Effect of Reversal of Whey-Protein to Casein Ratio of Cow Milk, on Insulin, Incretin, and Amino Acid Responses in Humans.

SCOPE: Milk-proteins, besides lactose, stimulate insulin and incretin secretion. Although whey-proteins (WP) are more efficient than casein (Cas) in hormone secretion, the effects of reversal of the (WP/Cas) ratio in whole-milk are poorly known. METHODS AND RESULTS: Healthy volunteers received two different cow-milk drinks, at identical lactose (0.36 g × kg-1 BW) and total-protein (0.18 g × kg1 BW) loads, but at reversed WP/Cas ratio. One is cow-whole milk with a ≈20/80 [WP/Cas] ratio, the other an experimental cow-milk with a ≈70/30 [WP/Cas] ratio ([↑WP↓Cas]-milk). Both milk-types induced the same mild hyperglycemic response. Following [↑WP↓Cas]-milk, the [20'-90'] insulin incremental area (iAUC) (+ ≈44%, p < 0.035), and the [20'-120'] C-peptide iAUC (+ ≈47%, p < 0.015) are greater than those with cow-milk. Similarly, following [↑WP↓Cas]-milk, the GLP-1 [20'-90'] iAUC (+96%, p < 0.025), and the GIP [30'-60'] iAUC (+140%, p < 0.006), were greater than those with cow-milk. Plasma total and branched-chain amino acids are also greater following the [↑WP↓Cas] than cow-milk. CONCLUSIONS: Reversal of the (WP/Cas) ratio in cow-milk enhanced the insulin response, an effect possibly mediated by incretins and/or amino acids(s). These data may be useful in designing specific milk formulas with different effects on insulin and incretin response(s).

Estradiol-Testosterone Imbalance Is Associated with Erectile Dysfunction in Patients with Klinefelter Syndrome.

Erectile dysfunction (ED) is a frequent sexual disorder in adult men. Klinefelter syndrome (KS) is the most common sex chromosomal disorder and a frequent cause of male hypogonadism. Psychological and cognitive aspects are quite typical in KS and have been linked to ED, while the role of testosterone (T) levels in sexual function of KS subjects has not been fully elucidated. The purpose of the present study is to investigate the role of hormonal disturbances in erectile function of subjects with KS. We conducted a retrospective study involving 52 Klinefelter patients newly diagnosed who never received androgen replacing therapy. All the subjects underwent medical history, accurate physical examination, and blood tests. The International Index of Erectile Function questionnaire (IIEF-EF) score correlated negatively with estradiol/testosterone ratio (E2/T); this correlation remained statistically significant after correction for age (ρ -0.320 p = 0.018). A multiple linear regression analysis identified age and E2/T as the main predictors of IIEF-EF score (R2 0.169 F = 3.848 p = 0.008). Our findings corroborate previous KS data obtained in the general population showing an association between higher E2/T ratio and impaired erectile function. Larger studies are required to better elucidate the pathophysiology of ED in patients with KS.

Association Between Penile Color Doppler Ultrasonography and Cardiorespiratory Fitness in Patients With Vascular Erectile Dysfunction.

INTRODUCTION: Vascular erectile dysfunction (ED) is a burdensome condition, associated with increased cardiovascular risk. Peak systolic velocity (PSV) represents the maximum pulse velocity in the cavernous artery measured by a penile color doppler ultrasonography (PCDU) during a pharmacologically induced erection and is considered a reliable parameter for the diagnosis of vascular ED. However, the cut-off value of standard PSV (30 cm/s) provides high sensitivity only in the diagnosis of advanced arteriogenic disease. Thus, an age-adjusted PSV (6.73 + 0.7 x age cm/s) has been proposed to offer a more accurate diagnosis of vascular ED. AIM: In this study it was aimed to answer the following question: "Is there any positive association between indexes of vascular erectile dysfunction and cardiorespiratory fitness?" MAIN OUTCOME MEASURE AND METHODS: 25 patients with a medical history of ED (median age 55.3 years) underwent PCDU after pharmacological stimulation. Subsequently, a functional evaluation with ECG-monitored, incremental, maximal cardiopulmonary exercise testing was performed. RESULTS: Peak oxygen uptake (VO2 peak), peak oxygen uptake per body weight (VO2 peak/kg) and Watt/kg correlated with standard PSV, even when corrected for age and BMI (p < 0.05). No differences emerged in cardiopulmonary fitness between pathological and healthy patients (4 vs 21) identified using the standard PSV cut-off. Conversely, the age-adjusted PSV cut-off identified a greater number of patients as pathological (18 vs 7), presenting a significantly lower cardiopulmonary fitness, exercise capacity and efficiency when compared to patients with normal age-adjusted PSV (all p < 0.05). CONCLUSION: Data showed an age and BMI independent association between vascular disfunction of cavernous artery and cardiopulmonary fitness, a known solid predictor of all-cause and disease-specific mortality. Moreover, the age-adjusted PSV better identified a subgroup of patients with vascular ED presenting impaired cardiorespiratory fitness and thus increased cardiovascular risk. De Rocco Ponce M, Vecchiato M, Neunhaeuserer D, et al. Association Between Penile Color Doppler Ultrasonography and Cardiorespiratory Fitness in Patients With Vascular Erectile Dysfunction. Sex Med 2021;9:100347.

