Abstract: INTRODUCTION: The three effective, commercially available drugs for the treatment of erectile dysfunction-sildenafil, vardenafil, and tadalafil-inhibit the same substrate, the erectolytic enzyme phosphodiesterase type 5 (PDE5). Although there are pharmacological differences between these three compounds, few comparative studies have been conducted to date. AIM: The aim of this study was to determine the efficacy of sildenafil, tadalafil, and vardenafil in a randomly assigned 8-week fixed regimen. METHODS: This was a spontaneous, open-label, randomized, multicenter, crossover study where the patients were randomized to receive sildenafil 50 mg, sildenafil 100 mg, tadalafil 20 mg, or vardenafil 20 mg. MAIN OUTCOME MEASURES: The primary outcome included the posttreatment analysis of erectile function domains of the abridged International Index of Erectile Function (IIEF5+1). The secondary objectives included the analysis of peak-systolic velocities (PSVs), end-diastolic velocities (EDVs), and resistive index (RI), and the estimate of the percentage of men with normal penile hemodynamic parameters after each treatment. RESULTS: In all groups of patients taking sildenafil 50 mg, sildenafil 100 mg, tadalafil 20 mg, and vardenafil 20 mg at a frequency reflecting the common treatment regimens in real life, there was a statistically significant baseline-to-end point improvement in subjective perception of erectile function measured by IIEF5+1. When the four groups were compared, the treatments were not different in modifying IIEF5+1 and penile flow parameters. However, the within-group analysis showed that PSV improved in the sildenafil 50 mg group and that PSV together with RI significantly ameliorated in patients receiving 100 mg of sildenafil. Regression analysis confirmed an independent effect of sildenafil on hemodynamic efficacy parameters. CONCLUSIONS: An overall equivalence was demonstrated in the subjective perception of treatment benefits for all the PDE5i tested. However, sildenafil, in a dose-dependent manner, was the unique PDE5i able to ameliorate some of the penile flow parameters within the 8-week treatment period. These findings should be interpreted conservatively because of the observational nature of the study.
Abstract: 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.
Abstract: 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.
Abstract: 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.
Abstract: OBJECTIVE: Diabetic patients have a reduced endothelial response to phosphodiesterase-5 inhibitors. The aim of this study was to determine the effects of chronic therapy with sildenafil on endothelial function in patients with Type 2 diabetes mellitus (DM2). METHODS: In a double-blind, placebo-controlled parallel design, 20 patients without erectile dysfunction randomly received a loading dose of sildenafil (100 mg) for 3 days, followed by either sildenafil 25 mg three times a day (t.d.s.) for 4 weeks or sildenafil 25 mg t.d.s. for 4 days followed by placebo t.d.s. for 3 weeks. RESULTS: After 1 week, flow-mediated dilatation (FMD) improved significantly (> 50% compared with baseline) in patients allocated to both sildenafil arms (62 and 64%, respectively). In patients allocated to chronic sildenafil, a progressive increase in percentage of patients with FMD improvement was noted (78, 86 and 94% at 2, 3 and 4 weeks, respectively) while a progressive decrease in the placebo group occurred (45, 18 and 6% at 2, 3 and 4 weeks, respectively). At the end of the study, a significant improvement in FMD compared with baseline was noted after chronic sildenafil (FMD from 6.8 +/- 0.5 to 12.5 +/- 0.7%, P = 0.01 vs. baseline). A decrease in endothelin-1 levels and an increase in nitrite/nitrate levels were found after chronic sildenafil; significant changes from baseline in C-reactive protein, interleukin 6, intercellular adhesion molecule and vascular adhesion molecule levels were also found. CONCLUSIONS: In DM2 patients, daily sildenafil administration improves endothelial function and reduces markers of vascular inflammation, suggesting that the diabetes-induced impairment of endothelial function may be improved by prolonged phosphodiesterase-5 inhibition.
Abstract: 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.
Abstract: Aldosterone is a steroid hormone that controls blood pressure by binding to the mineralocorticoid receptor (MR), a ligand-activated transcription factor, and regulating genes that play a role in salt and water homeostasis in the kidney. Dysregulation of the mineralocorticoid system reveals its crucial role in various human diseases including hypertension, atherosclerosis, cardiac failure, mineralocorticoid resistance, and disorders of the nervous system. Recently, experimental animal models of mineralocorticoid/salt-induced hypertension and atherosclerosis have revealed an epithelial, pro-inflammatory role for MR activation. Extensive investigation has begun to elucidate the mechanisms underlying the vascular effects of MR activation which involve its direct role in cardiomyocytes, vascular smooth muscle cells, and endothelial cells. More specifically, in patients with cardiovascular risk factors and disease, including diabetes, hypertension, and/or congestive heart failure, an excess of MR activation has been shown to have a negative impact on endothelial function hence disrupting the physiological balance between vasoconstriction and vasodilation. Such a mechanism may play a role in the pathogenesis of erectile dysfunction (ED), a condition that occurs frequently in patients with increased cardiovascular risk and involves endothelial dysregulation of vascular relaxation. The aim of this review is to summarize the latest concepts in MR signaling, with particular attention to the endothelium, and to discuss the potential benefits of tissue-selective MR blockade in treating subsets of ED patients, such as those with congestive heart failure and hypertension, in which the MR system may be over activated.
Abstract: Erectile dysfunction (ED) and endothelial dysfunction are common in individuals with multiple cardiovascular risk factors (CRFs) and are longitudinal predictors of cardiovascular events. ED is associated with systemic endothelial cell activation/dysfunction independent from CRFs or from diffuse, unrecognized vascular damage. The pathogenesis of endothelial dysfunction and ED is intimately linked through decreased expression and activation of endothelial nitric oxide (NO) synthase and the subsequent physiologic actions of NO. Furthermore, reduced biologic activity of endothelium-derived NO links atherosclerosis to ED and underscores the role of altered endothelium in the pathogenesis of both conditions. Evidence-based data suggest that daily use of phosphodiesterase type-5 inhibitors (PDE5-i) improves endothelial and erectile functions and that this benefit is lost upon drug withdrawal. Daily PDE5-i may also improve lower tract urinary symptoms related to benign prostatic hyperplasia through a reduction of adrenergic overtone. The relevance for these drugs in the prevention of complications in internal medicine diseases, i.e. cardiovascular disease, clotting disorders and autoimmune disease is uncertain. Finally, endothelial dysfunction is present in testosterone deficiency syndromes and replacement therapy is able to revert ED and to improve endothelial function. Aim of the present review is to discuss the systemic effects of drugs designed to treat ED, such as testosterone and PDE5-i, with regard to safety, unwanted effects and efficacy in improving endothelial function; finally, a goal-oriented approach to rehabilitation using daily vs. on-demand PDE5-i in difficult patients is discussed.
Abstract: Historically, high androgen levels have been linked with an increased risk for coronary artery disease (CAD). However, more recent data suggest that low androgen levels are associated with adverse cardiovascular risk factors, including an atherogenic lipid profile, obesity and insulin resistance. The aim of the present study was to evaluate the relationship between plasma sex hormone levels and presence and degree of CAD in patients undergoing coronary angiography and in matched controls. We evaluated 129 consecutive male patients (mean age 58+/-4 years, range 43-72 years) referred for diagnostic coronary angiography because of symptoms suggestive of CAD, but without acute coronary syndromes or prior diagnosis of hypogonadism. Patients were matched with healthy volunteers. Out of 129 patients, 119 had proven CAD; in particular, 32 of them had one, 63 had two and 24 had three vessel disease, respectively. Patients had significantly lower levels of testosterone than controls (9.8+/-6.5 and 13.5+/-5.4 nmol/l, P<0.01) and higher levels of gonadotrophin (12.0+/-1.5 vs 6.6+/-1.9 IU/l and 7.9+/-2.1 vs 4.4+/-1.4, P<0.01 for follicle-stimulating hormone and luteinizing hormone, respectively). Also, both bioavailable testosterone and plasma oestradiol levels were lower in patients as compared to controls (0.84+/-0.45 vs 1.19+/-0.74 nmol/l, P<0.01 and 10.7+/-1.4 vs 13.3+/-3.5 pg/ml, P<0.05). Hormone levels were compared in cases with one, two or three vessel disease showing significant differences associated with increasing severity of coronary disease. An inverse relationship between the degree of CAD and plasma testosterone levels was found (r=-0.52, P<0.01). In conclusion, patients with CAD have lower testosterone and oestradiol levels than healthy controls. These changes are inversely correlated to the degree of CAD, suggesting that low plasma testosterone may be involved with the increased risk of CAD in men.
