditions or use of medications affecting bone metabolism, alterations of hormonal and nutritional status, vitamin D supplementation, recent weight loss and prior bariatric surgery. Patients underwent measurements of bone mineral density (lumbar and hip) and body composition (lean mass, total and trunk fat mass) by dual X-ray absorptiometry and were evaluated for hormonal and metabolic profile and inflammatory markers.Higher lean body mass (LM%) was inversely correlated with homeostasis model assessment of insulin resistance (p0.0091; r(2) 0.03938) and associated with lower fibrinogen levels (p0.0001; r(2) 0.1263). Interestingly, in obese subjects, LM% was associated with higher levels of vitamin D (p0.0001, r(2) 0.1140), osteocalcin (p0.0001, r(2) 0.2401) and insulin-like growth factor-1 (IGF-1) (p0.0002, r(2) 0.1367).Our results show for the first time that in obese patients, higher amounts of lean mass are directly linked to a lower inflammatory profile and to better insulin sensitivity, but also to the presence of higher level of vitamin D and IGF-1. Moreover, these data suggest that higher levels of lean mass in obese people correlate with a better metabolic profile and, thus, strongly suggest the need to develop programs to facilitate an increase in physical activity in obese people.

Erectile dysfunction (ED) is one of the most common chronic diseases affecting men and its prevalence increases with aging. It is also the most frequently diagnosed sexual dysfunction in the older male population. A number of different diseases potentially worsening sexual function may occur in elderly people, together with polypharmacy. Related causes of ED are variable and can include arterial, neurogenic, hormonal, cavernosal, iatrogenic, and psychogenic causes. The aim of the present review was to examine the main aspects of erectile dysfunction going through epidemiology and pathophysiology and revise most of ED in elderly disabled men and in those affected with psychiatric disorders. Lastly we tried to focus on the main aspects of nonpharmacological and pharmacological treatments of ED and the recreational use in the elderly. Phosphodiesterase-5 inhibitors (PDE5-I) are commonly used for on-demand or chronic treatment of ED. It is widely known that PDE5-I have lower response rates in older men than in younger patients, but they have the advantages of ease of use and excellent safety profile, also in the elderly. The old and new PDE5-I as well as the alternative treatments for ED are extensively discussed.

Phosphodiesterase type 5 inhibitors (PDE5-i) are used for the oral treatment of erectile dysfunction (ED). Since the launch of sildenafil more than 15 years ago, new molecules have become available. At present, in addition to tadalafil and vardenafil, there are three other drugs, udenafil, avanafil and mirodenafil, marketed in some countries which appear to be promising.The clinical pharmacological differences in dosage and side effects of all PDE5-i are evaluated.All PDE5-i are equally effective and safe for the treatment of ED. On-demand use of any PDE5-i is also safe for patients with comorbid conditions. Tadalafil seems to be the preferred drug by patients and physicians, probably due to its peculiar pharmacological profile that makes sexual intercourse more spontaneous for the patients. Preliminary data suggest that the use of vardenafil may also be beneficial in cases of ED associated with premature ejaculation. Daily treatment is another option in men with ED and documented vascular or prostate disease. In geriatric or in difficult-to-treat populations, the evaluation of testosterone plasma levels will help to predict the efficacy of any PDE5-i. Remarkably, when such drugs are withdrawn for any reason, ED most often continues to occur because of the presence of an underlying disease.

AIM: To evaluate the potential interference of trunk fat (TF) mass on metabolic and skeletal metabolism. METHODS: In this cross-sectional study, 340 obese women (mean age: 44.8 ± 14 years; body mass index: 36.0 ± 5.9 kg/m2) were included. Patients were evaluated for serum vitamin D, osteocalcin (OSCA), inflammatory markers, lipids, glucose and insulin (homeostasis model assessment of insulin resistance, HOMA-IR) levels, and hormones profile. Moreover, all patients underwent measurements of bone mineral density (BMD; at lumbar and hip site) and body composition (lean mass, total and trunk fat mass) by dual-energy X-ray absorptiometry. RESULTS: Data showed that: (1) high TF mass was inversely correlated with low BMD both at lumbar (P < 0.001) and hip (P < 0.01) sites and with serum vitamin D (P < 0.0005), OSCA (P < 0.0001) and insulin-like growth factor-1 (IGF-1; P < 0.0001) levels; (2) a positive correlation was found between TF and HOMA-IR (P < 0.01), fibrinogen (P < 0.0001) and erythrocyte sedimentation rate (P < 0.0001); (3) vitamin D levels were directly correlated with IGF-1 (P < 0.0005), lumbar (P < 0.006) and hip (P < 0.01) BMD; and (4) inversely with HOMA-IR (P < 0.001) and fibrinogen (P < 0.0005).Multivariate analysis demonstrated that only vitamin D was independent of TF variable. CONCLUSION: In obese women, TF negatively correlates with BMD independently from vitamin D levels. Reduced IGF-1 and increased inflammatory markers might be some important determinants that account for this relationship.

