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Introduction In subjects with erectile dysfunction responding poorly to sildenafil, metformin was reported to improve erections. Aims The aim of this study is to investigate metformin's mechanism of action on erectile function, particularly focusing on adenosine ( ADO) and nitric oxide ( NO) signaling in an animal model of high-fat diet ( HFD)-induced metabolic syndrome. Methods In vitro contractility studies of penile strips. Penile expression of genes related to ADO or NO signaling was also evaluated. Main Outcome Measure In vitro contractility studies were used to investigate the effect of in vivo and ex vivo metformin administration on ADO- or acetylcholine ( Ach)-induced relaxation of penile strips from HFD as compared with animals fed a regular diet ( RD). Results Expression of ADO receptor type 3 ( A3R), ADO deaminase ( ADA), AMP deaminase type 1 ( AMPD1), and 2 ( AMPD2) was decreased in HFD as compared with RD. Accordingly, in HFD the ADO relaxant effect was potentiated as compared with RD ( P < 0.02). In vivo metformin treatment in both RD and HFD significantly increased the ADO relaxing effect ( P < 0.0001 and P < 0.01, respectively, vs. relative untreated groups) although to a different extent. In fact, the half-maximal inhibitory concentration ( IC50)/ IC50 ratio in RD increased fourfold vs. HFD ( RD IC50 ratio = 13.75 ± 2.96; HFD IC50 ratio = 2.85 ± 0.52). In corpora cavernosa ( CC) from HFD, in vivo metformin (i) normalized A3R, ADA, and AMPD1; (ii) further decreased AMPD2; (iii) increased dimethylarginine dimethylamino-hydrolase; and (iv) partially restored impaired Ach-induced relaxation. Ex vivo metformin time and dose dependently increased the relaxant effect of ADO in RD. The potentiating effect of metformin on ADO-induced relaxation was significantly reduced by preincubation with NO synthase inhibitor Nω-Nitro-L-arginine methyl ester hydrochloride ( L-NAME). Interestingly, in vivo testosterone supplementation in HFD rabbits (i) increased penile expression of endothelial NO synthase and AMPD2 and (ii) restored metformin's potentiating effect on ADO-induced relaxation up to RD level. Conclusion Metformin in vivo and ex vivo increases ADO signaling in CC, most probably interfering with NO formation and ADO breakdown. Vignozzi L, Filippi S, Comeglio P, Cellai I, Morelli A, Rastrelli G, Maneschi E, Mannucci E, and Maggi M. Metformin in vitro and in vivo increases adenosine signaling in rabbit corpora cavernosa. J Sex Med 2014;11:1694-1708. [ABSTRACT FROM AUTHOR]

Erectile dysfunction (ED) is a frequent complication of obesity. The aim of this review is to critically analyze the framework of obesity and ED, dissecting the connections between the two pathological entities. Current clinical evidence shows that obesity, and in particular central obesity, is associated with both arteriogenic ED and reduced testosterone (T) levels. It is conceivable that obesity-associated hypogonadism and increased cardiovascular risk might partially justify the higher prevalence of ED in overweight and obese individuals. Conversely, the psychological disturbances related to obesity do not seem to play a major role in the pathogenesis of obesity-related ED. However, both clinical and preclinical data show that the association between ED and visceral fat accumulation is independent from known obesity-associated comorbidities. Therefore, how visceral fat could impair penile microcirculation still remains unknown. This point is particularly relevant since central obesity in ED subjects categorizes individuals at high cardiovascular risk, especially in the youngest ones. The presence of ED in obese subjects might help healthcare professionals in convincing them to initiate a virtuous cycle, where the correction of sexual dysfunction will be the reward for improved lifestyle behavior. Unsatisfying sexual activity represents a meaningful, straightforward motivation for consulting healthcare professionals, who, in turn, should take advantage of the opportunity to encourage obese patients to treat, besides ED, the underlying unfavorable conditions, thus not only restoring erectile function, but also overall health. [ABSTRACT FROM AUTHOR]