Abstract: 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.
Abstract: Sexual potency declines with age, as does the efficiency of erection. Many studies show that different patterns of erectile dysfunction (ED), varying from occasional inability to obtain a full erection, impairment throughout intercourse and total absence of erectile response, might not be triggered by psychological factors only. Recent research indicates that ED relies on organic causes, and has challenged the development of new therapies. One therapeutic approach in patients who have testosterone deficiency is based on androgen therapy. Thus, we reviewed data on testosterone-induced effects relative to erectile function, summarizing the results from studies reported in 1991-2006 on testosterone therapy in patients with ED and hypogonadism, with a special focus on men not responding to phosphodiesterase-5 (PDE-5) inhibitors. We searched several computerized databases parallel with printed bibliographic references. Many studies have established animal models, which confirm that testosterone is important in modulating the central and peripheral regulation of ED. Testosterone deprivation has a strong negative impact on the structure of penile tissues and erectile nerves, which can be prevented by androgen administration. Combined therapy regimens with PDE-5 inhibitors and testosterone might improve ED in patients with hypogonadism of different causes. Thus, androgen treatment in hypogonadic patients, including those unresponsive to PDE-5 inhibitors, often results in an improvement of ED. Testosterone therapy is safe and convenient, while rapidly correcting low testosterone levels.
Abstract: 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.
Abstract: INTRODUCTION: In the era of orally active agents, dynamic penile color-duplex ultrasound (D-PCDU) is not considered a necessary first screening for all patients with erectile dysfunction (ED). Various parameters, such as peak systolic flow velocity, end diastolic velocity, resistance index, acceleration time, and degree of arterial dilatation, have been suggested for the diagnosis of vascular ED by D-PCDU. AIM: To highlight the clinical utility and evidence-based interpretation of D-PCDU criteria. METHODS: Extensive, unsystematic PubMed literature search reviewing relevant data on D-PCDU in the evaluation of male ED. RESULTS: The advantage of ultrasound is the minimally invasive nature of the procedure and the ability to screen patients to identify a normal arterial response of cavernous arteries. Men with sexual dysfunctions above 55 years of age and comorbidities are more likely to have multi-organ vascular dysfunction and may necessitate further testing because erectile failure may be the first presenting symptom requiring investigation and treatment even in the absence of cardiovascular risk factors. All patients affected with Peyronie's disease and younger men with persistent ED, a history of pelvic traumas, or fractures of the penile shaft should be offered ultrasonographic penile blood flow studies before referral to surgery or more invasive vascular investigations. CONCLUSIONS: In the near future, D-PCDU may be used in preference to patients presenting with or without vascular risk factors, particularly those not responding to first-line orally active drugs and seeking an explanation as to why these agents failed.
Abstract: Systemic Sclerosis 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. Moreover men with systemic sclerosis (SSc) present an increased risk of developing erectile dysfunction (ED). Recently, we evaluated the extent of penile vascular damage in sclerodermic patients using Duplex ultrasonography. The aim of this paper is to investigate whether penile thermal differences exist between sclerodermic patients and healthy controls. For this reason 10 men with SSc receiving current treatment for their disease, and 10 healthy controls were enrolled; penile thermal properties were assessed through non-contact thermal imaging (functional Infra Red Imaging fIRI); erectile function was evaluated using the sexual health inventory for men (SHIM) questionnaire. The SHIM results confirmed the presence of ED in sclerodermic patients. Baseline penile temperature in patients (32.1 +/- 1.4 degrees C) was lower than in controls (34.1 +/- 0.9 degrees C). Recovery from cooling test was seen to be faster in healthy controls than in patients, both in terms of recovery amplitude (patients 3.75 +/- 2.09 degrees C, controls 9.80 +/- 2.77 degrees C) and amplitude to time constant ratio (patients 1.21 +/- 0.64 degrees C/min, controls 1.96 +/- 0.48 degrees C/min). These results show that penile thermal abnormalities occur in almost all sclerodermic patients. Non-contact thermal imaging not only identifies thermal alterations but also clearly distinguishes between SSc patients and healthy controls and therefore could represent a valuable instrument in identifying early ED in SSc patients.
Abstract: OBJECTIVE: To investigate the effects of prolonged inhibition of phosphodiesterase type-5, using once-daily long-acting phosphodiesterase type-5 inhibitor (tadalafil) on erectile function and biomarkers of endothelial function in male patients with systemic sclerosis (SSc) and erectile dysfunction (ED). METHODS: In an open-label study, 14 nonconsecutive male patients with SSc with different degrees of ED were enrolled into the study irrespective of their clinical response to tadalafil, and received once-daily tadalafil 10 mg for 12 weeks. Primary endpoints were variations from baseline of penile arterial inflow [peak systolic velocity (PSV, cm/s); measured with dynamic color duplex ultrasound] and the erectile function domain score (measured with the International Index of Erectile Function questionnaire). Secondary endpoints were variations from baseline of morning erections (determined by modified question 13 of the Structured Interview on Erectile Dysfunction questionnaire) and plasma concentrations of endothelin-1 (ET1). RESULTS: The PSV and the erectile function domain score were significantly improved by once-daily tadalafil (from 21.3 +/- 6.4 to 30.0 +/- 7.0 cm/s and from 13.0 +/- 6.8 to 17.0 +/- 9.0 vs baseline, respectively; p <0.05). Question 13 scores decreased dramatically after treatment compared with baseline (from 2.2 +/- 0.2 to 0.8 +/- 0.5 arbitrary units; p < 0.001), and plasma ET1 levels decreased (from 24 +/- 15 to 9.8 +/- 7.4 pg/ml; p < 0.05). CONCLUSION: In men with SSc-related ED, once-daily tadalafil improved both erectile function and vascular measures of cavernous arteries. Increases in morning erections and decreases in plasma ET1 levels were found, which may play a potential role in preventing progression of penile fibrosis and erectile dysfunction.
Abstract: Erectile dysfunction (ED) has multifactor pathogenesis, with neurological, vascular, endocrinological and psychogenic components described. However, about 50-85% of ED population report the presence of one or more comorbidities i.e. hypertension, diabetes, cardiovascular disease, dyslipidemia which all impair endothelial function and, erection is a basically vascular event that necessitates an intact endothelium to occur. Hence, ED may be mostly considered as the clinical manifestation of a disease affecting penile circulation as a part of a generalized vascular disorder due to atherosclerosis. Orally active drugs, i.e. phosphodiesterase type-5 inhibitors (PDE5-i), are a group of on-demand drugs licensed for ED treatment and appear to offer advantages over past therapies in terms of ease of administration and cost, and they are now widely advocated as first-line therapy. The recent discovery that chronic not on-demand administration of these drugs may improve erectile and endothelial response in men previously unresponding to on-demand regimes, opens a new scenario in the treatment of men with ED and comorbidities. Finally, the recent approval of PDE5-i sildenafil for the treatment of pulmonary arterial hypertension represents the new challenge for these class of drugs. Aim of this article will be to provide an update on the pathophysiology of ED and how to use of different available PDE5-i in approaching sexual dysfunctional men, pointing out on their characteristic of efficacy and safety and different indications in special sub-populations.
