Testosterone does not affect lower urinary tract symptoms while improving markers of prostatitis in men with benign prostatic hyperplasia: a randomized clinical trial.

PURPOSE: Benign Prostatic Hyperplasia (BPH) is a result of prostate inflammation, frequently occurring in metabolic syndrome (MetS). Low testosterone is common in MetS. A randomized clinical trial was designed to evaluate if 24 weeks of testosterone therapy (TTh) in BPH men with MetS and low testosterone improve urinary symptoms and prostate inflammation. METHODS: One-hundred-twenty men with MetS waitlisted for BPH surgery were enrolled. They were categorized into normal testosterone (TT ≥ 12 nmol/L and cFT ≥ 225 pmol/L; n = 48) and testosterone deficient (TD) (TT < 12 nmol/L and/or cFT < 225 pmol/L; n = 72) then randomized to testosterone gel 2% (5 g/daily) or placebo for 24 weeks. At baseline and follow-up, questionnaires for urinary symptoms and trans-rectal ultrasound were performed. Prostate tissue was collected for molecular and histopathological analyses. RESULTS: No differences in the improvement of urinary symptoms were found between TTh and placebo (OR [95% CI] 0.96 [0.39; 2.37]). In TD + TTh, increase in prostate but not adenoma volume was observed (2.64 mL [0.07; 5.20] and 1.82 mL [- 0.46; 0.41], respectively). Ultrasound markers of inflammation were improved. In a subset of 61 men, a hyper-expression of several pro-inflammatory genes was found in TD + placebo when compared with normal testosterone. TTh was able to counteract this effect. For 80 men, the inflammatory infiltrate was higher in TD + placebo than in normal testosterone (0.8 points [0.2; 1.4]) and TD + TTh men (0.9 points [0.2; 1.5]). CONCLUSIONS: Twenty-four weeks of TTh in TD men with BPH and MetS improves ultrasound, molecular and histological proxies of prostate inflammation. This does not result in symptom improvement.

Effect of two different pre-anaesthetic omeprazole protocols on gastroesophageal reflux incidence and pH in dogs.

OBJECTIVES: Gastroesophageal reflux can occur during anaesthesia and may lead to esophagitis and occasionally oesophageal stricture formation. The aim of the study is to assess two omeprazole protocols on gastroesophageal reflux incidence and pH in anaesthetised dogs. MATERIALS AND METHODS: Fifty-five dogs undergoing elective ovariectomy were randomly assigned to: omeprazole single dose 1 mg/kg orally the evening before anaesthesia (20 dogs), omeprazole two doses 1 mg/kg orally the evening and 3 hours before anaesthesia (15 dogs), and control group that did not receive omeprazole (20 dogs). An oesophageal impedance/pH probe was used to measure gastroesophageal reflux incidence and pH during anaesthesia. RESULTS: Gastroesophageal reflux was observed in 55% (11/20) of control dogs, 55% (11/20) of dogs receiving omeprazole once and 47% (7/15) of dogs receiving omeprazole twice. The incidence was not statistically significant different between groups. Gastroesophageal reflux pH (mean ± sd) was higher in dogs receiving omeprazole twice (6.3 ± 1.5), when compared to either control dogs (3.8 ± 1.1) or dogs receiving omeprazole once (4.1 ± 1.5). Strongly acidic reflux (pH < 4) was observed in 7% (1/15) of dogs receiving omeprazole twice versus 55% (11/20) and 35% (7/20) of control dogs and dogs receiving omeprazole once, respectively. CLINICAL SIGNIFICANCE: Omeprazole administered the evening and 3 hours before anaesthesia increased gastroesophageal reflux pH and decreased the incidence of strongly acidic reflux in dogs. A single dose of omeprazole given the evening before anaesthesia had no effect on reflux pH.

The European Academy of Andrology (EAA) ultrasound study on healthy, fertile men: Scrotal ultrasound reference ranges and associations with clinical, seminal, and biochemical characteristics.