Highlights: [•] Steatohepatitis (NASH) develops in a rabbit model of metabolic syndrome (MetS). [•] NASH is tightly associated to increased blood TNFα and erectile dysfunction (ED). [•] Liver TNFα is the major determinant of erectile dysfunction. [•] Testosterone or OCA dosing reduce liver and blood TNFα levels and normalize ED. [•] We propose NASH as an active player in MetS-induced erectile dysfunction. [ABSTRACT FROM AUTHOR]

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. Filippi S, Vignozzi L, Morelli A, Chavalmane AK, Sarchielli E, Fibbi B, Saad F, Sandner P, Ruggiano P, Vannelli GB, Mannucci E, and Maggi M. Testosterone partially ameliorates metabolic profile and erectile responsiveness to PDE5 Inhibitors in an animal model of male metabolic syndrome. J Sex Med 2009;6:3274–3288. [ABSTRACT FROM AUTHOR]

Introduction. Phosphodiesterase type 5 inhibitors (PDE5i), the most widely used drugs for erectile dysfunction, could also improve lower urinary tract symptoms, essentially due to overactive bladder (OAB), a condition hypothesized to be a result of an increased RhoA/Rho-kinase (ROCK) signaling. Phosphorylation/inactivation of RhoA by cyclic guanosine monophosphate (cGMP)-dependent protein kinase (PKG) activity has been described in vascular smooth muscle. Aim. The aim of this paper was to investigate whether vardenafil-induced cGMP accumulation reduces RhoA/ROCK signaling in bladder. Methods. Spontaneously hypertensive rats (SHRs), a strain genetically prone to develop OAB, were treated with vardenafil (10 mg/kg/day) for 2 weeks. Wistar-Kyoto rats (WKY) were used as control. In vitro experiments were performed in human bladder smooth muscle cells (hBCs). Main Outcome Measures. Urodynamic parameters were registered in vivo in anesthetized WKY and SHRs. RhoA/ROCK activity in bladder was evaluated by molecular and functional studies in tissues and cells. Results. The intercontraction interval and bladder capacity, and were decreased in SHRs and restored by vardenafil. The in vitro relaxant effect of the ROCK inhibitor Y-27632 was higher in bladder strips from SHR than from WKY and reduced by vardenafil. Nω-nitro-L-arginine-methyl-ester (a NO-synthase inhibitor, 40 mg/kg/day during the last week of the 2-week treatment with vardenafil) partially antagonized vardenafil effect on Y-27632 responsiveness. Vardenafil prevented RhoA membrane translocation/activation, decreased ROCK activity, and increased cGMP levels in vivo (rat) and in vitro (hBCs). Exposing hBCs to vardenafil increased Ser188 RhoA phosphorylation, to the same extent as the PDE5-insensitive PKG agonist Sp-8-Br-PET-cGMP. Moreover, vardenafil inhibited several RhoA-dependent functions in hBCs, including smooth muscle gene transcription and endothelin-1-induced migration. These effects were reverted by the PKG inhibitor KT 5823, further suggesting a cGMP/PKG-dependency. In hBCs, vardenafil was active in the low nanomolar range. Conclusions. This is the first study demonstrating that the effect of vardenafil on OAB could be partially determined by a cGMP-dependent RhoA/ROCK signaling inhibition. Morelli A, Filippi S, Sandner P, Fibbi B, Chavalmane AK, Silvestrini E, Sarchielli E, Vignozzi L, Gacci M, Carini M, Vannelli GB, and Maggi M. Vardenafil modulates bladder contractility through cGMP-mediated inhibition of RhoA/Rho kinase signaling pathway in spontaneously hypertensive rats. J Sex Med 2009;6:1594–1608. [ABSTRACT FROM AUTHOR]