Abstract: INTRODUCTION: Systemic sclerosis is a connective tissue disease characterized by Raynaud's phenomenon, degenerative changes and vascular lesions in the presence of thickened, sclerotic skin lesions determined by cellular proliferation, and excess of extracellular matrix production. The role of ultrasound in the investigation of penile pathology is well established as vasculogenic impotence accounts for more than 30% out of overall causes. AIM: In this article, we report for the first time the extent of penile vascular damage in a series of 15 sclerodermic patients (mean age 47 +/- 12.5 SD) under current treatment for their disease irrespective of their sexual dysfunction complaints. METHODS: After disease classification (mean duration of disease 7.2 +/- 5.1 years), all patients were interviewed about the presence or absence of erectile dysfunction (ED) by using the Sexual Health Inventory for Men (SHIM) questionnaire, and then blood flow velocity in the cavernous artery following standardized pharmacostimulation was determined with Duplex ultrasonography along with the intima media thickness (IMT) of the common carotid artery, a valid index for atherosclerosis. RESULTS: Mean SHIM scores revealed the presence of moderate-to-severe ED (mean 13.3 +/- 6.3). Interestingly, in all patients diffuse hyperechoic "spots" inside the corpora cavernosa along with thickening of the tunica albuginea were found. Severely impaired mean peak systolic velocities (20.2 +/- 5.5 cm/second) in the presence of mild venous leakage as expressed by mean end diastolic velocities (4.6 +/- 2.9 cm/second) were found along with normal IMT (0.065 +/- 0.010 cm) and acceleration time (92.3 +/- 32.7 cm/second). CONCLUSION: Penile fibrosis almost invariably occurs in sclerodermic patients and this determines incomplete penile arterial and smooth muscle cell relaxation and ED despite the absence of indirect signs of early atherosclerosis, that is, abnormal IMT and acceleration time.
Abstract: INTRODUCTION: It has been reported that lack of sexual activity due to erectile dysfunction (ED) may be associated with testosterone (T) decline. AIM: To investigate whether the known changes in sex hormones associated with resumption of sexual activity are sustained in the long term. MAIN OUTCOME MEASURES: Primary endpoints were variations from baseline of steroid hormones: total T, free T (f T), and estradiol (E). Secondary endpoints were variations of erectile function domain scores at International Index of Erectile Function-5 (IIEF-5). METHODS: In an open-label fashion, 20 patients (mean age 54.8 +/- 8.4 years) received tadalafil 10-20 mg on demand for 12 months. Exclusion criteria were those reported for phosphodiesterase inhibitors, including hypogonadism and hyperprolactinemia. RESULTS: Tadalafil assumption was safe and well tolerated (overall adverse effects in 15% of patients) and none discontinued medication. A significant decrease in E levels occurred at the end of the study (from 19.9 +/- 9.6 to 16.6 +/- 8.1 ng/dL, P = 0.042 vs. baseline), with parallel increase in the T:E ratio (26.3 +/- 15.3 to 32.6 +/- 17.7, P = 0.05), whereas no changes in T and f T serum levels were observed, respectively (411.4 +/- 131.4 to 434.2 +/- 177.1 ng/dL and 47.7 +/- 15.3 to 49.9 +/- 19.1 pmol/L, not significant). Interestingly, nonparametric subgroup analysis for related samples revealed that E decrease was detectable only in lean (N = 14) but not in obese (N = 6, body mass index > 27.5 kg/m2) subjects (17.8 +/- 10.1 vs. 13.5 +/- 6.8, P < 0.05). A net increase in IIEF-5 scores was observed at the endpoint (13.7 +/- 5.9 vs. 25.7 +/- 2.9, P < 0.0001). CONCLUSIONS: Sustained improvement in sexual function after 12 months of tadalafil administration is associated with increased T:E ratio mainly related to reduction of E levels. We hypothesize that androgen-estrogen cross-talk and possible inhibition of aromatase activity during chronic exposure to tadalafil might have a role in the regulation of erectile function.
Abstract: INTRODUCTION: Erectile dysfunction (ED) and decline of testosterone levels are frequently observed with age and also in illnesses with a common basis of endothelial damage. OBJECTIVES: To review molecular mechanisms underlying androgen action upon its receptor and phosphodiesterase type 5 (PDE5) expression and regulation by testosterone in cavernous tissue and their clinical implication in the treatment of ED refractory to PDE5 inhibitors (PDE5-Is). METHODS: From January 2003 to May 2006 [corrected] we performed an extensive, unsystematic MEDLINE literature search reviewing relevant data on basic and clinical studies regarding the efficacy of combination therapies. RESULTS: Most trials using testosterone alone for treatment of ED in hypogonadal men suffer from methodologic problems and report inconsistent results, but overall the trials suggest that testosterone is superior to placebo. Orally effective PDE5-Is, such as sildenafil, tadalafil, or vardenafil, may be ineffective depending on the demonstration of testosterone regulation of PDE5 expression in human corpus cavernous, and their efficacy may be enhanced by testosterone adjunction whenever necessary. CONCLUSIONS: Screening for hypogonadism in all men with ED is necessary to identify men with severe hypogonadism and some cases of mild to moderate hypogonadism, who may benefit from testosterone treatment. Identification of threshold values for testosterone supplementation to appropriately benefit from PDE5-Is failure may improve clinical management of unresponsive patients with minimization of unwanted effects.
Abstract: Hypogonadism may play a significant role in the pathophysiology of erectile dysfunction (ED). A threshold level of testosterone may be necessary for normal erectile function. Testosterone replacement therapy is indicated in hypogonadal patients and is beneficial in patients with ED and hypogonadism. Monotherapy with testosterone for ED is of limited effectiveness and may be most promising in young patients with hypogonadism and without vascular risk factors for ED. A number of laboratory and human studies have shown the combination of testosterone and other ED treatments, such as phosphodiesterase type 5 (PDE5) inhibitors, to be beneficial in patients with ED and hypogonadism, who fail PDE5 inhibitor therapy alone. There is increasing evidence that combination therapy is effective in treating the symptoms of ED in patients for whom treatment failed with testosterone or PDE5 inhibitors alone. Testosterone replacement therapy has potentially evolved from a monotherapy for ED in cases of low testosterone, to a combination therapy with PDE5 inhibitors. Screening for hypogonadism may be useful in men with ED who fail prior PDE5 inhibitors, especially in populations at risk for hypogonadism such as type 2 diabetes and the metabolic syndrome.
Abstract: OBJECTIVES: The role of androgen decline in the sexual activity of adult males is controversial. To clarify whether sexual function would benefit from testosterone (T) treatment in men with partially or severely reduced serum T levels, we conducted a systematic review and meta-analysis of placebo-controlled studies published in the past 30 years. The aim of this study was to assess and compare the effects of T on the different domains of sexual life. DATA SOURCE: A comprehensive search of all published randomized clinical trials was performed in MEDLINE, the Cochrane Library, EMBASE and Current Contents databases. REVIEW METHODS: Guided by prespecified criteria, software-assisted data abstraction and quality assessed by two independent reviewers, a total of 17 randomized placebo-controlled trials were found to be eligible. For each domain of sexual function we calculated the standardized mean difference relative to T and reported the results of pooled estimates of T treatment using the random effect model of meta-analysis. Heterogeneity, reproducibility and consistency of the findings across studies were explored using sensitivity and meta-regression analysis. RESULTS: Overall, 656 subjects were evaluated: 284 were randomized to T, 284 to placebo (P) and 88 treated in cross-over. The median study length was 3 months (range 1-36 months). Our meta-analysis showed that in men with an average T level at baseline below 12 nmol/l, T treatment moderately improved the number of nocturnal erections, sexual thoughts and motivation, number of successful intercourses, scores of erectile function and overall sexual satisfaction, whereas T had no effect on erectile function in eugonadal men compared to placebo. Heterogeneity was explored by grouping studies according to the characteristics of the study population. A cut-off value of 10 nmol/l for the mean T of the study population failed to predict the effect of treatment, whereas the presence of risk factors for vasculogenic erectile dysfunction (ED), comorbidities and shorter evaluation periods were associated with greater treatment effects in the studies performed in hypogonadal, but not in eugonadal, men. Meta-regression analysis showed that the effects of T on erectile function, but not libido, were inversely related to the mean baseline T concentration. The meta-analysis of available studies indicates that T treatment might be useful for improving vasculogenic ED in selected subjects with low or low-normal T levels. The evidence for a beneficial effect of T treatment on erectile function should be tempered with the caveats that the effect tends to decline over time, is progressively smaller with increasing baseline T levels, and long-term safety data are not available. The present meta-analysis highlights the need, and pitfalls, for large-scale, long-term, randomized controlled trials to formally investigate the efficacy of T replacement in symptomatic middle-aged and elderly men with reduced T levels and ED.
