Linda Vignozzi

A systematic review and meta-analysis on the use of phosphodiesterase 5 inhibitors alone or in combination with α-blockers for lower urinary tract symptoms due to benign prostatic hyperplasia

CONTEXT Several randomized controlled trials (RCTs) on phosphodiesterase type 5 inhibitors (PDE5-Is) have showed significant improvements in both lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) in men affected by one or both conditions, without a significant increase in adverse events. However, the results are inconsistent. OBJECTIVE Perform a systematic review and meta-analysis of available prospective and cross-sectional studies on the use of PDE5-Is alone or in combination with α1-adrenergic blockers in patients with LUTS/benign prostatic hyperplasia (BPH). EVIDENCE ACQUISITION A systematic search was performed using the Medline, Embase, and Cochrane Library databases through September 2011 including the combination of the following terms: LUTS, BPH, PDE5-Is, sildenafil, tadalafil, vardenafil, udenafil, α-blockers, and α1-adrenergic blocker. The meta-analysis was conducted according to the guidelines for observational studies in epidemiology. EVIDENCE SYNTHESIS Of 107 retrieved articles, 12 were included in the present meta-analysis: 7 on PDE5-Is versus placebo, with 3214 men, and 5 on the combination of PDE5-Is with α1-adrenergic blockers versus α1-adrenergic blockers alone, with 216 men. Median follow-up of all RCTs was 12 wk. Combining the results of those trials, the use of PDE5-Is alone was associated with a significant improvement of the International Index of Erectile Function (IIEF) score (+5.5; p<0.0001) and International Prostate Symptom Score (IPSS) (-2.8; p<0.0001) but not the maximum flow rate (Q(max)) (-0.00; p=not significant) at the end of the study as compared with placebo. The association of PDE5-Is and α1-adrenergic blockers improved the IIEF score (+3.6; p<0.0001), IPSS score (-1.8; p = 0.05), and Q(max) (+1.5; p<0.0001) at the end of the study as compared with α-blockers alone. CONCLUSIONS The meta-analysis of the available cross-sectional data suggests that PDE5-Is can significantly improve LUTS and erectile function in men with BPH. PDE5-Is seem to be a promising treatment option for patients with LUTS secondary to BPH with or without ED.

Testosterone Partially Ameliorates Metabolic Profile and Erectile Responsiveness to PDE5 Inhibitors in an Animal Model of Male Metabolic Syndrome

INTRODUCTION Metabolic syndrome (MetS) is a clustering of cardio-metabolic risk factors (hyperglycemia, hypertension, dyslipidemia, visceral fat accumulation) that is also associated with hypogonadism and erectile dysfunction (ED). AIM To clarify the relationships among MetS, hypogonadism, and ED, we developed an animal model of MetS. METHODS Male rabbits fed a high-fat diet (HFD), with or without testosterone (T) supplementation, were compared with control rabbits (fed a standard chow) and with rabbits made hypogonadal by a single injection of a long-acting GnRH-analog, triptorelin. MAIN OUTCOME MEASURES Evaluation of metabolic disturbances (plasma glucose, cholesterol, triglycerides, testosterone, LH, FSH level, glucose tolerance, mean arterial pressure, visceral fat accumulation), and corpora cavernosa (CC) relaxant capacity (in vitro contractility study) in HFD animals as compared with control, GnRH analog-treated rabbits, and T-supplemented HFD rabbits. RESULTS HFD rabbits showed all the features of MetS. HFD induced hypogonadotropic hypogonadism is characterized by a reduction of plasma T, FSH, LH levels, testis and seminal vesicles weight, and testicular steroidogenic enzymes. Such a phenotype is similar to that induced by triptorelin administration. A reduced GnRH immunopositivity in hypothalamus suggests a central origin of HFD-related hypogonadism. HFD also induced penile alterations, as demonstrated by a reduction of acetylcholine-and electrical field stimulation-induced CC relaxation, hyper-responsiveness to the NO donor, SNP, and unresponsiveness to PDE5 inhibitors. Similar penile alterations were observed in triptorelin treated rabbit. In HFD, as well as in triptorelin treated rabbits, PDE5 and eNOS mRNA expression quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) were significantly decreased. T administration prevented almost all penile alterations observed in HFD rabbits. T treatment dramatically reduced HFD-induced visceral obesity, partially ameliorating also the metabolic profile. CONCLUSION We have developed an animal model of MetS associated with hypogonadotropic hypogonadism and penile alterations including unresponsiveness to PDE5 inhibitors. T supplementation was able to partially revert HFD-induced phenotype.

Testosterone protects from metabolic syndrome-associated prostate inflammation: an experimental study in rabbit.