Weight loss in sexually active women improves their quality of life. At present, no studies have investigated whether weight loss may affect female sexual function in severe obese women.The aim of this study was to investigate the effects of different programs of weight loss on female sexual dysfunction complaints and on endothelial function in premenopausal obese females.Forty-four out of overall 80 obese fertile women (age 18-49 years; mean 36 years) were enrolled because of sexual complaints at Female Sexual Function Index-6 (FSFI-6 score ≤19). Patients were then allocated to different treatments of 8 weeks duration each: an intensive residential program with hypocaloric diet plus controlled physical exercise along with lifestyle modifications at a specialized clinic (Group A, N = 23) and a non-intensive outpatient clinic program consisting of hypocaloric diet and physical exercise at home (Group B, N = 21). Afterward, overall patients were allocated to an extended 8-week follow-up period consisting of outpatient clinic controlled diet plus physical exercise at home.Primary end points were modifications of FSFI-6 scores and endothelial function as measured by reactive hyperemia (RHI) with EndoPat-2000. Secondary end points were modifications in body composition as measured by dual-energy X-ray absorptiometry (DEXA).After 16 weeks, FSFI-6 score and the frequency of sexual activity were significantly higher in Group A compared with Group B (P 0.01), and significant improvements in arousal, lubrication, and satisfaction sub-domain scores were also found (P 0.01). Group A showed improvements in RHI (P 0.01) and marked improvement in homeostasis model assessment of insulin resistance (P 0.001), anthropometric parameters as weight (P 0.01), body mass index (P 0.01), fat mass (P 0.0001), and percentage of fat mass (P 0.005) compared with Group B. A relationship between peak insulin (P 0.0001) and RHI (P 0.001) vs. FSFI-6 scores was found, respectively.A multidisciplinary approach to female obesity appears to be superior to conventional outpatient clinic to produce weight loss and to improve several aspects of sexual dysfunction in obese women. Such changes might be related to persistent improvements in endothelial function and in insulin resistance.

We evaluated the effects of long-term testosterone replacement therapy (TRT) on the bone mineral density (BMD) in obese patients with metabolic syndrome (MS) and late-onset hypogonadism (LOH). Sixty men (mean age 57 ± 10) with low serum testosterone (T < 320 ng/dL) and MS regardless the presence of osteoporosis were enrolled. Forty men received intramuscular T-undecanoate (TU) four times/year for 36 months and 20 age-matched hypogonadal men with MS in whom T treatment was contraindicated were used as controls. Hormonal, biochemical markers, vertebral and femoral BMD by dual-energy x-ray absorptiometry were measured. At baseline, overall patients had mild osteopenia (lumbar BMD= 0.891 ± 0.097 g/cm(2); femoral BMD= 0.847 ± 0.117 g/cm(2)). TU induced a significant improvement of bone mass after 36 months (lumbar BMD=1.053 ± 0.145 g/cm(2); p < 0.002; femoral BMD=0.989 ± 0.109; p < 0.003 g/cm(2)) with a 5%/year increase and a significant reduction in hs-CRP without changes in body mass index. A direct relationship between serum T and BMD increments at the lumbar (r(2) = 0.66, p < 0.0001) and femoral (r(2) =0.52, p < 0.0001) sites was demonstrated. Study adherence was 50% without serious side effects. Long-term TRT in middle-aged men with LOH and MS determines a significant increase in both vertebral and femoral BMD related to increased serum T levels, probably independently from estradiol modifications.