Abstract: OBJECTIVE: Erectile dysfunction (ED) is often associated with a cluster of risk factors for coronary artery disease and reduced endothelial function. Acute and chronic administration of oral sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, improves endothelial function in patients with ED. Tadalafil (TAD) is a new PDE5 inhibitor with a long half life that allows alternate day administration. Aim of the study was to evaluate whether chronic therapy (4 weeks) with TAD improves endothelial function in patients with increased cardiovascular risk and whether this effect is sustained after discontinuation of therapy. METHODS: We randomized 32 patients with increased cardiovascular risk to receive either TAD 20 mg on alternate days or matching placebo (PLB) for 4 weeks. Patients underwent evaluation of brachial artery flow-mediated dilation (FMD), nitrite/nitrate and endothelin-1 plasma levels at baseline, at the end of treatment period and after two-weeks follow-up. RESULTS: At 4 weeks, FMD was significantly improved by TAD (from 4.2+/-3.2 to 9.3+/-3.7%, p<0.01 vs. baseline), but was not modified by PLB (from 4.1+/-2.8 to 4.0+/-3.4%, p=NS). At 6 weeks the benefit in FMD was sustained in patients that received TAD (9.1+/-3.9% vs. 4.2+/-3.2%, p=0.01 vs. baseline; 9.1+/-3.9% vs. 9.3+/-3.7%, vs. 4 weeks, p=NS) while no changes in FMD were observed in patients randomized to PLB. Also, compared to baseline, a net increase in nitrite/nitrate levels (38.2+/-12.3 vs. 52.6+/-11.7 and 51.1+/-3.1, p<0.05) and a decrease in endothelin-1 levels (3.3+/-0.9 vs. 2.9.+/-0.7 and 2.9+/-0.9, p<0.05) was found both at four and six-weeks after TAD; these changes were inversely correlated as shown by regression analysis (adjusted R2=0.81, p<0.0001). CONCLUSIONS: Chronic therapy with TAD improves endothelial function in patients with increased cardiovascular risk regardless their degree of ED. The benefit of this therapy is sustained for at least two weeks after the discontinuation of therapy. Larger studies are needed in order to assess the possible clinical implications of chronic therapy with TAD.
Abstract: In the last few years, the clinical context of the diagnosis and treatment of erectile dysfunction (ED) has changed radically. In fact, oral drug treatment with phosphodiesterase type-5 inhibitors (PDE5-i), licensed in the past years, appeared to offer advantages over other medical approaches in terms of ease of administration and cost. PDE5-i are now widely advocated as first-line therapy for ED. PDE5-i represent a class of orally active drugs for ED, which inhibit PDE5 enzyme and in turn enhance smooth muscle relaxation via prolongation of cyclic GMP action within the cavernous smooth muscle. Although the various types of PDE5-i differ with respect to selectivity and pharmacokinetic profiles, efficacy and safety of these agents are mostly comparable in broad populations of men with erectile ED, including those with diabetes, cardiovascular disease or those taking multiple antihypertensive agents. Aim of this article will be to review the different efficacy and safety profiles of oral short-acting compounds and to give indication for treatment of special populations of men with ED.
Abstract: 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.
Abstract: Erectile dysfunction (ED) has been defined by the National Institute of Health (NIH) as the inability to achieve and/or to maintain an erection for a sufficiently long period of time so as to permit satisfactory sexual intercourse. ED affects millions of men throughout the world and could have a negative influence on the individual's well-being as well as on the quality of life of affected subjects. Discordant data have been reported on ED epidemiology with prevalence ranging from 12% to 52%, probably depending on the different criteria utilized in the different studies for patient selection. ED is a symptom, sometimes the first, of different pathological conditions. In 15.7% of 45-yr-old patients with vascular ED a dynamic ergometric test has shown electrocardiographic alterations in the absence of any cardiac symptom. In 15% of the patients with ED, high fasting glucose plasma levels are discovered for the first time and in patients with ED and normal fasting glucose plasma levels the prevalence of undiagnosed diabetes mellitus is 12.1% after an oral glucose tolerance test (OGTT). The different risk factors are often additive in the possible development of systemic vasculopathy, neuropathy and ED. ED, underestimated in clinical practice due to archaic prejudice which hinders the patient in spontaneously revealing the problem and the physicians in investigating it, can mark the point where evaluation and prevention of important diseases (such as diabetes, arterial hypertension, atherosclerosis) hitherto unknown by the patients, can begin. The physicians' cultural baggage must include the ability to identify the pathology that can determine ED and the ability to program a specific diagnostic workup. In this paper the different specialists involved in ED diagnosis agreed that a clinical approach which allows the identification of systemic pathologies contributing to the development of ED constitutes an improvement in disease prognosis and may either induce a spontaneous reduction of ED or facilitate its specific treatment.
Abstract: The role of testosterone on sexual desire is well established. However, the effects of low testosterone levels in the pathophysiology of erectile mechanism in humans remains unclear. Recent evidence indicate that approximately 10-20% of men with erectile dysfunction (ED) have hormonal abnormalities, raising up to 35% over the age of sixty. It is now clear that sexual desire and erectile function in humans are both responsive to androgens, probably at different threshold values. In fact, different degrees of testosterone deficiency may determine a sequence of molecular penile events leading to reduced capacity of penile smooth muscle and endothelial cells of relaxation, without greatly affecting sexual desire. Also, androgens may directly control the expression and activity of phosphodiesterase type-5 in human corpus cavernosum. In some selected men with total testosterone below 10-13nmol/l and/or free testosterone below 200-250pmol/l, androgen supplementation may improve therapeutic efficacy of phosphodiesterase type-5 inhibitors. For ageing men with partial androgen deficiency (PADAM) who fail first-line oral treatments in whom androgens are not contraindicated, a combination of testosterone and phosphodiesterase type-5 inhibitors may be considered to improve erectile function and improve the quality of life.
Abstract: By real-time RT-PCR and Western blot analysis, we found that phosphodiesterase type 5 (PDE5) mRNA and protein abundance was several fold higher in human male than in female reproductive tracts. The highest mRNA level (>1 x 10(7) molecules/microg total RNA) was detected in human corpora cavernosa (CC), where PDE5 protein was immunolocalized in both muscular and endothelial compartment. The possible role of androgens in regulating PDE5 expression was studied using a previously established rabbit model of hypogonadotropic hypogonadism. In this model, hypogonadism reduced, and testosterone (T) supplementation restored, CC PDE5 gene and protein expression. In addition, T supplementation completely rescued and even enhanced cyclic GMP conversion to metabolites, without changing IC(50) for sildenafil (IC(50) = 2.16 +/- 0.62 nm). In control CC strips, sildenafil dose-dependently increased relaxation induced by electrical field stimulation, with EC(50) = 3.42 +/- 1.7 nm. Hypogonadism reduced, and T increased, sildenafil effect on electrical field stimulation, again without changing their relative EC(50) values. CC sensitivity to the NO-donor NCX4040 was greater in hypogonadal rabbit strips than in control or T-treated counterparts. Moreover, sildenafil enhanced NCX4040 effect in eugonadal rabbit strips but not in hypogonadal ones. This suggests that androgens up-regulate PDE5 in rabbit penis. We also measured PDE5 gene expression and metabolic activity in human CC from male-to-female transsexual individuals, chronically treated with estrogens and cyproterone acetate. Comparing the observed values vs. eugonadal controls, PDE5 mRNA, protein, and functional activity were significantly reduced. In conclusion, we demonstrated, for the first time, that androgens positively regulate PDE5, thus providing a possible explanation about the highest abundance of this enzyme in male genital tract.