Metabolic syndrome (MetS) and benign prostatic hyperplasia (BPH)/lower urinary tract symptoms (LUTS) are often associated. One of their common denominators is hypogonadism. However, testosterone supplementation is limited by concerns for potential prostatic side effects. The objective was to determine whether MetS-associated prostate alterations are prevented by testosterone supplementation. We used a previously described animal model of MetS, obtained by feeding male rabbits a high-fat diet (HFD) for 12 weeks. Subsets of HFD rabbits were treated with testosterone or with the farnesoid X receptor agonist INT-747. Rabbits fed a standard diet were used as controls. HFD-animals develop hypogonadism and all the MetS features: hyperglycemia, glucose intolerance, dyslipidemia, hypertension, and visceral obesity. In addition, HFD-animals show a prostate inflammation. Immunohistochemical analysis demonstrated that HFD-induced prostate fibrosis, hypoxia, and inflammation. The mRNA expression of several proinflammatory (IL8, IL6, IL1β, and TNFα), T lymphocyte (CD4, CD8, Tbet, Gata3, and ROR γt), macrophage (TLR2, TLR4, and STAMP2), neutrophil (lactoferrin), inflammation (COX2 and RAGE), and fibrosis/myofibroblast activation (TGFβ, SM22α, αSMA, RhoA, and ROCK1/ROCK2) markers was significantly increased in HFD prostate. Testosterone, as well as INT-747, treatment prevented some MetS features, although only testosterone normalized all the HFD-induced prostate alterations. Interestingly, the ratio between testosterone and estradiol plasma level retains a significant, negative, association with all the fibrosis and the majority of inflammatory markers analyzed. These data highlight that testosterone protects rabbit prostate from MetS-induced prostatic hypoxia, fibrosis, and inflammation, which can play a role toward the development/progression of BPH/LUTS.

Testosterone, cardiovascular disease and the metabolic syndrome

Recent evidence suggests that low, rather than high, testosterone (T) is associated with increased male morbidity and mortality. We reviewed relationships between hypogonadism, metabolic syndrome (MetS) and cardiovascular (CV) disease (CVD), along with erectile dysfunction (ED), a common condition in the three diseases. Although several experimental data indicate that T exerts a protective effect on vascular function, epidemiological studies do not support a link between hypogonadism and CVD and three meta-analyses found no significant effect of testosterone replacement therapy (TRT) on CV events. Low T is associated with increased risk of CV death in community-dwelling men, and in men with ED. It is possible that both low T and CVD are associated with another, still unknown (or not assessed) factor, thus explaining the association, in the absence of any causal relationship. A meta-analysis on the effect of TRT in MetS-associated hypogonadism demonstrated positive effects of T on some of the components of MetS. Large-scale interventional studies with TRT are therefore advisable.

Hypogonadism and metabolic syndrome

Background: The relationship between metabolic syndrome (MetS), male hypogonadism and their possible interaction in cardiovascular (CV) risk stratification are not completely understood. Aim: We reviewed relationships between testosterone (T) and MetS emphasizing their possible interaction in the pathogenesis of CV diseases. Materials and methods: A systematic search of published evidence was performed using Medline (1969 to January 2011). Results: Cross-sectional data have shown that subjects with MetS have lower levels of total T (TT) (about 3 nmol/l), as hypogonadism is more evident in subjects with than in those without erectile dysfunction (ED) than in those without. Longitudinal evidence shows that low T is allocated with a higher risk of subsequent development of MetS, although the reverse condition is also possible. Which are the factors in MetS responsible for the low T is not completely clarified. In clinical studies, increased waist circumference is the major determinant of MetS-associated hypogonadism. Our experiments in rabbits do not support the idea that visceral fat is the main determinant of MetS-associated male hypogonadism. Only few randomized clinical trials have evaluated the impact of T replacement therapy (TRT) in patients with MetS. Available evidence suggests that TRT decreases visceral fat accumulation and ameliorates insulin sensitivity, whereas androgen deprivation increases abdominal adiposity. Conclusions: The clinical significance of the MetS-associated hypogonadism needs further clarifications. In particular, it has not been completely clarified if low T might be considered a cause or a consequence of MetS. The benefit of TRT in term of the reduction of CV risk needs to be confirmed in larger and longer studies.