Background. Most men following radical retropubic prostatectomy (RRP) are afflicted by erectile dysfunction (ED). RRP-related ED occurs as a result of surgically elicited neuropraxia, leading to histological changes in the penis, including collagenization of smooth muscle and endothelial damage. Aim. To verify whether hypogonadism could contribute to the pathogenesis of RRP-ED. Methods. Effects of testosterone (T), alone or in association with long-term tadalafil (Tad) treatment in a rat model of bilateral cavernous neurotomy (BCN). Main Outcome Measures. Penile tissues from rats were harvested for vasoreactivity studies 3 months post-BCN. Penile oxygenation was evaluated by hypoxyprobe immunostaining. Phosphodiesterase type 5 (PDE5), endothelial nitric oxide synthase (eNOS), and neuronal nitric oxide synthase (nNOS) mRNA expression were quantified by Real Time quantitative reverse transcription polymerase chain reaction (qRT-PCR). Results. In BCN rats, we observed the onset of an overt condition of hypogonadism, characterized by reduced T plasma level, reduced ventral prostate weight, reduced testis function (including testis weight and number of Leydig cells), with an inadequate compensatory increase of luteinizing hormone. BCN induced massive penile hypoxia, decreased muscle/fiber ratio, nNOS, eNOS, PDE5 expression, increased sensitivity to the nitric oxide donor, sodium nitroprusside (SNP), and reduced the relaxant response to acetylcholine (Ach), as well as unresponsiveness to acute Tad dosing. In BCN rats, chronic Tad-administration normalizes penile oxygenation, smooth muscle loss, PDE5 expression, SNP sensitivity, and the responsiveness to the acute Tad administration. Chronic Tad treatment was ineffective in counteracting the reduction of nNOS and eNOS expression, along with Ach responsiveness. T supplementation, in combination with Tad, reverted some of the aforementioned alterations, restoring smooth muscle content, eNOS expression, as well as the relaxant response of penile strips to Ach, but not nNOS expression. Conclusion. BCN was associated with hypogonadism, probably of central origin. T supplementation in hypogonadal BCN rats ameliorates some aspects of BCN-induced ED, including collagenization of penile smooth muscle and endothelial dysfunction, except surgically induced altered nNOS expression. Vignozzi L, Filippi S, Morelli A, Marini M, Chavalmane A, Fibbi B, Silvestrini E, Mancina R, Carini M, Vannelli GB, Forti G, and Maggi M. Cavernous neurotomy in the rat is associated with the onset of an overt condition of hypogonadism. J Sex Med 2009;6:1270–1283. [ABSTRACT FROM AUTHOR]

Background. Numerous men develop postprostatectomy erectile dysfunction (PPED), due to surgery-related nervous damage. PPED is often refractory to phosphodiesterase type 5 (PDE5) inhibitors therapy. Aim. To verify whether chronic tadalafil (CT) preserves bilateral cavernous neurotomy (BCN)-induced penile damage and hypo-oxygenation. Methods. In a rat model of BCN we evaluated in vitro and ex vivo effect of CT treatment (2 mg/kg, daily for 3 months). Results. Bilateral cavernous neurotomy induced massive hypoxia and decreased muscle/fiber ratio, completely restored by CT. Hypersensitivity of hypoxic tissues to the relaxant effect of the endothelin type B receptor (ETB) agonist IRL-1620 was observed, along with ETB mRNA and protein overexpression. CT restored sensitivity to IRL-1620, and normalized ETB expression. Hypoxic penis showed increased sensitivity to the relaxant effect of the nitric oxide donor sodium nitroprusside (SNP), while acute tadalafil (100 nM) did not amplify the SNP effect. Accordingly, PDE5 mRNA and protein were reduced in BCN penile tissues. By restoring PDE5, CT decreased SNP-induced relaxation and rescued sensitivity to acute tadalafil. However, in hypoxic penis, CT normalizes neither acetylcholine hyporesponsiveness nor neuronal nitric oxide synthase-endothelial nitric oxide synthase expression. Conclusion. Chronic tadalafil restores some of the investigated BCN-induced alterations, including PDE5 and tadalafil efficacy. Vignozzi L, Filippi S, Morelli A, Ambrosini S, Luconi M, Vannelli GB, Donati S, Crescioli C, Zhang X-H, Mirone V, Forti G, and Maggi M. Effect of chronic tadalafil administration on penile hypoxia induced by cavernous neurotomy in the rat. J Sex Med 2006;3:419–431. [ABSTRACT FROM AUTHOR]