Efficacy of penile low-intensity shockwave treatment for erectile dysfunction: correlation with the severity of cavernous artery disease.

We analyzed the efficacy of penile low-intensity extracorporeal shockwave treatment for erectile dysfunction (ED) combined with cavernous artery disease (CAD). ED was evaluated by the International Index of Erectile Function, subdividing patients into mild and moderate/severe forms. CAD was assessed using penile color Doppler ultrasonography. Patients (n = 111) with a positive outcome after treatment, based upon the minimal clinically important difference of the International Index of ED, were followed up for 3 months and 6 months. We found a significant mean increase in the index of erectile function, with an overall improvement in hemodynamic parameters of the cavernous artery. In particular, 93.9% of the patients with mild ED without CAD responded to treatment and 72.7% resumed normal erectile function. Only 31.2% of the patients with moderate/severe ED and CAD responded to treatment, and none resumed normal erectile function. All patients with mild ED and no CAD maintained the effects of therapy after 3 months, while no patients with moderate/severe ED and CAD maintained the benefits of treatment after 3 months. Thus, patients with mild ED and no CAD have better and longer lasting responses to such treatment, with a higher probability of resuming normal erectile function than patients with moderate/severe ED and CAD.

Sperm Count and Hypogonadism as Markers of General Male Health.

BACKGROUND: Some evidence suggests that infertile men, who are at increased risk for hypogonadism, metabolic derangements, and osteoporosis, have higher long-term morbidity and mortality than controls, but data are scarce and not conclusive. OBJECTIVE: We tested whether semen quality and reproductive function could represent a marker of general male health. DESIGN, SETTING, AND PARTICIPANTS: A retrospective study of 5177 individuals from a prospectively collected database of 11516 males of infertile couples who had semen analysis in a tertiary university center. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Of them, 5177 had all data for reproductive hormones, testis ultrasound, and biochemical determinations for glucose and lipid metabolism. Hypogonadism was defined as testosterone <10.5nmol/l and/or luteinizing hormone >9.4 IU/l. Individuals with a total sperm count of <10 million had genetic testing (karyotype, Y chromosome microdeletions, and CFTR gene mutations) and those with hypogonadism underwent dual-energy x-ray absorptiometry for bone mineral density. Descriptive statistics and odds ratio (OR) calculation were used. RESULTS AND LIMITATIONS: Men with a low sperm count (<39 million/ejaculate) are at a high risk of hypogonadism (OR 12.2, 95% confidence interval [CI] 10.2-14.6) and have higher body mass index, waist circumference, systolic pressure, low-density lipoprotein cholesterol, triglycerides, and homeostatic model assessment (HOMA) index; lower high-density lipoprotein cholesterol; and a higher prevalence of metabolic syndrome (OR 1.246, 95 CI 1.005-1.545). All data are worse in men with hypogonadism, but a low sperm count per se is associated with a poor metabolic parameter. Men with hypogonadism have lower bone mineral density and 51% prevalence of osteoporosis/osteopenia. Longitudinal studies are necessary to support these data. CONCLUSIONS: This is the largest study with comprehensive evaluation of semen quality and reproductive function, etiology and risk factor determination, and metabolic, cardiovascular, and osteoporosis risk assessment, performed in men referred for fertility evaluation. A low sperm count is associated with poorer metabolic, cardiovascular, and bone health. Hypogonadism is mainly involved in this association, but a low sperm count in itself is a marker of general health. PATIENT SUMMARY: This large study evaluated semen quality, reproductive function, and metabolic risk in men referred for fertility evaluation, and showed that a man's semen count is a marker of his general health. Men with low sperm counts are more likely than those with normal sperm counts to have greater body fat, higher blood pressure, higher "bad" (low-density lipoprotein) cholesterol and triglycerides, and lower "good" (high-density lipoprotein) cholesterol. They also have a higher frequency of metabolic syndrome and insulin resistance, a condition that can lead to diabetes. Men with low sperm counts had a 12-fold increased risk of hypogonadism or low testosterone levels, and half of them had osteoporosis or low bone mass. Fertility evaluation gives men the unique opportunity for health assessment and disease prevention.