Phosphodiesterase Type 5 Expression in Human and Rat Lower Urinary Tract Tissues and the Effect of Tadalafil on Prostate Gland Oxygenation in Spontaneously Hypertensive Rats

INTRODUCTION In humans, prostate phosphodiesterase type 5 inhibitors (PDE5) expression was prominently localized in the endothelial and smooth muscle cells of the vascular bed, suggesting a possible action of PDE5 inhibitors (PDE5i) on prostate blood flow. AIM To investigate PDE5 expression in human and rat lower urinary tract (LUT) tissues, including vasculature, and determine the effects of PDE5 inhibition with tadalafil on prostatic blood perfusion. MAIN OUTCOME MEASURES Human vesicular-deferential arteries (which originate from the inferior vesical artery, the main arterial source of blood supply to the bladder and prostate) were analyzed for PDE5 expression and activity. The effects of tadalafil on prostate oxygenation were studied in spontaneously hypertensive rats (SHR), characterized by ischemia/hypoxia of the genitourinary tract. METHODS PDE5 expression was evaluated by quantitative reverse transcription-polymerase chain reaction and immunohistochemistry. SHR were treated with tadalafil (2 mg/kg/day) for 1, 7, or 28 days and compared with untreated SHR and the unaffected counterpart Wistar-Kyoto (WKY) rats. Prostate oxygenation was detected by Hypoxyprobe-1 and hypoxia markers (hypoxia-inducible factor-1α[HIF-1α] and endothelin-1 type B [ETB]) immunostaining. RESULTS Human vesicular-deferential artery expressed high levels of PDE5, similar to corpora cavernosa, immunolocalized in the endothelial and smooth muscle layer. In these arteries, tadalafil inhibited cyclic guanosine monophosphate breakdown (half maximal inhibitory concentration (IC(50) ) in the low nanomolar range, as in corpora cavernosa) and increased the relaxant response to sodium nitroprusside. SHR prostate resulted markedly hypoxic (hypoxyprobe immunopositivity) and positive for HIF-1α and ETB, while tadalafil treatment restored oxygenation to WKY level at each time point. The mRNA expression of the HIF-1α target gene, BCL2/adenovirus E1B 19 kDa interacting protein 3, was significantly increased in SHR prostate and partially restored to WKY level by tadalafil. CONCLUSION Human vesicular-deferential artery is characterized by a high expression and activity of PDE5, which was inhibited by tadalafil in vitro. In SHR, tadalafil increases prostate tissue oxygenation, thus suggesting a possible mechanism through which PDE5i exert beneficial effects on LUT symptoms.

Characterization of Phosphodiesterase Type 5 Expression and Functional Activity in the Human Male Lower Urinary Tract

INTRODUCTION Phosphodiesterase type 5 (PDE5) inhibitors ameliorate low urinary tract (LUT) symptoms in men with ED and symptomatic benign prostatic hyperplasia (BPH). PDE5 is highly expressed in rat and human bladder, where it regulates cyclic guanosine monophosphate (cGMP) degradation, muscle tone, and proliferation. AIM To investigate PDE5 tissue distribution and activity in human LUT tissues (urethra, prostate, and bladder). MAIN OUTCOME MEASURES PDE5 expression and activity were analyzed and compared within the same BPH patient in LUT tissues and in smooth muscle cells (SMCs) cultured from urethra, prostate, and bladder. METHODS In LUT tissues, PDE5 was localized by immunohistochemistry and mRNA expression by quantitative real-time polymerase chain reaction. Proliferation assay was used as readout of PDE5 activity, evaluated as ability of vardenafil to increase the antiproliferative effect of different nitric oxide (NO)/cGMP pathway activators [the PDE5-resistant cGMP analog Sp-8-Br-PET-cGMPS, the NO donor sodium nitroprusside (SNP), and the soluble guanylate cyclase (sGC) stimulator BAY 41-8543]. RESULTS In all the LUT tissues, PDE5 was immunolocalized in blood vessels and in muscular fibres, but not in epithelium. PDE5 mRNA expression was higher in urethra and bladder than in prostate SMC. The antiproliferative effect of Sp-8-Br-PET-cGMPS was similar in all LUT SMC. In prostatic SMC, SNP and BAY 41-8543 show a dose-dependent antiproliferative effect that resulted marginally enhanced by vardenafil. Conversely, in urethra and bladder SMC the antiproliferative effect of SNP and BAY 41-8543 was lower than in prostatic SMC, but it was significantly enhanced by vardenafil. In urethral and bladder cells vardenafil half-maximal response inhibiting concentration was in the subnanomolar range, whereas in prostate cells it resulted significantly higher. CONCLUSIONS The highest expression and biological activity of PDE5 was found in bladder. However, a consistent PDE5 expression and activity was also found in prostatic urethra. In contrast, the prostate gland showed the lowest PDE5 abundance and cultures derived from this tissue were less sensitive to vardenafil.