There are no interventional studies on the impact of sexual distress (SD) in men with obesity. We investigated the effects of vardenafil (VAR) on SD in middle-aged (mean age 49 ± 8), healthy, obese men in the absence of premature ejaculation, ED or hypogonadism. After a 4-week run-in period, 20 men with high body mass index (BMI=40 ± 8) and SD at the Sexual Distress Esteem Questionnaire-Male (mean score 65 ± 20 AU) were randomized to receive either VAR 10 mg on demand (N=10) or matched-placebo (PLB, N=10). Primary endpoints were variations from baseline in the intravaginal ejaculatory latency time (IELT) measured by the stopwatch technique; secondary endpoints were variations from baseline in Self-Esteem and Relationship (SEAR) and Male Sexual Health Questionnaire-Ejaculatory domain (MSHQ-EjD) scores. VAR significantly improved IELT (P0.0001), as well as SEAR (P0.001) and MSHQ-EjD (P0.005) scores, whereas no changes were observed after PLB. Interestingly, an inverse relationship between BMI and IELT was found in all the men studied (r(2)=0.37, P0.001). SD in healthy obese men seems to be correlated mainly with inadequate ejaculatory control, especially in men with higher BMI. Our preliminary results suggest that treatment with VAR may improve ejaculatory control, thus ameliorating self-esteem and sexual performance in men with obesity.

Androgen deprivation therapy (ADT) for prostate carcinoma (PCa) may cause cardiometabolic complications unless intermittent androgen blockade (IAB) is instituted. An 80-year-old caucasian man was diagnosed intermediate grade (Gleason 4 + 3) PCa and was treated with continuous ADT with triptorelin plus bicalutamide. After 6 months of treatment, he experienced an acute myocardial infarction and 1 month after hospitalization he came to our outpatient clinic for fatigue, weight gain, and hyperglycemia. Due to iatrogenic hypogonadism, we decided to proceed with IAB, but after 3 months ADT withdrawal his serum testosterone (T) was still 0.5 ng/mL. Due to very low concomitant PSA levels (0.1 ng/mL) he was then proposed intermittent T-gel supplementation (Tostrex(®)) which was initiated according to the following scheme: 6 months on and 3 months off. T-gel dose was titrated tri-weekly in order to achieve T plasma levels below 3.49 ng/mL. After 6 months on, his serum T raised to a mean value of about 2.0 ng/mL without increments in PSA. After overall 12 months on, his serum T peaked to a mean value of 3.0 ng/mL while a delay in PSA rise was seen after 24 months (0.6 ng/mL) but remained stable until the last observation carried forward (LOCF), at 45 months. No clinical and biochemical PCa progression were observed at LOCF. Reversion of iatrogenic metabolic syndrome started after 6 months of T supplementation without using any add-on treatment. This case provides support that once regression of PCa growth is attained, T supplementation may be administered in well differentiated PCa, especially if IAB is not successful in reverting iatrogenic hypogonadism and its associated cardiac and metabolic complications.

Prolonged tadalafil administration in men with erectile dysfunction is associated with increased testosterone (T): estradiol (E(2)) ratio mainly related to reduction of E(2) levels.To investigate the presence of phosphodiesterase type 5 (PDE5) isoenzyme in primary human visceral adipocytes and whether different PDE5 inhibitors (PDE5i) could directly modulate aromatase (ARO) expression in differentiated human visceral adipocytes in culture.PDE5 mRNA and protein expression in primary human visceral adipocytes as well as mRNA and protein expression of ARO, with functional activity after selective PDE5 blockade by tadalafil and sildenafil.Purified primary human visceral pre-adipocytes were differentiated ex vivo and were exposed to tadalafil or sildenafil (1 µM) for different intervals of time (6-12-24-96 hours). ARO mRNA content and expression were measured by Western Blot and quantitative reverse transcription-polymerase chain reaction (qRT-PCR), respectively. T and E(2) in supernatants were measured by ELISA also in the presence of letrozole.Differentiated adipocytes were found to express detectable levels of PDE5 transcripts. Acute exposure (6 hours) to both PDE5i tadalafil and sildenafil increased ARO mRNA expression by 4.7- and 2.8-fold, respectively (P0.001). ARO mRNA and protein levels were increased by the treatment with PDE5i in a time- and dose-dependent manner. Such effect was mimicked by 8-bromo-cGMP but was lost after 24 and 96 hours; differently, the PDE3B specific inhibitor milrinone (1 µM), displayed no effect. Accordingly, long-term exposure (24 and 96 hours) to PDE5i caused a significant increase in E(2) concentrations in the supernatant (1.7 and 2 fold, respectively; P0.001), with a parallel reduction of T (15% and 30%, respectively; P0.001). Such effect was reversed by the co-incubation with the specific ARO-inhibitor letrozole.Our results demonstrate that PDE5 is expressed in human visceral adipocytes and that acute exposure to PDE5i selectively stimulates ARO expression, which is related to a specific PDE5 blockade. We speculate that modulation of ARO activity by PDE5i could be one of the mechanisms responsible, at least in part, for the beneficial effects of PDE5i on endothelial and metabolic functions.