Estradiol correlates with erectile dysfunction and its severity in type 2 diabetic patients.

AIMS: Erectile dysfunction (ED) is a frequent microvascular complication of type 2 diabetes mellitus (T2DM). Hormonal derangements such as hypogonadism and hyperestrogenism are common in T2DM. Our aim was to investigate the relationship between estrogens and ED in diabetic patients. METHODS: We performed a retrospective study on 57 patients with T2DM suffering from ED. ED was assessed with the International Index of Erectile Function questionnaire (IIEF-5) and penile color-doppler ultrasound (PCDU). Blood tests included glycated hemoglobin, lipid profile, total testosterone (T), and estradiol (E2). RESULTS: E2 was negatively correlated with IIEF-5 score after correction for age, diabetes duration, BMI, HbA1c, LDL- and HDL-cholesterol, T and PSA (r = -0.457, p < 0.01). Patients in the higher E2 quartile, had statistically higher probability of severe ED (61.5%). In the same patients, the PCDU demonstrated a statistically longer Acceleration Time (120.0 ±â€¯24.5, p = 0.048) indicating an impaired arterial flow. CONCLUSIONS: In diabetic patients, higher E2 is associated with worse erectile function and impaired cavernous arterial flow. Diabetic patients with high E2 are more prone to severe ED. It could be suggested to include estradiol measurement in the hormonal assessment of ED in patients with T2DM.

Bisphenols and Male Reproductive Health: From Toxicological Models to Therapeutic Hypotheses.

Bisphenols, and in particular bisphenol A (BPA), have been widely used for the production of plastic manufacts in the last 50 years. Currently, BPA is present in a variety of daily use polycarbonate plastics and epoxy resins, and dietary ingestion is considered the main route of human exposure. Accordingly, BPA is the chemical pollutant with the widest exposure in humans, involving nearly 90% of general population, according to recent studies. Concerns about BPA effects on human health date back to 1930s, when severe impact on male sexual development was suggested. Now, the acknowledged biological effects of BPA are various. In regard to human fertility, BPA has been shown to disrupt hormone signaling even at low concentrations. Results from human epidemiological studies have reported BPA interference with follicle stimulating hormone, inhibin B, estradiol, testosterone levels, and sexual function in male subjects. Moreover, recent studies have reported an association between BPA levels and reduced sperm concentration, motility, normal morphology, sperm DNA damage, and altered epigenetic pattern, resulting in trans-generational legacy of BPA effects. In this review, the recognized effects of BPA on male reproductive health are described, from the most recent issues on experimental models to epidemiological data. In addition, the very recent interest about the use of nutraceutical remedies to counteract BPA effects are discussed.

Osteocalcin: A Protein Hormone Connecting Metabolism, Bone and Testis Function.

During the last decade, the disclosure of systemic effects of osteocalcin (OCN) in its undercarboxylated form contributed to switch the concept of bone from a merely structural apparatus to a fully endocrine organ involved in the regulation of systemic functions. Since that time, the role of OCN as osteokine has been more and more widened appreciated and detailed by the major use of animal models, starting from the original function in the bone extracellular matrix as Gla-protein and spanning from the protective effects towards weight gain, insulin sensitivity and glucose homeostasis, to the anabolic and metabolic roles in skeletal muscle, to the stimulating effects on the testis endocrine function and male fertility, to the most recent preservation from anxious and depressive states through a direct activity on the central nervous system. In this review, experimental data supporting the inter-organ communication roles of this protein are discussed, together with the available data supporting the consistency between experimental data obtained in animals and those reported in humans. In addition, a specific session has been devoted to the possible significance the OCN as a template agonist on its receptor GPRC6A, for the development of novel therapeutic and pharmacological approaches for the treatment of dismetabolic states and male infertility.