BACKGROUND: Scrotal color Doppler ultrasound (CDUS) still suffers from lack of standardization. Hence, the European Academy of Andrology (EAA) has promoted a multicenter study to assess the CDUS characteristics of healthy fertile men (HFM) to obtain normative parameters. OBJECTIVES: To report and discuss the scrotal organs CDUS reference ranges and characteristics in HFM and their associations with clinical, seminal, and biochemical parameters. METHODS: A cohort of 248 HFM (35.3 ± 5.9years) was studied, evaluating, on the same day, clinical, biochemical, seminal, and scrotal CDUS following Standard Operating Procedures. RESULTS: The CDUS reference range and characteristics of the scrotal organs of HFM are reported here. CDUS showed a higher accuracy than physical examination in detecting scrotal abnormalities. Prader orchidometer (PO)- and US-measured testicular volume (TV) were closely related. The US-assessed TV with the ellipsoid formula showed the best correlation with the PO-TV. The mean TV of HFM was ~ 17 ml. The lowest reference limit for right and left testis was 12 and 11 ml, thresholds defining testicular hypotrophy. The highest reference limit for epididymal head, tail, and vas deferens was 12, 6, and 4.5 mm, respectively. Mean TV was associated positively with sperm concentration and total count and negatively with gonadotropins levels and pulse pressure. Subjects with testicular inhomogeneity or calcifications showed lower sperm vitality and concentration, respectively, than the rest of the sample. Sperm normal morphology and progressive motility were positively associated with epididymal head size/vascularization and vas deferens size, respectively. Increased epididymis and vas deferens sizes were associated with MAR test positivity. Decreased epididymal tail homogeneity/vascularization were positively associated with waistline, which was negatively associated with intratesticular vascularization. CDUS varicocele was detected in 37.2% of men and was not associated with seminal or hormonal parameters. Scrotal CDUS parameters were not associated with time to pregnancy, number of children, history of miscarriage. CONCLUSIONS: The present findings will help in better understanding male infertility pathophysiology, improving its management.

Testosterone treatment is associated with reduced adipose tissue dysfunction and nonalcoholic fatty liver disease in obese hypogonadal men.

PURPOSE: In both preclinical and clinical settings, testosterone treatment (TTh) of hypogonadism has shown beneficial effects on insulin sensitivity and visceral and liver fat accumulation. This prospective, observational study was aimed at assessing the change in markers of fat and liver functioning in obese men scheduled for bariatric surgery. METHODS: Hypogonadal patients with consistent symptoms (n = 15) undergoing 27.63 ± 3.64 weeks of TTh were compared to untreated eugonadal (n = 17) or asymptomatic hypogonadal (n = 46) men. A cross-sectional analysis among the different groups was also performed, especially for data derived from liver and fat biopsies. Preadipocytes isolated from adipose tissue biopsies were used to evaluate insulin sensitivity, adipogenic potential and mitochondrial function. NAFLD was evaluated by triglyceride assay and by calculating NAFLD activity score in liver biopsies. RESULTS: In TTh-hypogonadal men, histopathological NAFLD activity and steatosis scores, as well as liver triglyceride content were lower than in untreated-hypogonadal men and comparable to eugonadal ones. TTh was also associated with a favorable hepatic expression of lipid handling-related genes. In visceral adipose tissue and preadipocytes, TTh was associated with an increased expression of lipid catabolism and mitochondrial bio-functionality markers. Preadipocytes from TTh men also exhibited a healthier morpho-functional phenotype of mitochondria and higher insulin-sensitivity compared to untreated-hypogonadal ones. CONCLUSIONS: The present data suggest that TTh in severely obese, hypogonadal individuals induces metabolically healthier preadipocytes, improving insulin sensitivity, mitochondrial functioning and lipid handling. A potentially protective role for testosterone on the progression of NAFLD, improving hepatic steatosis and reducing intrahepatic triglyceride content, was also envisaged. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02248467, September 25th 2014.

The prevalence of midline prostatic cysts and the relationship between cyst size and semen parameters among infertile and fertile men.