Introduction. Hypogonadism is often associated with diabetes and both conditions represent major risk factors for erectile dysfunction (ED). Aim. To investigate the role of hypogonadism on phosphodiesterase type 5 (PDE5) expression and sildenafil responsiveness in diabetes. Methods. Two different models of experimental diabetes were used: (i) alloxan-induced diabetic rabbit; and (ii) streptozotocin (STZ)-induced diabetic rat. In both experimental models, animals were separated into three groups: control, diabetic, diabetic supplemented with testosterone (T) enanthate. Rabbits were used for “in vitro” experiments. Conversely, each rats group was further subdivided: no further treatment or acute sildenafil dosing (25 mg/kg, 1 hour before “in vivo” electrical stimulation [ES]). Main Outcome Measure. Erectile capacity was evaluated either by “in vitro” contractility study (alloxan-induced diabetic rabbit) and “in vivo” evaluation of erectile response elicited by ES of cavernous nerve (STZ-induced diabetic rats). Also endothelial nitric oxide synthase, neural nitric oxide synthase (nNOS), and PDE5 protein (Western blot) and mRNA (quantitative real-time reverse transcriptase polymerase chain reaction [RT-PCR]) expression were measured in rat penile samples of each group. Results. In both models, hypogonadism was observed, characterized by reduced T and atrophy of androgen-dependent accessory glands. T substitution completely reverted hypogonadism and diabetes-induced penile hyposensitivity to “in vitro” (acetylcholine, rabbit) or “in vivo” (ES, rat) relaxant stimuli, along with nNOS expression, which was reduced ( P < 0.05) in STZ rats. In diabetic animals, T substitution reinstated sildenafil-induced enhancement of both “in vitro” nitric oxide donor (NCX 4040) relaxant effect (rabbit) and “in vivo” ES-induced erection (rat). PDE5 was reduced in diabetic STZ rats ( P < 0.05) and normalized by T. In STZ rats, sodium nitroprusside (SNP) intracavernous injection induced a more sustained erection than in control rats, which was no further enhanced by sildenafil. T substitution normalized both hyper-responsiveness to SNP and sildenafil efficacy. Conclusion. In two models of diabetes T deficiency underlies biochemical alterations leading to ED. Normalizing T in diabetes restores nNOS and PDE5, and reinstates sensitivity to relaxant stimuli and responsiveness to sildenafil. Zhang X-H, Filippi S, Morelli A, Vignozzi L, Luconi M, Donati S, Forti G, and Maggi M. Testosterone restores diabetes-induced erectile dysfunction and sildenafil responsiveness in two distinct animal models of chemical diabetes. J Sex Med 2006;3:253–266. [ABSTRACT FROM AUTHOR]

The farnesoid X receptor (FXR) is critically involved in the regulation of the hepato-biliary system. Recent data suggest a role for FXR in modulating other metabolic pathways and vascular function. To investigate whether long-term administration of the selective FXR agonist INT-747 ameliorates erectile function, we tested it in two animal models of metabolic derangements: a rabbit model of high-fat diet (HFD)-induced metabolic syndrome (MetS) and a rat model of streptozotocin (STZ)-induced type 1 diabetes. HFD rabbit or STZ rats with or without chronic INT-747 dosing (10 mg/kg/day for 12 weeks). INT-747 addition to rabbit penile smooth muscle cells (rpSMCs). Effects of INT-747 on metabolic features and erectile function in animal models and clarification