Use of Biosimilar Follicle-Stimulating Hormone in Asthenozoospermic Infertile Patients: A Multicentric Study.

There is increasing data in favour of follicle-stimulating hormone (FSH) therapy in patients with oligo-asthenozoospermia and normal-range gonadotropins in order to increase sperm count and above all sperm motility. Some studies showed an improvement in DNA fragmentation and spontaneous pregnancy. Recently, biosimilar FSH has been marketed with the same indications. We performed a retrospective multicentric case-control study involving 147 asthenozoospermic patients between 18 and 45 years of age. A total of 97 patients were treated with biosimilar FSH 150 UI three times a week for 3 months, while 50 control subjects received no treatment. Patients were evaluated at baseline and after 3 months with semen analysis including DNA fragmentation, testicular colour Doppler ultrasound, and blood tests. Spontaneous pregnancies were recorded during a further follow-up period of 6 months. Treated patients showed after treatment a statistically significant increase in sperm concentration, total sperm count, and total motile sperm, as well as improved progressive motility and non-progressive motility. DNA fragmentation showed a significant reduction. Conversely, in the control group, no significant change was found. Pregnancy rate was significantly higher in treated patients. These data suggest comparable efficacy of biosimilar FSH in the treatment of male infertility; however, larger studies are needed to confirm our results.

Comparison of NGS panel and Sanger sequencing for genotyping CAG repeats in the AR gene.

BACKGROUND: The androgen receptor (AR) is a nuclear receptor, encoded by the AR gene on the X chromosome. Within the first exon of the AR gene, two short tandem repeats (STR), CAG and GGC, are a source of polymorphism in the population. Therefore, high-throughput methods for screening AR, such as next-generation sequencing (NGS), are sought after; however, data generated by NGS are limited by the availability of bioinformatics tools. Here, we evaluated the accuracy of the bioinformatics tool HipSTR in detecting and quantify CAG repeats within the AR gene. METHOD: The AR gene of 228 infertile men was sequenced using NGSgene panel. Data generated were analyzed with HipSTR to detect CAG repeats. The accuracy was compared with the results obtained with Sanger. RESULTS: We found that HipSTR was more accurate than Sanger in genotyping normal karyotype men (46,XY), however, it was more likely to misidentify homozygote genotypes in men with Klinefelter syndrome (47,XXY). CONCLUSION: Our findings show that the bioinformatics tool HipSTR is 100% accurate in detecting and assessing AR CAG repeats in infertile men (46,XY) as well as in men with low-level mosaicism.

Testosterone is sequestered in dysfunctional adipose tissue, modifying androgen-responsive genes.

BACKGROUND/OBJECTIVE: The recognized association between male hypogonadism and obesity has multifactorial implications on adipose tissue (AT) physiology. The fat solubility of testosterone (T) suggests a sequestration process in fat depots, leading to reduced circulating levels of T in obesity. Several evidence suggest that steroids play a two-sided inhibitory role on adipogenesis by locally decreasing lipid accumulation and by stimulating lipolysis. The current study investigates T trafficking and activity in dysfunctional AT. SUBJECTS/METHODS: Samples of subcutaneous AT (SAT) were obtained from explants from lipoaspirate plastic surgery in six obese and six normal weight male patients. Experimental procedures on both SAT explants and insulin-resistant (IR) 3T3-L1 adipocytes were performed, including real-time PCR and mass-spectrometry quantification. RESULTS: A significant deregulation of gene responsiveness to androgens in IR cells and obese SAT was observed (all p < 0.05), together with reduced T release after adrenergic stimulation (-10% compared with -55% in lean SAT, p = 0.021). Higher concentrations of intracellular T and estradiol in obese SAT were also observed (2.4 vs. 1.3 ng/g, p = 0.013 and 0.075 vs. 0.22 ng/g, p = 0.004, respectively). Testosterone accumulation resulted in even lower expression in androgen-responsive genes involved in lipolytic and anti-adipogenic pathways from both in vitro and ex vivo experiments. CONCLUSIONS: These results suggest an altered response of dysfunctional fat cells to testosterone stimulation, which normally favors lipolysis and induces an anti-adipogenic effect. The considerable reduction of lipolytic T release after adrenergic stimulation in obese SAT contributes to AT dysfunction, in a feedforward loop further reducing T levels in obese hypogonadal males.