article i nfo Article history: Background: It is known that the incidence of endothelial dysfunction in patients with vascular erectile dysfunction (ED) is increased. The effects of daily vardenafil on endothelial function and arterial stiffness in patients with erectile dysfunction (ED) have never been investigated. Methods: 20 men complaining vascular ED (mean IIEF5=12±6 and peak systolic velocity-PSV=24±2 cm/ s) were enrolled in a 4-week, randomized, double-blind, double-dummy, crossover study (mean age 59±11) and received either vardenafil 10 mg daily or 20 mg on-demand with a two-week washout interval. Primary endpoints were variation from baseline of reactive hyperemia (RH) and augmentation index (AI) calculated by fingertip peripheral arterial tonometry (PAT) device. Secondary endpoints were variations of IIEF-5 and SEP3 scores from baseline and plasma surrogate markers of endothelial function, i.e. endothelin-1 (ET-1) and adrenomedullin (ADM). Results: Patients who took daily vardenafil (vs. on-demand) reported significant (Pb0.01) improvements in arterial stiffness as evaluated by AI and reduction of plasma ADM levels (pb0.05) but no improvement in average RH. When corrected for heart rate, ADM showed a strong direct relationship with AI (r 2 =0.22; pb0.005). The proportion of patients with an IIEF5 score of ≥22 or in SEP3 percentage of success rates were similar. Each treatment resulted in significantly greater IIEF5 scores (pb0.001) and better SEP3 response rates (pb0.0001) compared with baseline. Conclusions: We demonstrated that daily vardenafil improves arterial stiffness and erectile function measurements in men with severe vasculogenic ED. This effect may be mediated, at least in part, by a reduction in ADM circulating levels.

Introduction. Longitudinal studies have demonstrated that male hypogonadism could be considered a surrogate marker of incident cardiovascular disease. Aim. To evaluate the effects of parenteral testosterone undecanoate (TU) in outclinic patients with metabolic syndrome (MS) and late-onset hypogonadism (total testosterone (T) at or below 11 nmol/L or free T at or below 250 pmol/L). Methods. This is a randomized, double-blind, double-dummy, placebo-controlled, parallel group, single-center study. Fifty patients (mean age 57 8) were randomized (4:1) to receive TU 1,000 mg (every 12 weeks) or placebo (PLB) gel (3-6 g/daily) for 24 months. Main Outcome Measures. Homeostasis model assessment index of insulin resistance (HOMA-IR), carotid intima media thickness (CIMT), and high-sensitivity C-reactive protein (hsCRP). Results. At baseline, all patients fulfilled the National Cholesterol Education Program-Third Adult Treatment Panel (NCEP-ATPIII) and International Diabetes Federation (IDF) criteria for the definition of MS. An interim analysis conducted at 12 months showed that TU markedly improved HOMA-IR (P < 0.001), CIMT (P < 0.0001), and hsCRP (P < 0.001) compared with PLB; thus, all patients were shifted to TU treatment. After 24 months, 35% (P < 0.0001) and 58% (P < 0.001) of patients still presented MS as defined by NCEP-ATPIII and IDF criteria, respectively. Main determinants of changes were reduction in waist circumference (P < 0.0001), visceral fat mass (P < 0.0001), and improvement in HOMA-IR without changes in body mass index (BMI). Conclusions. TU reduced fasting glucose, waist circumference, and improved surrogate markers of atherosclerosis in hypogonadal men with MS. Resumption and maintenance of T levels in the normal range of young adults determines a remarkable reduction in cardiovascular risk factors clustered in MS without significant hematological and prostate adverse events. Aversa A, Bruzziches R, Francomano D, Rosano G, Isidori AM, Lenzi A, and Spera G. Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle- aged men with late onset hypogonadism and metabolic syndrome: Results from a 24-month, randomized, double-blind, placebo-controlled study. J Sex Med 2010;7:3495-3503.