STUDY QUESTION: When is the investigation and treatment of midline prostatic cysts (MPC) of clinical value in the work-up of males of infertile couples? SUMMARY ANSWER: With a prevalence of 10.2% in infertile men, MPC should be investigated according to a seminal algorithm detecting a MPC volume >0.117 ml, which may impair semen parameters, and could be treated to improve sperm count and achieve natural pregnancy. WHAT IS KNOWN ALREADY: MPC are frequent and are considered a correctable cause of male infertility. However, they have been poorly investigated in an infertility setting. In addition, no study has investigated clinical and ultrasound (US) characteristics of men with MPC. STUDY DESIGN, SIZE, DURATION: A cross-sectional analysis was carried out of 693 consecutive subjects consulting for couple infertility from September 2012 to March 2017. As a control group, 103 age-matched healthy, fertile men were studied. Furthermore, a longitudinal evaluation of 11 infertile men undergoing trans-rectal ultrasonically-guided cyst aspiration (TRUCA), semen analyses 1 and 3 months after TRUCA and a follow-up 1 year after TRUCA to assess natural pregnancy were performed. PARTICIPANTS/MATERIALS, SETTING, METHODS: All subjects underwent, in our outpatient clinic, clinical, hormonal, scrotal and transrectal US evaluation and semen analysis within the same day. Of 693 males of infertile couples, 648 (37.1 ± 7.9 years, mean+SD) without genetic abnormalities were studied, along with 103 fertile men (36.6 ± 5.0 years). Eleven infertile men underwent TRUCA and were followed-up as reported above. MAIN RESULTS AND THE ROLE OF CHANCE: A MPC was present in 66/648 (10.2%) males of infertile couples and in 6/103 (5.8%) fertile men. MPC occurrence and volume were higher in patients with severe oligo- or azoospermia than in fertile men (all P < 0.05). Infertile men with a MPC showed a lower seminal volume and sperm count and a higher prevalence of azoospermia than the rest of the infertile sample or fertile men, and a higher frequency of US signs suggestive of ejaculatory duct obstruction. MPC volume was negatively associated with total sperm count (r = -0.452, P < 0.0001). In fertile men, the highest MPC volume was 0.117 ml, suggesting it as a biological threshold not compromising semen quality. In infertile men, using receiver operating characteristic curve analyses, a MPC volume >0.117 ml identified subjects with severe oligo- or azoospermia with an overall accuracy of ~75% (both P < 0.005). Eleven men with infertility, semen abnormalities and large MPC (>0.250 ml) underwent TRUCA, which led to sperm count improvement in all patients 1 month after surgery. Three months after TRUCA a lower sperm count and a higher MPC volume than 2 months before were observed (P < 0.005 and P < 0.05, respectively), although improved when compared to baseline. After TRUCA a natural pregnancy occurred in four couples. Finally, we propose an algorithm, based on semen parameters, useful in identifying a MPC in males of infertile couples. LIMITATIONS, REASONS FOR CAUTION: Although in line with the sample size of previous studies (n = 7-20), the number of infertile men with MPC evaluated longitudinally after treatment is limited (n = 11). In addition, although a MPC volume >0.117 ml can negatively affect the sperm count, only MPC > 0.250 ml have been treated in this study. WIDER IMPLICATIONS OF THE FINDINGS: First, the algorithm proposed is easy to use and useful for selecting patients who can benefit from a prostate US in the infertility work-up. Second, a MPC volume ≤0.117 ml may not impair semen quality, while a larger volume can lead to severe oligo- or azoospermia and could be treated. Third, TRUCA is effective, and simpler and less invasive than other surgical techniques for MPC treatment. Finally, since the MPC can increase in size and sperm count decrease over time after TRUCA, semen cryopreservation should be considered 1 month after TRUCA. STUDY FUNDING/COMPETING INTEREST(S): Grants from the Ministry of University and Scientific Research (SIR project to F.L., protocol number: RBSI14LFMQ). No conflicts of interest.

Epididymal more than testicular abnormalities are associated with the occurrence of antisperm antibodies as evaluated by the MAR test.