Abstract: In the last few years the pathophysiological mechanisms of erection have been partially clarified, and the molecular machinery of the cellular components of the corpus cavernosum (CC) has been widely investigated. Since erection is a vascular event and the penis is a vascular organ, there must be an intact endothelium for an erection to occur. The regulation of penile tumescence inside the CC involves a balance between contracting and relaxing factors which regulate the functional state of smooth muscle cells. Recent studies have highlighted the importance of new local factors (i.e. phosphodiesterases, rho-kinases and endothelins), and pharmacological agents are available in the armamentarium of the specialist which are targeted to modulate the function of those mediators of erection. It is now well understood that male erectile dysfunction (ED) is a symptom rather than a disease; for this reason in the near future both general practitioners and specialists in internal medicine would have to interplay with sexual medicine. This review is intended to give the clinician some basic concepts of the pathophysiology of erection with relevance to the clinical practice, and to discuss the newest therapeutic approaches for those patients who do not respond to the treatment with oral inhibitors of phosphodiesterase Type 5.
Abstract: The aim of the study was to analyse the socio-demographic and epidemiological characteristics of the Italian male population affected by sexual disturbances. Men complaining of erectile dysfunction (ED) who called the Pfizer program "Man and Woman in Health" between April 18th 2001 and May 27th 2002 and asked for information about their medical condition, were interviewed by trained doctors using a computer-assisted questionnaire. 16007 out of 25018 calls were considered for statistical analysis. Mean age of callers was 48.8+/-14.2 yr, reporting ED in 83% of cases. In the majority of men ED was severe (58%) and lasting more than 3 yr (25%). Multivariate analysis revealed that diabetes, depression, prostate surgery, heart disease, neurological disorders, liver and renal diseases were all significant and independent contributors to the degree of erectile impairment adjusted for age (p<0.001). The principal concomitant medications were anti-hypertensive (23%), antidiabetic (9%) and cardiovascular agents (6%). Cigarette smoking was present in 24%. On directed questioning of the caller, anxiety and distress were perceived as the most frequent causes of ED (42%) across all age groups, followed by the presence of concomitant disease/s (26%) especially in aging men. Also, a large number of men (41 %) with severe ED waited for more than 3 yr before looking for medical referral. Interestingly, only 19% had ever tried any specific medication for ED. These data indicate that 5 yr after worldwide approval and release of sildenafil, ED is still largely undiagnosed and under-treated, possibly because it is still perceived as a condition mainly due to distress or advancing age and therefore not deserving medical referral. Effective prevention of ED commences with better awareness of the pathological causes by the population and modification of risk factors by the doctors.
Abstract: Erectile dysfunction (ED) is defined as the inability to achieve and maintain a penile erection which is adequate for satisfactory sexual intercourse. It is a significant male health problem affecting approximately 150 million men worldwide. This value is expected to more than double by the year 2025. The incidence of ED increases sharply with age since it is a common cross-cultural denominator, affecting 19 to 64% of men aged 40 to 80 years, both in developing and industrialized countries. Epidemiological studies may underestimate the true dimensions of the problem because of the embarrassment or stigma that is associated with ED. Men with ED may experience diminished self-image and self-esteem, anxiety and fears of rejection, and even depression as psychogenic factors. Pathologic conditions which are commonly encountered in the ageing male (diabetes, hypertension, atherosclerosis, cardiovascular disease, etc) as well as chronic diseases (arthritis, renal and hepatic failure, pulmonary disease) represent a frequent cause of organic ED and are often treated with medications that can interfere with sexual function at central and/or peripheral level. In addition, incorrect lifestyle--i.e. obesity, cigarette smoking, alcohol or drug abuse--may all contribute to the onset of ED. Finally, trauma or surgery affecting either the nervous system or interfering with the blood supply to the penis are associated with increased incidence of ED.
Abstract: OBJECTIVES: We have recently shown that, in men with erectile dysfunction (ED), free testosterone (FT) directly correlates with penile arterial inflow. This led us to further investigate the effect(s) of androgen administration on cavernous arteries in patients failing sildenafil treatment. DESIGN: Prospective randomized placebo-controlled pilot study. PATIENTS: Twenty patients with arteriogenic ED as evaluated by dynamic colour duplex ultrasound (D-CDU) studies, normal sexual desire but testosterone (T) and FT in the lower quartile of normal range (low-normal), not responding to sildenafil treatment (100 mg) on six consecutive attempts. MEASUREMENTS: All patients had D-CDU, hormonal [LH, prostate-specific antigen (PSA), total and free testosterone, sex hormone-binding protein (SHBG), oestradiol], biochemical [haematocrit, low-density lipoprotein (LDL) and HDL cholesterol, triglycerides], and sexual evaluations [International Index of Erectile Function (IIEF)] before and after 1 month of therapy with transdermal testosterone (5 mg/day, n = 10) or placebo along with sildenafil treatment on demand. Measurement of flow parameters by D-CDU on cavernous arteries was the primary endpoint of the study. Improvement of erectile function was assessed using the IIEF questionnaire and the Global Assessment Question (GAQ). RESULTS: One month treatment with transdermal testosterone led to a significant increase in T and FT levels (23.7 +/- 3.3 SD vs. 12.8 +/- 2.1 nmol/l and 473 +/- 40.2 vs. 260 +/- 18.1 pmol/l, P < 0.01, respectively). In addition testosterone administration induced a significant increase in arterial inflow to cavernous arteries measured by D-CDU (32 +/- 3.6 vs. 25.2 +/- 4 cm/s, P < 0.05), with no adverse effects. Also, a significant improvement in erectile function domain score at IIEF was found in the androgen but not in the placebo-treated patients (21.8 +/- 2.1 vs. 14.4 +/- 1.4, P < 0.05) which was associated with significant changes in the GAQ score (80%vs. 10%, P < 0.01). CONCLUSIONS: In patients with arteriogenic ED and low-normal androgen levels, short-term testosterone administration increases T and FT levels and improves the erectile response to sildenafil likely by increasing arterial inflow to the penis during sexual stimulation.
Abstract: In the era of orally active agents the clinical context of the diagnosis and treatment of erectile dysfunction (ED) has radically changed. There is a general trend oriented towards choosing invasive diagnostic testing and surgical treatment solutions. Along this view, penile pharmacotesting (PPT) may represent an inexpensive and easy diagnostic procedure to be performed in the office setting. However, this procedure provides no direct vascular imaging, has a high percentage of false diagnoses and its accuracy for subsequent treatment decisions remains quite limited. Hence, home testing with orally active agents may provide better information for the patient's goals. In the diagnostic work-up of ED, the combination of PPT plus colour-duplex Doppler ultrasonography (CDDU) has gained more credit because of a higher diagnostic accuracy than PPT alone, so that it should be always performed when possible. It represents an accurate mean to predict cavernous artery inflow and venous leakage when compared to more invasive diagnostic techniques; in fact it allows the measurement of the resistive index when maximal response to vasodilator challenge has occurred. In conclusion, we recommend CDDU to all ED patients with a significant risk of cardiovascular disease, as well as in the presence of penile plaques whereas a frequent involvement of neuro-anatomical structures occurs. Other vascular testing--i.e. natural penile tumescence, cavernosometry/graphy, angiography are reserved to selected patients in whom CDDU alone has provided inconsistent information.