Systemic Sclerosis (SSc) is a connective tissue disorder featuring vascular alterations and an immunological activation leading to a progressive and widespread fibrosis of several organs such as the skin, lung, gastrointestinal tract, heart, and kidney. Men with SSc are at increased risk of developing erectile dysfunction (ED) because of the evolution of early microvascular tissutal damage into corporeal fibrosis. The entity of penile vascular damage in SSc patients has been demonstrated by using Duplex ultrasonography and functional infra-red imaging and it is now clear that this is a true clinical entity invariably occurring irrespective of age and disease duration and constituting the ‘‘sclerodermic penis’’. Once-daily phosphodiesterase type-5 (PDE5) inhibitors improve both sexual function and vascular measures of cavernous arteries by improving surrogate markers of endothelial dysfunction, that is, plasma endothelin-1 and adrenomedullin levels, which may play a potential role in preventing progression of penile fibrosis and ED. Also, the beneficial effect of long-term PDE5i add-on therapy to SSc therapy in the treatment of Raynaud's phenomenon is described.

To investigate efficacy and safety of two different preparations of testosterone undecanoate (TU) in 52 hypogonadal men [mean age 57 yr and mean testosterone (T)320 ng/dl] with metabolic syndrome (MS).Randomized, double-blind, double-dummy study with three parallel treatment arms [oral TU; transdermal placebo gel (P); im TU] administration for 12 months (mo). Each subject was randomized (1:1:3) to receive either oral TU (2 capsules of 40 mg/twice per day at breakfast and dinner, equalling a total dose of 160 mg/day; no.=10) for 6 mo and continued with im TU for further 6 mo, or P (3-4 g/day; no.=10) and im TU (1000 mg/12 weeks from week 6; no.=32) for 12 mo.After 6 mo, im TU increased T and free- T levels (p0.0001), and improved metabolic parameters [reduction in Homeostasis Model Assessment (HOMA) index, p0.0001; waist circumference and fat mass, p0.001, respectively], in International Index of Erectile Function-5 and Aging Males' Symptoms scores (p0.01, respectively). After 12 months, im TU produced further increases in T and free- T levels (p0.0001) and metabolic parameters (reduction in HOMA-index, p0.0001; waist circumference p0.0001; fat mass, p0.001). No major adverse event due to T treatment occurred.Clinical efficacy of T replacement therapy in hypogonadal men with MS is reached when its plasmatic levels approach into the medium-high range of normality (5 ng/ml), although subjective threshold values may be different. Administration of im TU was more effective than oral TU to reach the target for T levels and to improve MS parameters. TU was safe over 12 months and discontinuation rates were similar to placebo.

Normal vascular endothelium is essential for the synthesis and release of substances affecting vascular tone (e.g. nitric oxide; NO), cell adhesion (e.g. endothelins, interleukins), and the homeostasis of clotting and fibrinolysis (e.g. plasminogen inhibitors, von Willebrand factor). The degeneration of endothelial integrity promotes adverse events (AEs) leading to increased atherogenesis and to the development of vascular systemic and penile end-organ disease. Testosterone (T) is an important player in the regulation of vascular tone through non-genomic actions exerted via blockade of extracellular-calcium entry or activation of potassium channels; also, adequate T concentrations are paramount for the regulation of phosphodiesterase type-5 (PDE5) expression and finally, for the actions exerted by hydrogen sulphide, a gas involved in the alternative pathway controlling vasodilator responses in penile tissue. It is known that an age-related decline of serum T is reported in approximately 20 to 30% of men whereas T deficiency is reported in up to 50% of men with metabolic syndrome or diabetes. A number of laboratory and human studies have shown the combination of T and other treatments for erectile dysfunction (ED), such as PDE5 inhibitors, to be more beneficial in patients with ED and hypogonadism, who fail monotherapy for sexual disturbances. The aim of this review is to show evidence on the role of T and PDE5 inhibitors, alone or in combination, as potential boosters of endothelial function in internal medicine diseases associated with reduced T or NO bioavailability, i.e. metabolic syndrome, obesity, diabetes, coronary artery disease, hyperhomocysteinemia, that share common risk factors with ED. Furthermore, the possibility of such a strategy to prevent endothelial dysfunction in men at increased cardiovascular risk is discussed.