ORIGINAL RESEARCH—OUTCOMES ASSESSMENT Development and Validation of a 6-Item Version of the Female Sexual Function Index (FSFI) as a Diagnostic Tool for Female Sexual Dysfunction

INTRODUCTION A limiting step in the evaluation of female sexual dysfunction (FSD) is the availability of a rapid screening procedure. Often, practitioners avoid investigating sexual symptoms due to concerns of insufficient time or lack of proper tools to address FSD. AIM The purpose of this study was to prepare and validate an abridged form of the most popular psychometric diagnostic test (Female Sexual Function Index, FSFI-19) to provide a fast screener of FSD for easy use in outpatient visits, epidemiological studies, and assessment of treatment response. METHODS We interviewed and administered the FSFI-19 to 200 women attending outpatient clinics for sexual and reproductive medicine. Forty women were excluded because they had no sexual activity or failed to attend the retest visit. Patients were evaluated on two subsequent visits to validate the abridged form of the questionnaire. Overall, 105 were found to suffer from a FSD. MAIN OUTCOME MEASURE We assessed, individually, the sensibility and sensitivity of all questions of the full-length FSFI. We then estimated the performance of each item with respect to the specific sexual domain they address. By selecting the best combination of performing items in each domain, we built an abridged, 6-item form of the FSFI. RESULTS The Receiver Operating Characteristic curves of the FSFI-6 showed that women who scored <or=19 were classified as having FSD. Using the cut-off of 19, the sensitivity and specificity of the test were, 0.93 and 0.94, respectively. Reliability, internal consistency, and stability on retest were also good. CONCLUSIONS The abridged FSFI-6 is a valuable tool for screening women that are likely to suffer from FSD. In six simple questions, taking no more than 3 minutes, a score of less than 19 indicates the need for further investigations, including the full-length FSFI-19 and a dedicated interview. In conclusion, this is a novel tool that can help any doctor to disclose FSD rapidly and efficiently.

Metabolic syndrome and lower urinary tract symptoms: the role of inflammation.

Background:Epidemiological data indicate that lower urinary tract symptoms (LUTS)/BPH can be associated with metabolic syndrome (MetS). Chronic inflammation has been proposed as a candidate mechanism at the crossroad between these two clinical entities.Aim of study is to examine the correlation among pre-operatory LUTS/BPH severity, MetS features and inflammatory infiltrates in prostatectomy specimens.Methods:A total of 271 consecutive men treated with simple prostatectomy were retrospectively selected for this study in two tertiary referral centers for LUTS/BPH. Prostate diameters and volume were measured by transrectal ultrasound, LUTS scored by International Prostate Symptom Score (IPSS) and obstruction by uroflowmetry. The International Diabetes Federation and American Heart Association and the National Heart, Lung and Blood Institute was used to define MetS. The inflammatory infiltrate was investigated combining anatomic location, grade and extent of flogosis into the overall inflammatory score (IS); the glandular disruption (GD) was used as a further marker.Results:Eighty-six (31.7%) men were affected by MetS. Prostatic volume and anterior-posterior (AP) diameter were positively associated to the number of MetS components. Among MetS determinants, only dyslipidaemia (increased serum triglycerides and reduced serum high-density lipoprotein) was associated with an increased risk of having a prostatic volume >60 cm3 (hazard ratio (HR)=3.268, P<0.001). A significant positive correlation between the presence of MetS and the IS was observed. MetS patients presented lower uroflowmetric parameters as compared with those without MetS (Maximum flow rate (Qmax): 8.6 vs 10.1, P=0.008 and average flow rate (Qave): 4.6 vs 5.3, P=0.033, respectively), and higher obstructive urinary symptoms score (P=0.064). A positive correlation among both IS–GD and IPSS Score was also observed (adjusted r=0.172, P=0.008 and adjusted r=0.128, P=0.050).Conclusions:MetS is associated with prostate volume, prostatic AP diameter and intraprostatic IS. The significantly positive association between MetS and prostatic AP diameter could support the observation that MetS patients presented lower uroflowmetric parameters. In conclusion, MetS can be regarded as a new determinant of prostate inflammation and BPH progression.

The hormonal control of ejaculation

Hormones regulate all aspects of male reproduction, from sperm production to sexual drive. Although emerging evidence from animal models and small clinical studies in humans clearly point to a role for several hormones in controlling the ejaculatory process, the exact endocrine mechanisms are unclear. Evidence shows that oxytocin is actively involved in regulating orgasm and ejaculation via peripheral, central and spinal mechanisms. Associations between delayed and premature ejaculation with hypothyroidism and hyperthyroidism, respectively, have also been extensively documented. Some models suggest that glucocorticoids are involved in the regulation of the ejaculatory reflex, but corresponding data from human studies are scant. Oestrogens regulate epididymal motility, whereas testosterone can affect the central and peripheral aspects of the ejaculatory process. Overall, the data of the endocrine system in regulating the ejaculatory reflex suggest that widely available endocrine therapies might be effective in treating sexual disorders in these men. Indeed, substantial evidence has documented that treatments of thyroid diseases are able to improve some ejaculatory difficulties.