Abstract: Penile pharmacotesting (PPT) with alprostadil (PGE1) represents the most common diagnostic approach to male erectile dysfunction (ED). A positive response - i.e. normal erectile rigidity of sustained duration - is presumed to exclude venous or arterial pathology with enough accuracy. To test this assumption we compared PPT vs. flowmetric results obtained by colour-duplex Doppler ultrasound (CDDU) in patients (pts) undergoing diagnostic evaluation for ED under conditions of maximal cavernous relaxation. A total of 195 non-consecutive impotent pts were diagnosed after dynamic CDDU as non-vasculogenic (NOR), or having arteriogenic (AR), veno-occlusive (VO) or mixed (MX) ED. Maximal erection obtained after PPT was scored as: type-1 (full tumescence - no sustained rigidity, angle on the abdominal plane >90 degrees), type-2 (sustained partial erection, valid for intromission, angle=90 degrees) and type-3 (sustained full erection, angle <90 degrees). Comparing PPT with flowmetric results, we found that a type-3 response had 20% false negative diagnosis of NOR (17% of AR- and 3% of VO- and MX-ED, respectively), while a type-2 response had 63% false negative diagnosis (20% of AR, 37% of VO- and 6% MX-ED, respectively). Type-1 response was associated with the presence of VO dysfunction in 99% of cases. These data suggest that a positive response to PPT (type-2 and type-3) assessed by the visual rating of erection is associated with both arterial (up to 20%) and/or VO (up to 43%) ED, as detected by CDDU. We conclude that PPT alone is a misleading diagnostic test to exclude vascular ED and that dynamic CDDU should be offered to pts investigated for male ED.
Abstract: Platelet-derived growth factor (PDGF) overactivity has been implicated in atherosclerosis and several fibrotic conditions including lung and kidney fibrosis, liver cirrhosis and myelofibrosis. Low oxygen tension (hypoxia) is a known stimulus for transcriptional induction of PDGF ligand and receptor genes in different tissues. We studied the expression and localization of PDGF-A, PDGF-B, and PDGF receptor (PDGFR)-alpha and -beta subunits in adult rat isolated corpus cavernosum (CC) under generalized transient hypoxia (pO(2) 10%) in comparison with normoxic conditions. Semi-quantitative RT-PCR analysis of mRNA extracted from rat penis showed higher amounts of PDGF-A, PDGF-B and PDGFR-beta mRNA transcripts in hypoxic versus normoxic animals. The immunohistochemical analysis showed that the localization of PDGF subunits and PDGFR-beta was confined to the cytoplasm of the perivascular smooth muscle cells, endothelium and trabecular fibroblasts. Our findings indicate that transient low oxygen tension induces PDGF overexpression in rat CC, which in the long term may lead to an increase of connective tissue production. We suggest that a local impairment of the PDGF/PDGFR system may contribute to CC fibrosis, which is an established cause of erectile dysfunction in man.
Abstract: In mammals, the function of the reproductive system is dependent on the availability of energy in the environment. It is well established that acute modifications of energy balance modulate the hypothalamic-pituitary-gonadal axis. In several species, fasting and caloric restriction have been shown to cause the suppression of pulsatile luteinizing hormone secretion, via an inhibition of the gonadotropin-releasing hormone pulse generator. Such a mechanism probably prevents energy being wasted for reproduction. By contrast, excessive energy storage and obesity interfere with the correct regulation of the reproductive axis. The identification of leptin and leptin receptors, along with studies performed in animal models of leptin deficiency and resistance, has focused attention on the role of this molecule in reproduction, and disclosed new aspects of the relationship between energy stores, adipose tissue and reproductive function. Here, we discuss the central and peripheral effects of leptin on reproductive tissues, and try to fit a complex reality into a simplified model. In particular, the roles of leptin in reproduction at different anatomical levels and in various clinical and experimental settings are discussed.
Abstract: Erectile dysfunction (ED) is a highly prevalent disorder affecting an estimated 152 million men worldwide and is associated with a variety of behavioral risk factors, such as cigarette smoking and excessive alcohol consumption, as well as numerous age-related medical conditions, notably type-2 diabetes mellitus and cardiovascular disease. A rational step-wise approach which includes comprehensive medical and sexual history, a focused physical examination and essential laboratory tests such as fasting glucose, lipid profile and testosterone assay is to be preferred. Current diagnostic work-up does not recommend any of the specialized tests which were previously considered mandatory-i. e. penile pharmacotesting, Duplex ultrasound and nocturnal penile tumescence. Hormonal replacement therapy is appropriate only in the hypogonadal male with ED. Prior to direct intervention, the physician should consider altering modifiable risk factors or causes, although frequently insufficient to reverse ED completely. When indicated, oral therapy with new molecules (phosphodiesterase inhibitors or apomorphine) is the first-line treatment for the majority of patients because of potential benefits and lack of invasiveness.
Abstract: Sildenafil is a specific inhibitor of phosphodiesterase (PDE) type 5 and represents a powerful therapy for male erectile dysfunction (ED) of different aetiology. Recently, sildenafil has been shown to restore erections in temporary ED related to the need of semen collection for assisted reproductive techniques. In this study, we investigated whether sildenafil administration modifies seminal parameters and/or erectile function in normal healthy volunteers. In a double-blind, randomized, placebo-controlled, cross-over two period investigation we enrolled 20 healthy male volunteers (mean +/- SE age 32 +/- 0.5 years). Subjects were not using any medication for the 3 month period prior to the study and were engaged in a stable relationship with proven fertility. The effects of sildenafil (100 mg) on seminal parameters and erectile function after audiovisual sexual stimulation were evaluated by semen analysis and by colour-Duplex ultrasound (the Resistive Index) respectively. In all subjects, sildenafil caused no changes in seminal and erection parameters when compared to placebo. Interestingly, sildenafil administration led to a marked reduction of the post-ejaculatory refractory time (10.8 +/- 0.9 min versus 2.6 +/- 0.7 min for placebo and sildenafil respectively; P < 0.0001). These results indicate that in normal subjects acute sildenafil treatment does not modify semen characteristics and has a positive influence over the resumption of erections following ejaculation in the presence of a continuous erotic stimulus.
Abstract: Aging is associated with changes in plasma levels of several hormones. There are conflicting reports on whether circulating leptin levels change during aging, the possible explanation for which is that alterations in adiposity and body mass index (BMI) also occur. In this study we measured plasma leptin and other hormonal parameters known to influence leptin in 150 men and 320 women of a wide age (18-77 yr) and BMI (18.5-61.1 kg/m2) range. Subjects of each gender were separated into 2 groups of similar BMI, i.e. nonobese (BMI, <30) and obese (BMI, >30), and treated separately. Statistical analysis was performed, treating each group of subjects as a whole population or divided into age groups (<30, 30-50, and >50 yr). BMI-adjusted leptin levels were progressively lower with increasing age in women, with a consistent fall after menopause (-21%; P < 0.001); in men, leptin levels also tended to be lower in subjects more than 50 yr of age, but the reduction was not significant. Multiple linear regression analysis, performed on subjects treated either as a whole population or divided into obese and nonobese, showed that in both genders BMI and age were independent contributors of leptin levels, and there was an inverse relationship between leptin and age in both obese (standardized coefficient beta = -0.25 in women and -0.23 in men; P < 0.01) and nonobese (-0.22 in women and -0.20 in men; P < 0.05) subjects. The correlation of leptin and age with plasma levels of sex and thyroid hormones, GH, insulin-like growth factor I, PRL, and insulin was also evaluated. The variables that correlated with leptin were included in a multiple regression model that included BMI and age. Testosterone in men (-0.43 in nonobese and -0.19 in obese; P < 0.05) and estradiol in women (0.22 in nonobese and 0.24 in obese; P < 0.05) were important contributors to leptin levels; also, dehydroepiandrosterone sulfate in obese women (-0.16) and sex hormone-binding globulin in obese subjects of both genders (0.15 in women and 0.19 in men) were significant determinants in the model. However, none of the hormonal parameters abolished the negative correlation between leptin and age or the gender difference in leptin levels. In conclusion, our data show that in adult humans of different body weight, serum leptin gradually declines during aging; leptin reduction is higher in women than in men, but it is independent from BMI and other age-related endocrine changes.