Evaluation of Serum/Urine Genomic and Metabolomic Profiles to Improve the Adherence to Sildenafil Therapy in Patients with Erectile Dysfunction.

Type V-phosphodiesterase-inhibitors (PDE5i) are the first choice drugs in the treatment of erectile dysfunction (ED), being effective in 60-70% of patients. However, approximately 50% of patients per year discontinue the treatment with PDE5i after reporting poor drug efficacy or major adverse drug reactions (ADR). To identify early markers of efficacy/safety for the treatment of ED with PDE5i, the basal clinical characteristics of patients, integrated with metabolomics analysis of serum and urine and genomic data, were here correlated with the PDE5i efficacy and the occurrence of ADR upon administration. Thirty-six males with new diagnosis of ED were consecutively recruited and characterized at baseline for anthropometrics, blood pressure, blood glucose, lipid profile, serum levels of thyroid/sex hormones and erectile function evaluated by IIEF-15 questionnaire. Targeted Next Generation Sequencing (NGS) was applied to genes involved in PDE5i pharmacodynamics and pharmacokinetics. Fasting metabolic profiles of serum and urine were assessed by nuclear magnetic resonance (NMR)-based metabolomics analysis. Patients were prescribed on-demand therapy with Sildenafil oro-dispersible film and followed-up after 3 months from recruitment. Baseline data were compared with IIEF-15 score at follow-up and with the occurrence of ADR recorded by a dedicated questionnaire. Twenty-eight patients were finally included in the analysis. Serum LDL-cholesterol levels were increased in those reporting ADR (143.3 ± 13.2 mg/dl ADR vs. 133.1 ± 12.4 mg/dl No ADR; p = 0.046). NGS data showed that specific variants of PDE11A and CYP2D7 genes were more represented in drug responders (both relative risk = 2.7 [0.9-5.1]; p = 0.04). NMR-based metabolomics showed the highest association between serum LDL-cholesterol metabolites and the occurrence of ADR (Hazard ratio = 17.5; p = 0.019). The association between lipid profile and the ADR pattern suggests major cues in the tailoring of ED therapy with PDE5i.

Effect of treatment with testosterone on endothelial function in hypogonadal men: a systematic review and meta-analysis.

Despite several studies showing an inverse correlation of total testosterone with endothelial damage, the effect of testosterone replacement therapy (TTh) on endothelial function has been scarcely investigated. In order to systematically assess the relationship between endothelial dysfunction and TTh, we performed a review and meta-analysis of available prospective and cross-sectional studies. A thorough research was performed on MEDLINE for hypogonadism and endothelial dysfunction. We retrieved 28 papers, among which 23 were excluded for different reasons: five papers accounting for six studies (two crossover randomized clinical trial (RCT), three observational, one placebo controlled RCT) were therefore included in analysis. Overall, 86 patients with hypogonadism were included in analysis (mean age 49.57 ± 8.85 years). Baseline total testosterone serum levels were 8.11 ± 2.42 nmol/L and significantly increased while undergoing TTh (standard mean difference (SMD) 2.93 nmol/L, 95% confidence interval (CI) 1.89:3.97, p < 0.001). Due to the paucity of studies available, flow-mediated dilation (FMD) was chosen as the best surrogate marker of endothelial dysfunction. FMD did not significantly change after testosterone administration (SMD -0.22, 95% CI -1.29:0.84, I2 = 90%); acute testosterone administration was associated with an increase in FMD, whereas a reduction in FMD emerged following chronic treatment, but statistical significance was not reached for both effects. This is the first meta-analysis study assessing the influence of TTh on endothelial function; however, results are far from conclusive, as proven by the high heterogeneity.

SHBG141-161 Domain-Peptide Stimulates GPRC6A-Mediated Response in Leydig and ß-Langerhans cell lines.

