Effects of testosterone undecanoate replacement and withdrawal on cardio-metabolic, hormonal and body composition outcomes in severely obese hypogonadal men: a pilot study.

PURPOSE: Modifications of cardiovascular and metabolic parameters during testosterone (T) replacement and withdrawal have never been investigated in severely obese hypogonadal men. METHODS: 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. RESULTS: At 54 weeks, DPE + T showed improvements in EF, ejection fraction, diastolic function, CIMT and endothelial function (p < 0.01 vs. controls). Also, hormonal (T, p < 0.0001; GH, p < 0.01), metabolic (HOMA, p < 0.01; microalbuminuria, p < 0.01), lipid (total cholesterol, p < 0.05) and inflammatory (fibrinogen, p < 0.05) parameters improved. After 24 weeks from T withdrawal, all cardiac and hormonal parameters returned to baseline, while fat but not lean mass and blood pressure ameliorations were maintained. An inverse relationship either between EF vs. endothelial function and EF vs. T levels was found (r (2) = -0.46, p < 0.001 and r (2) = -0.56, p < 0.0005, respectively) while direct relationship between T vs. endothelial function occurred (r (2) = 0.43, p < 0.005) in DPE + T. A 33 % dropout rate was reported in DPE without serious adverse events. CONCLUSIONS: In middle-aged hypogonadal obese men, 1-year T treatment was safe and improved cardio-metabolic and hormonal parameters. We firstly demonstrated that T withdrawal determines a return back to hypogonadism within 6 months, with loss of cardiovascular and some body composition improvements attained.

A pilot study to evaluate the effects of vardenafil on sexual distress in men with obesity.

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 (P<0.0001), as well as SEAR (P<0.001) and MSHQ-EjD (P<0.005) 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, P<0.001). 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.

Is there a role for phosphodiesterase type-5 inhibitors in the treatment of premature ejaculation?

Premature ejaculation (PE) is considered to be the most common male sexual dysfunction. The realization that PE may co-exist with ED prompted the use of PDE5-i's alone or in combination with selective serotonin reuptake inhibitors (SSRIs) for treating ejaculatory disorders. Until recently, there was little evidence that PDE5-i's alone may have a role in the treatment of PE in the absence of ED, and current available treatments include only on-demand dapoxetine. However, available data indicate that there is clinical, anatomical, physiological, pharmacological and genetic evidence to explain the efficacy of PDE5-i's. Nine manuscripts that examined the efficacy of PDE5-i's in the treatment of PE, alone or in combination with SSRIs, were retrieved. All studies reported some significant changes in the intravaginal ejaculatory latency time and sexual satisfaction scores, although not all were clinically meaningful. Well-designed multicenter studies are urgently required to further elucidate the efficacy and safety, as well as the mechanisms of action of PDE5-i's in the treatment of PE. The aim of this review is to discuss basic rationale and to show clinical evidence sustaining the possibility to use off-label PDE5-i's to treat PE.

The application of digital pulse amplitude tonometry to the diagnostic investigation of endothelial dysfunction in men with erectile dysfunction.

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.

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 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 (r(2)=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.

Plasma adrenomedullin and endothelin-1 levels are reduced and Raynaud's phenomenon improved by daily tadalafil administration in male patients with systemic sclerosis.

The aim of our study is to evaluate in Systemic Sclerosis (SSc) male patients the tadalafil effects on Raynaud's phenomenon and on AM and ET-1 plasma levels. In an open-label study 20 consecutive male patients with SSc were enrolled and received 10 mg of tadalafil daily for 12 weeks. The primary endpoint was the subjective reduction of frequency and duration of Raynaud's attacks measured with a 10-point Raynaud's Condition Score; the secondary aim was to modify Adrenomedullin (AM) and Endothelin-1 (ET-1) plasma levels. After the treatment Raynaud's phenomenon was improved by once-daily tadalafil (decrease of mean number of Raynaud's attacks and of Raynaud's Condition Score) and plasma AM and ET-1 levels decreased. The results of our study lead us to postulate the beneficial effect of adding long term inhibition of Phosphodiesterase type 5 to Systemic Sclerosis' therapy.

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 (r(2)=0.47, P<0.0001), which was maintained in men with organic ED (r(2)=0.62, P<0.0001). In cannabis consumers, a direct relationship between HOMA-IR and VOP was also found (r(2)=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.

Relationship between chronic tadalafil administration and improvement of endothelial function in men with erectile dysfunction: a pilot study.

Men with erectile dysfunction (ED) frequently have a disproportionate burden of comorbid vascular disorders including atherosclerotic disease. We investigated whether scheduled tadalafil is better than on-demand (OD) in improving endothelium-dependent vasodilatation of cavernous arteries in men with ED and whether this effect is also exerted on markers of endothelial function. We did an open-label, randomized, crossover study including 20 male outclinic patients aged 18 years or older (mean age 54 years) who had at least a 3-month history of ED of any severity or etiology. Tadalafil (20 mg) on alternate days (ADs) or OD was administered for 4 weeks. Primary end points were variations of basal inflow (peak systolic velocity (PSV)) and flow-mediated dilatation (FMD) of cavernous arteries compared with baseline at penile Duplex ultrasound. Secondary end points were variations of Q13-SIEDY scores regarding morning erections and of markers of endothelial function, that is, vascular cell adhesion molecule (VCAM), intercellular cell adhesion molecule, endothelin-1 (ET-1), insulin and C-reactive protein (CRP). PSVs and FMD were higher after AD treatment when compared with OD and baseline, respectively (P=0.0001), and improvements were maintained from 2 weeks after discontinuation (P<0.005). Patients receiving tadalafil AD experienced a significant improvement of morning erections as compared to AD treatment (P<0.0001); ET1, VCAM and CRP showed a robust decrease after chronic vs OD regimes (P<0.05), with concomitant increase in insulin levels (P<0.05), without any variation in blood pressure and other laboratory parameters. Chronic but not OD tadalafil improves endothelial function with sustained effects from its discontinuation. Chronic treatment also produces a dramatic increase in morning erections, which determines better oxygenation to the penis, thus providing a rationale for vascular rehabilitation.

Diagnosing erectile dysfunction: the penile dynamic colour duplex ultrasound revisited.

A number of disease processes of the penis including Peyronie's disease, priapism, penile fractures and tumors are clearly visualized with ultrasound. Diagnostic evaluation of erectile dysfunction (ED) by penile dynamic colour-duplex Doppler ultrasonography (D-CDDU) is actually considered a second level approach to ED patients because of the fact that intracavernous injections test IV with prostaglandin-E(1) may provide important information about the patients' erectile capacity. However, no direct vascular imaging and a high percentage of false negative diagnoses of vasculogenic ED are its major pitfalls and subsequent treatment decisions remain quite limited. The occurrence of ED and its sentinel relationship to cardiovascular disease has prompted more accurate vascular screening in all patients even in the absence of cardiovascular risk factors. The sonographic evaluation of the intima-media thickness of the carotid arteries may sometimes represent an early manifestation of diffuse atherosclerotic disease and endothelial damage. This latter finding is often the cause of failure to oral agents, i.e. phosphodiesterase inhibitors, because of inability of the dysfunctional endothelium to release nitric oxide. D-CDDU represents an accurate tool to investigate cavernous artery inflow and venous leakage when compared with more invasive diagnostic techniques i.e. selective arteriography and dynamic infusion cavernosometry along with cavernosography.