Abstract: OBJECTIVE: Androgens are essential in the maintenance of nitric oxide-mediated erectile activity in the rat. The objective of the present study was to investigate the role of androgens in regulating trabecular smooth muscle relaxation in the corpus cavernosum in response to vasoactive challenge in men with erectile dysfunction (ED). DESIGN: Retrospective, double-blind correlation analyses. PATIENTS: Fifty-two impotent patients without confounding risk factors for ED were obtained from a total of 250 undergoing diagnostic evaluation. MEASUREMENTS: All patients had dynamic colour duplex ultrasound (D-CDU) and hormonal evaluation for LH, total and free testosterone, SHBG and oestradiol. RESULTS: Based upon D-CDU results patients were diagnosed as having arteriogenic (AR, n = 18; mean age 51) or corporeal venocclusive (CVO, n = 13; mean age 49) ED; in other patients (n = 21, mean age 43) a diagnosis of psychogenic (P)-ED was made by comprehensive psychogenic testing and confirmed by normal D-CDU results. AR and CVO patients had altered compliance of cavernous arteries recorded by D-CDU [20-25% lower resistive index (RI) than patients with psychogenic ED], and lower free testosterone (FT) levels than psychogenic patients [42.3 +/-3.5 SE and 49.3+/-5.2 vs. 75.2+/-7.6 pmol/l, respectively; P<0.01]. More important, in all patients there was a strong direct correlation between resistive index values and FT levels (r = 0.47, P = 0.002); the relationship was maintained also when adjusted for age, SHBG and oestradiol (r = 0.37, P = 0.02). CONCLUSIONS: These results indicate that in men with erectile dysfunction low free testosterone may correlate independently of age with the impaired relaxation of cavernous endothelial and corporeal smooth muscle cells to a vasoactive challenge. These findings give clinical support to the experimental knowledge of the importance of androgens in regulating smooth muscle function in the penis.
Abstract: During penile pharmacotesting, anxiety may overcome complete smooth muscle relaxation and lead to false positive diagnosis of organic male erectile dysfunction (ED). We tested the efficacy and safety of re-dosing of PGE1 alone versus combination of PGE, and the alpha1,2-blocker phentolamine (PHE) to improve an incomplete pharmaco-induced erection during color-power-Doppler (CPD) sonography. 116 consecutive impotent patients were submitted to CPD and injected with 10 microg PGE, plus audiovisual sexual stimulation. Clinical evaluation of rigidity and CPD parameters were normal in 26 patients while in the remaining they were upgraded in 15% and 35% after redosing of 10 microg PGE1 alone and 10 microg PGE1 plus 1 mg PHE, respectively (P < 0.05); furthermore, in these latter patients CPD studies showed increased visualisation of distal ramifications of helicine arterioles. The final diagnosis was changed in those patients who responded to re-dosing with no differences in the occurrence of prolonged erections between the two treatments. We conclude that re-dosing of PGE1/PHE mixture is a safe and effective procedure to maximize erectile response during dynamic CPD sonography and has a better diagnostic sensitivity than re-dosing of PGE1 alone.
Abstract: Erectile dysfunction (ED) is the persistent inability to achieve or maintain an erection sufficient for satisfactory sexual performance. The disorder is age-associated, with estimated prevalence rates of 39% among men 40 years old and 67% among those 70 years old. ED is a common (2 to 3 million males in Italy) and multifactorial disease due to organic and/or psychological factors that strongly impair the quality of life in man. During the last decade many advances in the understanding of the pathophysiology of ED have been made and new therapeutic strategies have become available. It has been established that an insufficient production of nitric oxide by penile nerve terminals and/or vascular endothelium may result in an impaired erection or complete impotence. Nowadays, intracavernous injection of vasoactive drugs represents a standardised approach for the diagnosis and a treatment option for ED, but is not widely accepted by the patients. The possibility of treating ED with new oral agents (i.e. sildenafil, apomorphine, phentolamine) or intraurethral administration of prostaglandin-E1 made this therapy more acceptable. Vacuum erection devices and penile prostheses represent second-line treatments. Men with ED caused by endocrine disorders (i.e. hypogonadism, prolactinomas) should be treated appropriately (i.e. testosterone and dopaminergic agonists, respectively). Amongst new drugs, sildenafil is considered the most promising: it is a potent inhibitor of type-5 phosphodiesterase in the corpus cavernosum and therefore increases the penile response to sexual stimulation. Oral sildenafil (25-100 mg when needed) is an effective and well-tolerated treatment in impotent men suffering from ED of unknown etiology.
Abstract: Excess upper-body (android) fat is considered an health hazard. Exercise training is known to have the potential to modify body composition and to induce a preferential loss of abdominal fat. We studied and compared the composition of whole body and major body regions using dual-energy X-ray absorptiometry (DEXA) in 21 exercising (3-4 hours of intense physical activity/day) and 21 sedentary eumenorrhoic women of similar ages, body mass index (BMI), waist-to-hip ratio (WHR) and age of menarche. In a small number of women in each group (6 out of 21), the ACTH and cortisol response to CRH test and the 24-h urinary cortisol excretion was evaluated. Exercising women had 10% higher total and leg lean mass (p<0.05), and 38% lower total fat mass (p<0.01) than sedentary women. Furthermore, the proportion of android fat was 22% lower in exercising than sedentary women (p<0.01), while the proportion of lower-body (gynoid fat) was unchanged. BMI and WHR were not different between the two groups, while the android/gynoid fat ratios were 16% lower in exercising than in sedentary women (p<0.01). In the exercising women, ACTH and cortisol plasma levels, as well as the 24-h urinary cortisol excretion, were significantly (p<0.01) higher than in the sedentary women studied. In these subjects, a direct relationship between the peak delta percentage increases of ACTH and cortisol after the CRH test and the proportion of android fat was found (r=0.60, p<0.05 and r=0.69, p<0.02, respectively). These results demonstrate that in women who practise intense exercise there are significant differences in body fat distribution in comparison to sedentary women, with a marked less amount of android fat, and suggest that this difference may be related to a reduced response of the pituitary-adrenal axis to CRH.
Abstract: INTRODUCTION: We investigated the diagnostic accuracy of dynamic color Doppler sonography (D-CDS) in men with erectile dysfunctions (ED). Terminal microcirculation alterations and their correlation with erectile response after drug testing were investigated with power Doppler energy. MATERIAL AND METHODS: 134 impotent patients were submitted to CDS during flaccidity: 8 of them (6%) had sparse hyperechoic spots inside the corpora. A standardized intracavernous injection of 10 micrograms alprostadil (PGE1) was followed by audiovisual sexual stimulation. If rigid erection was not achieved after 20 minutes, patients were randomized to redosing of either 10 micrograms PGE1 (phase 2a) or 10 micrograms PGE1 plus 1 mg phentolamine (phase 2b), with reassessment of power Doppler recordings after 20 minutes (peak systolic velocities and the resistive index, RI). RESULTS: A rigid erection (RI > .90) was achieved in 26% of patients after the first injection. As for the remaining patients, the RI was improved in 12% after phase 2a and in 34% after phase 2b (p < .05), with no differences in mean peak systolic velocities. Power Doppler showed two/three orders of distal branches of helicine arterioles with regular morphology, in most of the latter subjects. A negative correlation (r = .68, p < .001) was found between penile fibrosis and the degree of rigidity achieved after the first injection. CONCLUSIONS: Penile sonography in the flaccid state can show calcificic plaques and/or fibrosis of the corpora. Redosing of PGE1 plus phentolamine during D-CDS is a safe procedure and improves diagnostic accuracy in erectile dysfunctions, with significantly fewer non-responders than redosing of PGE1 alone. Power Doppler energy shows altered morphology of helicine arterioles otherwise missed at color Doppler and is thus recommended to make an accurate diagnosis in some men with erectile dysfunctions.