GPRC6A is acknowledged as a major regulator of energy metabolism and male fertility through the action of undercarboxylated osteocalcin (ucOCN), representing a possible therapeutic target. We recently showed that the sex hormone-binding globulin (SHBG) binds to GPRC6A through the likely involvement of the 141-161 domain. To confirm this model, here we investigated the possible binding and agonist activity of SHBG(141-161) domain-peptide (SHBG141-161) on GPRC6A. The binding of SHBG141-161 to GPRC6A and downstream dissociation from Gαi(GDP) protein was computationally modelled. SHBG141-161 was obtained by solid-phase synthesis, characterized by circular dichroism (CD) and the receptor binding was assessed by displacement of ucOCN on HEK-293 cells transfected with GPRC6A gene. Agonist activity of SHBG141-161 was assessed on Leydig MA-10 and Langerhans ß-TC6 cell lines through the GPRC6A-mediated release of testosterone (T) and insulin. SHBG141-161 was predicted to bind to GPRC6A and to reduce the affinity for Gαi(GDP) at computational level. Conformational properties and binding to GPRC6A of the synthetic SHBG141-161 were confirmed by CD and displacement experiments. SHBG141-161 stimulated cell secretion of T and insulin, with dose dependency from 10-13 to 10-11M for T release (respectively P = 0,041 10-13M; P = 0,032 10-12M; P = 0,008 10-11M vs basal) and for 10-12 to 10-10M for insulin (respectively P = 0,041 10-12M; P = 0,007 10-11M; P = 0,047 10-10M; P = 0,045 vs basal). Blockade with anti GPRC6A IgG abolished the response to SHBG141-161, suggesting agonist specificity. SHBG141-161 showed stimulating activity on GPRC6A, representing a template peptide with possible therapeutic use for metabolic and endocrine disorders.

Prognostic Value of Ultrasound Stratigraphy in Long-Term Weight Loss: Results from a Nutritional Counseling Program.

BACKGROUND: Weight control through lifestyle interventions represents a suitable strategy to avoid the metabolic, endocrine, and reproductive comorbidities associated with overweight and obesity. Reduced testosterone (T) levels are a worsening factor in overweight males. However, prognostic parameters of long-term weight loss are not readily available. Here, we tested the prognostic value of early variations of anthropometric and hormonal parameters, with a focus on ultrasound stratigraphy (US) and the reduction in body mass index (BMI) associated with nutritional counseling/lifestyle interventions at 6-month follow-up. METHODS: Ninety-five male subjects (BMI 25-34.9 kg/m2) who had undergone nutritional/lifestyle interventions, were retrospectively analyzed for: body weight and composition; US evaluation at the triceps (TRC), abdominal (ABD), and thigh (THI) areas; and circulating levels of T, luteinizing hormone, and follicle-stimulating hormone. Sixty patients (63.2%) completed the 6-month follow-up program. RESULTS: At 6 months, a significant reduction in BMI (26.38 ± 1.55 vs. 31.5 ± 5.0 basal, p < 0.001) and increase in T levels (18 ± 5.4 vs. 9.5 ± 2.3 nmol/L basal, p = 0.04) were observed. Subjects in the highest quartile of the BMI reduction at 6 months (ΔBMI 6 mo), compared to the lowest, showed a significant difference at the 2-month follow-up variation of BMI (p = 0.025), and fat and muscle thickness at the TRC (both p < 0.001) and ABD (p < 0.001 and p = 0.002, respectively) areas. Variation of TRC muscle thickness at 2 months was the only independent predictor of ΔBMI 6 mo in the multiple stepwise regression analysis. CONCLUSIONS: BMI evaluation and US represent useful monitoring tools in the follow-up of nutritional/lifestyle interventions for overweight-to-mildly obese patients. The important effects on motivation and adherence to the intervention program are to be considered.

Sublingual Administration of Sildenafil Oro-dispersible Film: New Profiles of Drug Tolerability and Pharmacokinetics for PDE5 Inhibitors.