of mechanism of action in isolated cells. INT-747 dosing normalized visceral adiposity and glucose intolerance in HFD rabbits. INT-747 increased penile FXR expression and partially restored endothelial nitric oxide synthase and dimethylarginine dimethylaminohydrolase 1 expression as well as impaired nitric oxide (NO)-dependent relaxation (improved responsiveness to acetylcholine and electrical field stimulation). INT-747 was also effective in regulating NO downstream events, as shown by increased sodium nitroprusside-induced relaxation. Because phosphodiesterase type 5 and protein kinase G (PKG) were unaltered by INT-747, we analyzed the calcium-sensitizing RhoA/ROCK pathway. HFD increased, and INT-747 normalized, RhoA membrane translocation/activation. RhoA/ROCK signaling inhibition by INT-747 was confirmed in rpSMCs by confocal microscopy, MYPT1-phosphorylation, cytoskeleton remodeling, cell migration, and smooth muscle-related genes expression. In STZ rats, FXR penile expression was not altered but was significantly upregulated by INT-747 dosing. In this model, INT-747 improved penile erection induced by electrical stimulation of cavernous nerve and hypersensitivity to intracavernous injection of a ROCK-inhibitor, Y-27632, without improving hyperglycemia. In HFD rabbits, INT-747 dosing improved glucose sensitivity and MetS-associated erectile dysfunction, via upregulation of NO transmission and inhibition of RhoA/ROCK pathway. In STZ rats, INT-747 restored in vivo penile erection and sensitivity to ROCK inhibition, independently of effects on glycemia. [ABSTRACT FROM AUTHOR]

Introduction. One of the proposed mechanisms responsible for diabetes-related erectile dysfunction (ED) is overactivity of RhoA/ROCK signaling, as seen in experimental models of chemical diabetes. Aim. Because statins may interfere with RhoA/Rho-kinase (ROCK) signaling through the reduction of geranyl-geranyl pyrophosphate (GGPP), required for RhoA activation, we investigated whether atorvastatin ameliorated diabetes-related ED. Methods. Streptozotocin-induced (8 weeks) diabetic rats and alloxan-induced (8 weeks) diabetic rabbits received atorvastatin (5 mg/kg daily) for the last 2 weeks. In vitro contractility studies were conducted in the rabbit model. In the rat model, sildenafil effect on electrical stimulation (ES)-induced erection was investigated. Atorvastatin action was also analyzed using human fetal penile smooth muscle cells (hfPSMCs) exposed to low (5 mM), high (22 mM), and very high (40 mM) glucose. Main Outcome Measures. Atorvastatin effect on hyperglicemia-induced RhoA/ROCK signaling was evaluated using the ROCK inhibitor Y-27632 in both animal models and by analyzing functional effects downstream to RhoA activation in hfPSMCs. Results. In both diabetic models, atorvastatin did not affect glycemia, lipid plasma levels, and the hypogonadal state. In diabetic rats, atorvastatin ameliorated the erectile response to the ES of the cavernous nerve and normalized sildenafil effect on erectile function, strongly decreased by diabetes. In penile tissue from diabetic animals, atorvastatin completely restored the diabetes-induced hypersensitivity to Y-27632 and prevented RhoA membrane translocation/activation. In hfPSMCs, high glucose significantly increased not only membrane RhoA expression, but also ROCK activity (increased phosphorylation of the ROCK substrate myosin phosphatase target subunit 1) and several RhoA-dependent functions such as proliferation, migration, and smooth muscle-related gene expression. Atorvastatin restored all the high-glucose-induced effects, an action specifically reverted by GGPP. Conclusion. Atorvastatin improves diabetes-related ED and restores sildenafil responsiveness, most probably by inhibiting RhoA/ROCK signaling, which underlies several high-glucose-induced derangements in penile smooth muscle cell commitment. Morelli A, Chavalmane AK, Filippi S, Fibbi B, Silvestrini E, Sarchielli E, Zhang X-H, Vignozzi L, Vannelli GB, Forti G, and Maggi M. Atorvastatin ameliorates sildenafil-induced penile erections in experimental diabetes by inhibiting diabetes-induced RhoA/Rho-kinase signaling hyperactivation. J Sex Med 2009;6:91–106. [ABSTRACT FROM AUTHOR]