Premature ejaculation (PE) is thought to be the most common male sexual dysfunction; however, the prevalence of lifelong (LL)-PE is relatively low. The aim of this study was to investigate the effects of on-demand vardenafil (10 mg) to modify the intravaginal ejaculatory latency time (IELT) in men with LL-PE without erectile dysfunction. Forty-two men (18-35 years) were enrolled in a 16-week, double-blind, placebo-controlled, cross-over study. Primary end point was the modification from baseline of IELT assessed by stopwatch technique; secondary end points were post-ejaculatory refractory time (PERT) and variations of scores at the Index of Premature Ejaculation questionnaire. The changes in geometric mean IELT were superior after taking vardenafil (0.6+/-0.3 vs 4.5+/-1.1 min, P

Aim of the study was to evaluate whether endothelial dysfunction is a marker of erectile dysfunction (ED) in recreational drug abuse. Sixty-four non-consecutive men complaining of ED from at least 3 months were included. All patients underwent detailed history about recreational drug abuse and were then submitted to dynamic penile duplex ultrasound (PDU). According to pharmaco-stimulated peak systolic velocity (PSV) cutoff at 35 cm s(-1), patients were divided into two groups: organic (O; n=30) and non-organic (NO; n=34) ED. All subjects and 7 healthy age-matched subjects as controls, underwent veno-occlusive plethysmography (VOP) for the evaluation of endothelium-dependent dilatation of brachial arteries. Blood pressure, total and free testosterone, prolactin, estradiol, low-density lipoprotein and high-density lipoprotein cholesterol were also evaluated; patients were classified with regard to insulin resistance through the HOMA-IR index. Cannabis smoking was more frequent in O-ED vs NO-ED (78% vs 3%, P

Diabetes mellitus (DM) is an established risk factor predisposing to male erectile dysfunction (ED), and it has been calculated that more than 50% of diabetic men develop ED within ten years of diagnosis. It has been suggested that the risk of ED increases with metabolic indices of inadequate diabetes control and with a longer duration of disease. Loss of the functional integrity of the endothelium and subsequent endothelial dysfunction plays an integral role in the pathogenesis of diabetic ED. Coronary and peripheral atherosclerosis are frequent complications of DM and diabetic patients have an increased risk of future cardiovascular events comparable to that of patients with coronary artery disease. The prolonged half-life of tadalafil (17.5 hours) and its prolonged period of responsiveness (36- hours), constitute an ideal pharmacokinetic profile for once-a-day dosing and makes it an ideal candidate for rehabilitative therapy in DM patients, whereas a poor compliance with on-demand schedule is reported. The aim of this review will be to give an update on clinical overall efficacy and safety of tadalafil trials, i.e in diabetic population, and finally provide evidences for redefining the role of chronic treatment in selected group of patients.

Erectile dysfunction frequently represents a neurovascular complication of diabetes mellitus, and it has been calculated that almost 50% of diabetic men will have erectile dysfunction within 6 years after diagnosis. Penile endothelial and smooth muscle cell dysfunction are due to molecular pathway abnormalities (i.e., activation of PKC, increased oxidative stress and overproduction of advanced-glycosylation end products). The response rate to oral drug therapies, such as sildenafil, is lower than in most other groups. Because therapeutic alternatives (i.e., intracavernous injections with vasoactive agents) are not curative, clinical trials aimed to demonstrate rehabilitative effects with daily phosphodiesterase type-5 inhibitors are ongoing. If this approach proves successful, it will determine many advantages over the intracavernosal treatment and potentially induce sexual rehabilitation.