Abstract: The understanding of pharmacology of impotence has shown a steady improvement over the last 15 years which has resulted in a better appreciation of the neurovascular mechanisms of the erectile process especially at the level of the corpora cavernosa; however, central mechanisms which control libido and erection are not yet completely elucidated. Frequent diseases most commonly encountered in elderly patients--i.e. diabetes, hypertension, atherosclerosis, depression, etc--represent a frequent cause of erectile dysfunction (ED) and are treated with medications that can interfere with sexual functioning at the central and/or peripheral level. Antidepressants, including the tricyclics and the monoamine oxidase inhibitors, have been implicated in ED, decreased libido, and impaired ejaculation. Most antihypertensives have been associated with some erectile impairment, but diuretics seem to have little effect on erectile function. The calcium channel blockers and ACE inhibitors are associated with a low incidence of ED. Sympatholytic antihypertensives seldom cause importence but can cause retrograde ejaculation because of the relaxation of the smooth muscles in the prostatic urethra and bladder neck. The most commonly prescription drugs that can affect sexual function are briefly discussed and an integrated pharmacological approach to the patient with drug-induced ED is proposed.
Abstract: Adrenoleukodystrophy/adrenomyeloneuropathy (ALD/AMN) is a group of genetically determined peroxisomal disorders associated with progressive central demyelination, primary adrenal cortical insufficiency (Addison's disease) and, frequently, primary hypogonadism. Recently, testicular dysfunction was described in ALD/AMN patients but no information on sperm characteristics was provided. In this paper we studied the reproductive function of a patient with adult cerebral ALD, focusing our attention on sperm characteristics. At the time of diagnosis the patient was 22 years old, had high plasma C26 and C24 very-long-chain fatty acid (VLCFA) concentrations and adrenal insufficiency. Plasma testosterone concentration was in the normal range. The patient was prescribed a low-fat diet and 'Lorenzo's oil', which led to normalization of plasma VLCFA concentrations within 3 months of therapy. Semen analysis showed normal sperm count, gross morphological alterations and reduced motility. Electron microscopy analysis of sperm cells showed pathological changes in the head, the plasma membrane and the nucleus in 60% of the spermatozoa examined. However, isolated motile spermatozoa showed normal molecular dynamics of phospholipid bilayer surface and physiological responsiveness to progesterone. At the 12 months follow-up, the patient became azoospermic and testicular histology showed arrested maturation. To our knowledge, this is the first description of sperm alterations in a post-pubertal ALD patient, in which severe impairment of spermatogenesis and rapid progression to azoospermia occurred despite normalization of plasma VLCFA concentrations.
Abstract: Erectile dysfunction is a common (affecting 10-20 million men in the USA) and multifactorial disease due to organic and/or psychological factors that strongly impairs the quality of life in man. During the past decade many advances in the understanding of the pathophysiology of erectile dysfunction have been made and new therapeutic strategies have become available. It has been established that an insufficient production of nitric oxide by penile nerve terminals and/or vascular endothelium may result in an impaired erection or complete impotence. Nowadays, intracavernous injection of vasoactive drugs represents a standardized approach for the diagnosis, and the treatment of choice, for erectile dysfunction, but is not widely accepted by the patients. The possibility of treating erectile dysfunction with intraurethral administration of prostaglandin-E1 has recently become available in the USA, and is a therapy more acceptable to the patients. Other noninvasive medical therapies are undergoing evaluation.
Abstract: Much evidence suggests the fundamental role of the Y chromosome during spermatogenesis. Especially, a gene on the long arm (localized in a portion of the chromosome called Yq11), the AZF (azoospermic factor), is necessary for the achievement and the maintenance of the spermatogenetic process. In fact mutations and deletions in this part of the chromosome inevitably cause severe oligozoospermia or azoospermia. Furthermore other genes on the short arm seem to have a role during spermatogenesis: they are called ZFY (zink finger Y, which encodes a DNA binding protein) and TSPY (expressed in the spermatids nuclei); but the function of these genes is still uncertain, since at this moment no deletions or mutations have been found at this level. Further genes only recently cloned include the CREM (cAMP-responsive element modulator), whose mutation causes azoospermia with a spermatidic arrest in the mouse, and the complex c-kit/Steel-factor. The latter is essential for spermatogonial proliferation and differentiation, so that an alteration at this level can determine spermatogonial arrest or the absence of germinal cells with the presence of Sertoli cells only (Sertoli cells only syndrome). In contrast with AZF, both the CREM gene and c-kit/Steel-factor genes are autosomal (chromosome 10 for the CREM, 4 for c-kit, 1 for Steel-factor, respectively). Several genes may be involved in the spermatogenetic process, but their role, excepting for AZF, is still unclear.
Abstract: Intracavernous injection (ICI) of prostaglandin-E1 (PGE1) is used widely as the first diagnostic test in the study of erectile dysfunction. However, a lack of full erection after a maximal dose is frequent. As well as vascular incompetence, this may be due to stress-induced changes, related to the ICI procedure. The aim of this study was to investigate the influence of emotional disturbances on erectile response to ICI in impotent patients. Initially, 24 young men with non-organic impotence (age 34.6 +/- 1.5 years; mean +/- SEM) were selected and randomized single-blind to pharmacoerection with PGE1 alone (20 micrograms/mL) or a mixture (cocktail) containing 20 micrograms PGE1 plus an alpha-adrenergic receptor blocker, phentolamine (Phe, 0.5 mg/mL). Additional studies were also performed double-blind on 10 men with non-organic impotence (age 37.6 +/- 1.2 years) utilizing higher PGE1 dosages for ICI (25 micrograms/mL alone or in combination with Phe, 0.5 mg/mL). After a 7-day interval, all subjects were crossed-over to receive the alternative treatment. The presence of emotional disturbances was assessed in all patients by the administration of rapid tests (Stai-X1 and Stai-X1r for state-anxiety before and after ICI, respectively; Stai-X2 for trait-anxiety; Zung-test for depression) at the first and at the remaining (Stai-X1 and Stai-X1r) ICI sessions. ICI with 20 and 25 micrograms/mL PGE1 led to a comparable percentage of patients who reported a valid-for-intromission (VFI) erection (63 and 60%, respectively). In contrast, use of the cocktails significantly increased the percentage of subjects with a VFI (87 and 90% of the total number of patients tested, respectively; p < 0.05). Moreover, a strong inverse correlation between state-anxiety scores (Stai-X1) and the erectile response to ICI with 20 and 25 micrograms PGE1 was found (r = -0.69, p < 0.001); such a correlation was not present in patients who underwent ICI with the cocktails. Two cases of prolonged erection occurred (one after 20 micrograms PGE1 and the other after 20 micrograms PGE1 plus Phe) which were reversed promptly by the intracavernous injection of metharaminol. It is concluded that the lack of a full erectile response after ICI with PGE1 can be related to the presence of a high 'state-anxiety' in the patients. In such patients, a VFI erectile response can be induced by the administration of a cocktail test-dose.
Abstract: Hyperprolactinaemic patients are characterized by an altered psychological profile, positively modified by the administration of dopaminergic drugs. This would suggest that the same neurochemical disorder is responsible for both hyperprolactinaemia and abnormal psychological profile in these patients. To identify depression, anxiety, and aggressiveness, nine women affected by prolactin (PRL)-secreting pituitary adenomas were studied before and after 6 and 12 mo of bromocriptine therapy, by the use of different psychometric tests (Mean Minnesota Multiphasic Personality Inventory [MMPI], State-Trait Anxiety Inventory [STAI], and State and Trait Aggressiveness Scale [STAS]). As a group, the patients did not show any depressive, anxious, or aggressive tendencies. Furthermore, no significant modifications were observed during dopaminergic treatment. Patients bearing PRL adenomas seem to be characterized by a dopaminergic background different from that found in functional hyperprolactinaemia. This hypothesis could explain the different psychological configuration and behavior in response to the administration of dopaminergic compounds.