Introduction. The contractile RhoA/Rho-kinase (ROCK) signaling pathway is upregulated in penile tissue in animal models of experimental diabetes and has been proposed to contribute to diabetes-related erectile dysfunction (ED). Aim. To investigate the effect of testosterone (T) on the RhoA/ROCK signaling in diabetes. Methods. We used two distinct animal models of chemical diabetes (alloxan-induced in the rabbit and streptozotocin-induced in the rat) with or not T supplementation. Main Outcome Measures. The effect of diabetes and T supplementation on RhoA/ROCK signaling was evaluated as responsiveness to the selective ROCK inhibitor Y-27632 either by “in vitro” contractility study (diabetic rabbit) or “in vivo” as erectile response elicited by intracavernous injections (diabetic rats). RhoA/ROCK gene and protein expression were also analyzed. Results. In both models, hypogonadism was observed, characterized by reduced T plasma level and androgen-dependent accessory glands atrophy. Diabetic animals showed a significant increase in responsiveness to increasing concentrations of Y-27632. T substitution (30 mg/kg, weekly) completely prevented hypogonadism and diabetes-induced penile hypersensitivity to Y-27632. To test whether this effect was due to a T-dependent regulation of RhoA/ROCK gene expression, we measured RhoA/ROCK mRNA. Both isoforms of ROCK (ROCK1/ROCK2) were analyzed by real-time reverse transcriptase polymerase chain reaction (RT-PCR) in rat penile samples. We found that ROCK1 mRNA was significantly increased ( P < 0.05) in penile tissues from diabetic animals and maintained at the control values by T, as also confirmed by semiquantitative RT-PCR in rabbit. Conversely, RhoA and ROCK2 mRNA expression was not influenced either by diabetic condition or by T administration. Accordingly, ROCK1 protein expression, as evaluated by Western blot and immunohistochemistry analysis, was increased in penile samples from diabetic animals and normalized by T. Conclusions. Our data further support the hypothesis that the overexpression of RhoA/ROCK signaling contributes to diabetes-related ED. Moreover, treating hypogonadism in course of diabetes may maintain erectile function also by normalizing RhoA/ROCK pathway upregulation. Vignozzi L, Morelli A, Filippi S, Ambrosini S, Mancina R, Luconi M, Mungai S, Vannelli GB, Zhang X-H, Forti G, and Maggi M. Testosterone regulates RhoA/Rho-kinase signaling in two distinct animal models of chemical diabetes. J Sex Med 2007;4:620–632. [ABSTRACT FROM AUTHOR]

Introduction Estrogen receptor ( ER) α is critical in mediating the harmful effects of hyperestrogenism in fetal or neonatal life on the developing penis. In contrast, little is known on the impact of an excess of estrogens on penile function in adulthood. Aim To investigate the effect of estrogens on metabolic syndrome ( MetS)-associated erectile dysfunction ( ED). Methods We employed a recently established animal model of high fat diet ( HFD)-induced MetS. Subgroups of MetS rabbits were dosed with either testosterone ( T) or tamoxifen. We evaluated penile responsiveness to acetylcholine (Ach) as well as the expression of genes related to penile smooth muscle relaxation and contractility. Main Outcome Measure Associations between MetS-induced penile alterations and sex steroids were investigated in an animal model of HFD-induced MetS. To understand the role of either androgen deficiency or estrogen excess on ED, we treated subgroups of MetS rabbits with either T or tamoxifen, a classical