Objective: Type 5 phosphodiesterase inhibitors (PDE5i) are efficient drugs used for treatment of erectile dysfunction (ED); however, a large discontinuation rate due to major side effects is reported. The aim of this study was to evaluate the possible improvement of sildenafil (Sild) pharmacokinetics associated to the sublingual administration of the new available oro-dispersible film (ODF), compared to both the oro-dispersible tablet (ODT) and the film-coated tablet (FCT) as original per os formulation. Methods:In vitro disaggregation test, dissolution test, and permeation test in specific devices to estimate the trans-mucosal absorption. In vivo analysis of serum Sild levels, by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), was performed in 20 patients with psychogenic ED receiving alternatively per os FCT or sublingual ODT or ODF, at an equal dosage (50 mg). Pharmacokinetic parameters of Sild and adverse drug reactions experienced after the dosing of each formulation were compared. Results:In vitro, ODF showed the highest time to disaggregation and an increased rate of permeation compared to both ODT and FCT (P = 0.017 and P = 0.008, respectively). In vivo, compared to both FCT and ODT, ODF showed a faster increase of serum Sild levels (serum levels at 15 min from dosing, respectively: 2.24 ± 1.4 ng/ml FCT, 0.5 ± 0.3 ng/ml ODT, and 13.5 ± 9.1 ng/ml ODF; P < 0.01 and P < 0.05 vs. ODF) together with a higher drug bioavailability within 60 min from dosing (relative AUC60min vs. FCT, respectively: 100.0 ± 44.9% FCT, 183.8 ± 75.4% ODT, and 304.2 ± 156.0% ODF). A trend toward lower peak serum levels was observed for ODF. Finally, ODF showed a lower prevalence of headache compared to FCT (1 vs. 35%; P < 0.05) and improved pattern of flushing and nasal congestion. Conclusion: Sublingual Sild ODF improves the drug tolerability through a likely modified pharmacokinetic, suggesting a possible implication also in the clinical efficacy profile. Sublingual administration of oro-dispersible formulations may represent a strategy to ameliorate the adherence to therapy with PDE5i, particularly in patients discouraged by side effects.

Increased risk of testis failure in testicular germ cell tumor survivors undergoing radiotherapy.

Testicular germ cell tumors (TGCTs) are prevalent in males of reproductive age. Among the available therapeutic choices, pelvic radiotherapy (RT) and simple surveillance (SURV) are usually pursued. However, RT is considered to have life-threatening effects on testicular functions. In this study we sought to clarify this issue by evaluating sperm parameters and sex hormones in 131 TGCTs RT-treated-patients at both baseline (T0) and 12 (T1) and 24 months (T2) of follow-up. An age-matched group of 61 SURV patients served as control. Sperm parameters were comparable between SURV and RT at T0. The RT group showed a significant reduction of all sperm parameters at T1 (all P values < 0.05 vs T0 and vs SURV at T1) and increased levels of sperm aneuploidies, with some degree of recovery at T2. On the other hand, despite normal levels of total testosterone being detected in both groups, luteinizing hormone (LH) levels in the RT group progressively increased at T1 and T2 with a relative risk of developing subclinical hypogonadism of 3.03 (95% CI: 1,50-6,11) compared to SURV. Again, compared to SURV, exposure to RT was associated with a 5.78 fold (95% CI: 2,91-11,48) risk of developing vitamin D insufficiency. These data suggest a likely RT-dependent impairment of the Leydig cell compartment.

Human Papillomavirus Prophylactic Vaccination improves reproductive outcome in infertile patients with HPV semen infection: a retrospective study.

In this study we aimed to evaluate the effect on reproductive outcome of HPV vaccination in male subjects of infertile couples with HPV semen infection. In this single-center study, we retrospectively enrolled 151 infertile couples with detection of HPV in semen, attending our Hospital Unit of Andrology between January 2013 and June 2015, counseled to receive adjuvant HPV vaccination. Seventy-nine accepted vaccination (vaccine group) whilst 72 did not (control group). Our protocol of follow-up, aimed to evaluate HPV viral clearance, consisted in semen analysis, INNO-LiPA and FISH for HPV in semen cells after 6 and 12 months from basal evaluation. Spontaneous pregnancies, miscarriages and live births were recorded. Progressive sperm motility and anti-sperm antibodies were improved in the vaccine group at both time points (p < 0,05 vs control arm). Forty-one pregnancies, 11 in the control group and 30 in the vaccine group, were recorded (respectively 15% and 38,9%, p < 0,05) and resulted into 4 deliveries and 7 miscarriages (control group) and 29 deliveries and one miscarriage (vaccine group, p < 0,05 vs control group). HPV detection on sperms was predictive of negative pregnancy outcome. Adjuvant vaccination associated with enhanced HPV healing in semen cells and increased rate of natural pregnancies and live births.