STUDY QUESTION: Is there any association between mixed antiglobulin reaction (MAR) test positivity and clinical features or genital tract ultrasound (US) parameter values in males of infertile and fertile couples? STUDY ANSWER: In males of infertile and fertile couples MAR test positivity was associated with clinical and US features suggestive of chronic epididymal inflammation. WHAT IS KNOWN ALREADY: MAR test positivity has been more often reported in males of infertile couples than in fertile men. A positive MAR test has been detected in men with a history of testicular or post-testicular damage. No previous study has reported US alterations related to MAR test positivity. This is the first study that has systematically evaluated associations between a positive MAR test and clinical, seminal and US characteristics of the entire male genital tract. STUDY DESIGN, SIZE, DURATION: This cross-sectional analysis included 109 fertile men and 699 consecutive subjects seeking medical care for couple infertility from September 2012 to September 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: All subjects underwent, in our outpatient clinic, a complete physical, endocrine, scrotal and transrectal US evaluation and semen analysis (including sIL-8) on the same day. Of the 699 males of infertile couples, 181 (age 38.6 ± 6.6 years) had an assessable MAR test, whereas the test was assessable in all 109 fertile men (age 36.6 ± 5.2 years). The associations among MAR test positivity and the other studied parameters were investigated on a caseload of 290 men (patients + fertile men) and in the two cohorts of males of infertile and fertile couples. MAIN RESULTS AND THE ROLE OF CHANCE: Of the 181 men of infertile couples studied, 20 (11%) had a positive MAR test, including 12 (6.6%) who had a MAR test ≥ 50%, which is considered as a pathological threshold according to the WHO. Of the 109 fertile men, four (3.7%) had a positive MAR test, of which one (0.9%) had a MAR test ≥ 50%. MAR test positivity was therefore found more often in men of infertile couples (P < 0.05). In the entire caseload (n = 290) of males of both infertile and fertile couples, no correlations between MAR test positivity and seminal characteristics were observed. A positive MAR test was associated with epididymal US abnormalities, particularly with the mean size of the epididymal body and tail (both P < 0.0001), and in infertile men, a positive MAR test was also associated with an abnormal epididymal echotexture. In addition, subjects with a positive MAR test more frequently showed a history of epididymitis and high sIL-8 levels. Considering endocrine parameters, only a positive correlation between MAR test positivity and LH levels was observed, even after adjusting for age and life-style factors (adj. r = 0.232, P < 0.0001), while no associations with testosterone and FSH levels were found. LIMITATIONS, REASONS FOR CAUTION: Antisperm antibodies (ASA) were detected in this study by using the SpermMAR test IgG, but other tests are available. In addition, for technical reasons, the MAR test is not assessable in subjects with severe oligo-astheno-zoospermia and, therefore, this test may lead to an intrinsic selection bias. Finally, owing to the cross-sectional nature of the study, neither a causality hypothesis nor mechanistic models can be inferred. WIDER IMPLICATIONS OF THE FINDINGS: First, our results indicate that MAR test positivity is associated with clinical and US signs suggestive of chronic epididymal inflammation and not testicular damage. Hence, when investigating a subject with a positive MAR test, the epididymis and not just the testis should be evaluated. Furthermore, MAR test positivity was more often detected in males of infertile couples than in fertile men, but it was not associated with conventional semen parameter values. Our data support a role of ASA in couple infertility, regardless of the conventional sperm analysis. How ASA affects couple fertility needs to be addressed by further studies. STUDY FUNDING/COMPETING INTEREST(S): Grants were received from the Ministry of University and Scientific Research (SIR project to F.L., protocol number: RBSI14LFMQ). There are no conflicts of interest. TRIAL REGISTRATION NUMBER: N/A.

Cabozantinib Affects Osteosarcoma Growth Through A Direct Effect On Tumor Cells and Modifications In Bone Microenvironment.