Introduction. Longitudinal studies have demonstrated that male hypogonadism could be considered a surrogate marker of incident cardiovascular disease. Aim. To evaluate the effects of parenteral testosterone undecanoate (TU) in outclinic patients with metabolic syndrome (MS) and late-onset hypogonadism (total testosterone (T) at or below 11 nmol/L or free T at or below 250 pmol/L). Methods. This is a randomized, double-blind, double-dummy, placebo-controlled, parallel group, single-center study. Fifty patients (mean age 57 8) were randomized (4:1) to receive TU 1,000 mg (every 12 weeks) or placebo (PLB) gel (3-6 g/daily) for 24 months. Main Outcome Measures. Homeostasis model assessment index of insulin resistance (HOMA-IR), carotid intima media thickness (CIMT), and high-sensitivity C-reactive protein (hsCRP). Results. At baseline, all patients fulfilled the National Cholesterol Education Program-Third Adult Treatment Panel (NCEP-ATPIII) and International Diabetes Federation (IDF) criteria for the definition of MS. An interim analysis conducted at 12 months showed that TU markedly improved HOMA-IR (P < 0.001), CIMT (P < 0.0001), and hsCRP (P < 0.001) compared with PLB; thus, all patients were shifted to TU treatment. After 24 months, 35% (P < 0.0001) and 58% (P < 0.001) of patients still presented MS as defined by NCEP-ATPIII and IDF criteria, respectively. Main determinants of changes were reduction in waist circumference (P < 0.0001), visceral fat mass (P < 0.0001), and improvement in HOMA-IR without changes in body mass index (BMI). Conclusions. TU reduced fasting glucose, waist circumference, and improved surrogate markers of atherosclerosis in hypogonadal men with MS. Resumption and maintenance of T levels in the normal range of young adults determines a remarkable reduction in cardiovascular risk factors clustered in MS without significant hematological and prostate adverse events. Aversa A, Bruzziches R, Francomano D, Rosano G, Isidori AM, Lenzi A, and Spera G. Effects of testosterone undecanoate on cardiovascular risk factors and atherosclerosis in middle- aged men with late onset hypogonadism and metabolic syndrome: Results from a 24-month, randomized, double-blind, placebo-controlled study. J Sex Med 2010;7:3495-3503.

Purpose Testosterone (T) exerts different effects on the cardiovascular system. Despite this knowledge, the acute vascular effect of androgen remains still poorly understood. Methods We investigated the acute effects of T on vascular function in ten men (18–40 years age) with hypogonadism and severe hypotestosteronemia [serum total testosterone (TT) = 0.6 ± 0.3 ng/mL]. In a 4-day double-blind, randomized, placebo-controlled crossover study, we administered 80 mg daily dose of transdermal-T gel (TG) and evaluated endothelial variations with Endopat2000 (reactive hyperemia index, RHI and the augmentation index, AI); also, CAG repeat polymorphism in exon 1 of the androgen receptor gene was investigated. Results After TG administration, RHI significantly improved at 4 h (p

The relationship between testosterone deficiency syndrome (TDS) and men's vascular health has a great impact in the modern approach to the aging male. There is good evidence that low testosterone (T) is associated with erectile dysfunction (ED) and that ED is a strong marker for cardiovascular risk; also, TDS is frequently associated with increased cardiovascular and all-cause mortality. Noteworthy, the occurrence of increased levels of glucose, total cholesterol, low-density lipoprotein, pro-inflammatory cytokines, and myointimal carotid thickness may be associated with reduced T levels especially in cardiac older frail men. Screening for low T should be mandatory in high risk groups including those with type 2 diabetes, metabolic syndrome and obesity. The rising demand from patients to be treated for ED associated with TDS will increase the prescribing of T and facilitate future long-term studies on its impact on cardiovascular disease (CVD). Recent studies suggest warnings with regard to T prescription in older frail men, but we regret that these studies had consistent bias in inclusion criteria and statistical evaluation. Data from studies conducted in more selected populations suggest that T replacement therapy may improve multiple surrogate markers for CVD as well as reducing cardiovascular mortality. After analyzing the most important studies' limitation, we can conclude that at present there is insufficient evidence of a causal relationship between T therapy and adverse cardiovascular outcomes to support against T supplementation in older hypogonadal frail men.