ER antagonist. Results Feeding an HFD-induced MetS was associated to elevated estradiol ( E2) and low T levels. E2, but not T, was independently and negatively associated with genes able to affect penile erection. Smooth muscle-related markers decreased as a function of E2 and were positively associated with all the variables investigated. Increasing concentrations of circulating E2 were negatively associated with Ach-induced relaxation. In HFD rabbits, in vivo T dosing significantly improved MetS and completely normalized circulating E2. Conversely, in vivo tamoxifen dosing reduced visceral adiposity and partially restored T level. Ach-induced relaxation was severely impaired by HFD and significantly restored, up to the control level, by both tamoxifen and T dosing. In rabbit smooth muscle cells cultures 17β- E2 (1 nM) significantly reduced the expression of α-smooth muscle actin, transgelin, and phosphodiesterase type 5. The effects of 17β- E2 were completely reverted by tamoxifen (100 nM). Conclusions This study demonstrates, for the first time, that HFD-induced ED is more associated with a high E2, rather than to a low T, milieu. HFD-induced ED is partially restored by in vivo treatment not only with T but also with the nonsteroidal ER antagonist, tamoxifen. Vignozzi L, Filippi S, Comeglio P, Cellai I, Morelli A, Marchetta M, and Maggi M. Estrogen mediates metabolic syndrome-induced erectile dysfunction: A study in the rabbit. J Sex Med 2014;11:2890-2902. [ABSTRACT FROM AUTHOR]

Introduction. Phosphodiesterase type 5 inhibitors (PDE5-I) have acquired an established role in the treatment of post-prostatectomy erectile dysfunction (ED). Several trials in men with ED and lower urinary tract symptoms associated with benign prostatic hyperplasia suggest that PDE5-I could improve both erectile function and urinary symptoms. Aim. To assess the role of vardenafil in continence recovery after bilateral nerve sparing radical prostatectomy (BNS-RP). Methods. Thirty-nine patients with prostate cancer were recruited. After BNS-RP, patients were double-blinded assigned to three arms: a) vardenafil on demand; b) vardenafil nightly; and c) placebo. Main Outcomes Measures. Urinary function (UF) and urinary bother (UB) of University of California–Los Angeles Prostate Cancer Index questionnaire were assessed preoperatively and at 1, 3, 6, 9, 10, and 12 months. Twelve-month outcomes were compared to 1 month with a t-test. The differences in UF and UB (at 3, 6, 9, 10, and 12 months) between the three treatment arms were calculated by an analysis of variance. With ALLFIT we estimated half-maximal recovery times (ER50) and maximal recovery ( Rmax) in three groups. Results. The improvement of UF and UB between 1 and 12 months was significant in all arms except for placebo (UF: P = 0.125; UB: P = 0.089). Nightly resulted in greater UF at 3, 6, and 9 months and greater UB at 6 months compared with placebo ( P = 0.042, P = 0.044 and P = 0.039); after nightly administration, patients presented higher UB than after on-demand use, 3 and 6 months postoperatively ( P = 0.036 and P = 0.017). ALLFIT demonstrated a similar ER50 in all groups (2.6 months for both UF and UB) and indicated that nightly administration induced significant improvements in Rmax compared with placebo (both <0.0001). Conclusions. Vardenafil can improve continence recovery after BNS-RP compared with placebo. The daily use of vardenafil seems to provide better continence rate, although it does not seem to influence the timing needed to achieve full continence. Gacci M, Ierardi A, Delle Rose A, Tazzioli S, Scapaticci E, Filippi S, Maggi M, Nicita G, Carini M, and Montorsi F. Vardenafil can improve continence recovery after bilateral nerve sparing prostatectomy: Results of a randomized, double blind, placebo-controlled pilot study. J Sex Med 2010;7:234–243. [ABSTRACT FROM AUTHOR]