Osteosarcoma (OS) is the most common primary malignant tumor of the bone. Due to its high heterogeneity and to survival signals from bone microenvironment, OS can resist to standard treatments, therefore novel therapies are needed. c-MET oncogene, a tyrosine-kinase receptor, plays a crucial role in OS initiation and progression. The present study aimed to evaluate the effect of c-MET inhibitor cabozantinib (CBZ) on OS both directly and through its action on bone microenvironment. We tested different doses of CBZ in in vitro models of OS alone or in co-culture with bone cells in order to reproduce OS-tumor microenvironment interactions. CBZ is able to decrease proliferation and migration of OS cells, inhibiting ERK and AKT signaling pathways. Furthermore, CBZ leads to the inhibition of the proliferation of OS cells expressing receptor activator of nuclear factor κB (RANK), due to its effect on bone microenvironment, where it causes an overproduction of osteoprotegerin and a decrease of production of RANK ligand by osteoblasts. Overall, our data demonstrate that CBZ might represent a new potential treatment against OS, affecting both OS cells and their microenvironment. In this scenario, RANK expression in OS cells could represent a predictive factor of better response to CBZ treatment.

Testosterone treatment and cardiovascular and venous thromboembolism risk: what is 'new'?

In men, testosterone (T) production declines as a function of ageing. Late-onset hypogonadism (LOH) is the most commonly used term to indicate this age-related condition. In LOH, the relative clinical significance and the potential benefit of testosterone treatment (TTh) are still the subject of strong criticisms in the scientific community. The debate is further complicated by the recent position statement of the US Food and Drug Administration (FDA) emphasizing that, in LOH, the benefits and safety of TTh have not been fully established. Hence, the FDA required a labeling change to inform patients about a possible increased cardiovascular (CV) risk of TTh. Similar considerations were previously released by the FDA and by Health Canada concerning a TTh-related venous thromboembolism (VTE) risk. In this review, we will summarize the available evidence concerning a possible link among TTh and CV and VTE risks. For this purpose, data derived from epidemiological studies analyzing relationships between the aforementioned risks and endogenous T levels will be analyzed. In addition, evidence deriving from interventional studies including pharmacoepidemiological and placebo-controlled randomized controlled trials (RCTs) will be examined. Our analysis shows that available data do not support an increased CV risk related to TTh. Similar considerations can be drawn for the relationship between TTh and VTE. The previously reported cases of TTh-related VTE were frequently related to a previously undiagnosed thrombophilia-hypofibrinolysis status. Hence, an anamnestic screening for thrombophilia before starting TTh is recommended, just as it is for the use of oral contraceptives.

Short-term FSH treatment and sperm maturation: a prospective study in idiopathic infertile men.

The standard FSH treatment is based on a 3 months period, after which both quantitative/qualitative improvement of sperm parameters and increased pregnancy rate were reported. In this prospective clinical trial, for the first time, we studied (i) Sperm hyaluronic acid binding capacity after highly purified FSH (hpFSH) treatment; (ii) the effect after short-term and standard treatment on this functional parameter. As secondary objective, we analyzed three SNPs on FSHß and FSHR genes to define their potential predictive value for responsiveness. From a total of 210 consecutive patients, 40 oligo- and/or astheno- and/or teratozoospermic patients fulfilled the inclusion criteria. Treatment consisted in hpFSH 75 IU/L every other day for 3 months. To avoid potential biases derived from the lack of placebo, we analyzed each patient after 4-6 months of 'wash-out' period. After FSH treatment, we observed a statistically significant (p < 0.001) improvement of the percentage of hyaluronic acid bound spermatozoa from basal to T1 (after 1 month) and to T3 (after 3 months). Importantly, these values returned to near-baseline value after the wash-out. The same results were detected for total motile sperm count after 3 months with return to baseline after wash-out. Forty-two percent of patients responded to the therapy with increasing hyaluronic acid binding capacity above the double of the Intraindividual Variation (IV) while 24% of patients reached above the normal Sperm-Hyaluronan Binding Assay (HBA) value. Further increase in 'responders' was observed at T3. The responsiveness to treatment resulted independent from FSHR/FSHß polymorphisms. The significant positive effect on sperm maturity after 1 month opens novel therapeutic perspectives. In view of both the high cost and the relative invasiveness of treatment, the short protocol (1 month) could represent a viable FSH treatment option prior Assisted Reproductive Techniques since FSH, by acting on sperm maturation, increases the proportion of functionally competent cells.

