Davide Francomano

Endothelial dysfunction and erectile dysfunction in the aging man.

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

Effects of vardenafil administration on intravaginal ejaculatory latency time in men with lifelong premature ejaculation

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<0.01), compared with placebo (0.7±0.3 vs 0.9±1.0 min, ns). PERT dropped significantly after vardenafil (16.7±2.0 vs 4.3±0.9 min, P<0.001), compared with placebo (15.3±2.2 vs 15.8±2.3 min). Patients who took vardenafil (vs placebo) reported significantly (P<0.01) increased ejaculatory control (6±2 vs 16±2), improved overall sexual satisfaction (7±2 vs 15±1) and distress (4±1 vs 8±1) scores, respectively. Multiple regression analysis (r2=0.86) for IELT by the number of attempts at sexual intercourse showed significant differences between the slopes of lines for placebo and vardenafil (P<0.0001). The most common adverse events for vardenafil (vs placebo) were headache (10 vs 3%), flushing (12 vs 0%) and dyspepsia (10 vs 0%), which tended to disappear over the time. In conclusion, in our study, vardenafil increased IELT and reduced PERT in men with LL-PE. Besides, improvements in confidence, perception of ejaculatory control and overall sexual satisfaction were reported.

Efficacy and safety of two different testosterone undecanoate formulations in hypogonadal men with metabolic syndrome.

Aim: 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). Subjects and methods: 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. Results: After 6 mo, im TU increased T and free-T levels (p<0.0001), and improved metabolic parameters [reduction in Homeostasis Model Assessment (HOMA) index, p<0.0001; waist circumference and fat mass, p<0.001, respectively], in International Index of Erectile Function-5 and Aging Males’ Symptoms scores (p<0.01, respectively). After 12 months, im TU produced further increases in T and free-T levels (p<0.0001) and metabolic parameters (reduction in HOMA-index, p<0.0001; waist circumference p<0.0001; fat mass, p<0.001). No major adverse event due to T treatment occurred. Conclusions: 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.

Effects of Five-Year Treatment with Testosterone Undecanoate on Metabolic and Hormonal Parameters in Ageing Men with Metabolic Syndrome

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 ± 10 and −16 ± 8 mm 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.

Effects of long-acting testosterone undecanoate on bone mineral density in middle-aged men with late-onset hypogonadism and metabolic syndrome: results from a 36 months controlled study

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/cm2; femoral BMD= 0.847 ± 0.117 g/cm2). TU induced a significant improvement of bone mass after 36 months (lumbar BMD = 1.053 ± 0.145 g/cm2; p < 0.002; femoral BMD = 0.989 ± 0.109; p < 0.003 g/cm2) 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 (r2 = 0.66, p < 0.0001) and femoral (r2 = 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.

An update on pharmacological treatment of erectile dysfunction with phosphodiesterase type 5 inhibitors

Introduction: 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. Areas covered: The clinical pharmacological differences in dosage and side effects of all PDE5-i are evaluated. Expert opinion: 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.

Early endothelial dysfunction as a marker of vasculogenic erectile dysfunction in young habitual cannabis users

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<0.001) in the absence of any concomitant risk factor or comorbidity for ED. VOP studies revealed impaired endothelium-dependent vasodilatation in O-ED but not in NO-ED and controls (12±6 vs 32±4 and 34±5 ml min−1, respectively; P=0.003). Overall patients showed a direct relationship between HOMA-IR and PSV (r2=0.47, P<0.0001), which was maintained in men with organic ED (r2=0.62, P<0.0001). In cannabis consumers, a direct relationship between HOMA-IR and VOP was also found (r2=0.74, P<0.0001). Receiver-operating characteristic (ROC) curve analysis revealed that VOP values below 17.22 ml min−1 were suggestive for vasculogenic ED. We conclude that early endothelial damage may be induced by chronic cannabis use (and endocannabinoid system activation); insulin resistance may be the hallmark of early endothelial dysfunction and may concur to determine vascular ED in the absence of obesity. Further studies are warranted to establish a direct relationship between cannabis abuse, onset of insulin resistance and development of vascular ED.

Erectile dysfunction in the elderly: an old widespread issue with novel treatment perspectives.

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.

Negative association between trunk fat, insulin resistance and skeleton in obese women

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/m(2)) 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.

Exposure to Phosphodiesterase Type 5 Inhibitors Stimulates Aromatase Expression in Human Adipocytes in vitro

INTRODUCTION 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. AIM 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. MAIN OUTCOME MEASURES 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. METHODS 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. RESULTS 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 (P < 0.001). 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; P < 0.001), with a parallel reduction of T (15% and 30%, respectively; P < 0.001). Such effect was reversed by the co-incubation with the specific ARO-inhibitor letrozole. CONCLUSIONS 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.