Semen quality impairment is associated with sexual dysfunction according to its severity.

STUDY QUESTION: Is sexual dysfunction associated with severity of semen quality impairment in men with couple infertility? SUMMARY ANSWER: In males of infertile couples the prevalence of erectile dysfunction (ED) increases as a function of semen quality impairment severity. WHAT IS KNOWN ALREADY: Infertile men are at a higher risk for sexual dysfunction, psychopathological and general health disorders. However, it has never been systematically investigated if these problems are associated with severity of semen quality impairment. STUDY DESIGN, SIZE, DURATION: Cross-sectional analysis of a first-time evaluation of 448 males of infertile couples attending an outpatient clinic from September 2010 to November 2015. In addition, 74 age-matched healthy, fertile men from an ultrasound study on male fertility were studied for comparison. PARTICIPANTS/MATERIALS, SETTING, METHODS: All subjects underwent a complete physical, biochemical, scrotal and flaccid penile colour-Doppler ultrasound evaluation and semen analysis. Patients had already undergone at least one semen analysis; therefore, the majority were aware of their sperm quality before taking part in the study. Validated tools, such as the International Index of Sexual Function-15 (IIEF-15), Premature Ejaculation Diagnostic Tool (PEDT), Middlesex Hospital Questionnaire (MHQ), National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI), International Prostate Symptom Score and Chronic Disease Score (CDS), were used to evaluate, respectively, sexual dysfunction, premature ejaculation (PE), psychopathological traits, prostatitis-like symptoms, lower urinary tract symptoms and general health status. MAIN RESULTS AND THE ROLE OF CHANCE: Among men with couple infertility, 96 showed azoospermia (Group #1), 245 at least one sperm abnormality (Group #2) and 107 normozoospermia (Group #3). Fertile men were considered as a control group (Group #4). After adjusting for age, we observed a higher prevalence of ED (IIEF-15-erectile function domain score <26) (18.3% versus 0%; P = 0.006) and PE (PEDT score >8) (12.9% versus 4.1%; P = 0.036) in males of infertile couples compared with fertile men. The ED prevalence increases as a function of semen quality impairment severity (P < 0.0001), even after adjusting for confounders (age, CDS, MHQ and NIH-CPSI total score), despite similar hormonal, glyco-metabolic and penile vascular status. Compared to fertile men, all three groups of males with couple infertility showed a poorer erectile function, associated with an overall psychopathological burden (MHQ total score), particularly with somatized anxiety (MHQ-S). Azoospermic men showed the worst erectile function and general health: in this group, erectile function was negatively associated not only with psychopathological disturbances (MHQ total and MHQ-S scores; P < 0.0001) but also with a less healthy phenotype (higher CDS; P = 0.015). In addition, azoospermic men reported higher PE prevalence and lower sexual desire and orgasmic function when compared to fertile men (all P < 0.05), all of which were related to psychopathological symptoms. LIMITATIONS, REASONS FOR CAUTION: The cross-sectional nature of the study represents its main limitation. A possible selection bias concerning the control group of healthy, fertile men recruited into an ultrasound study might have occurred. Finally, causality cannot be inferred in this type of study design and hence there should be some caution in interpreting the results. WIDER IMPLICATIONS OF THE FINDINGS: Investigation of male sexual function, general health and psychological status in infertile couples, especially if azoospermic, is advisable, in order to improve not only reproductive but also general and sexual health. STUDY FUNDING/COMPETING INTERESTS: Grants were received from the Ministry of University and Scientific Research (SIR project to F.L., protocol number: RBSI14LFMQ). There are no conflicts of interest. TRIAL REGISTRATION NUMBER: None.

The impact of premature ejaculation on the subjective perception of orgasmic intensity: validation and standardisation of the 'Orgasmometer'.

To the best of our knowledge, no psychometric tools have been specifically developed to measure if premature ejaculation (PE) is related to low sexual pleasure in terms of perception of orgasmic intensity. Hence, the aim of this study was to evaluate if men with PE suffer from a low perception of orgasmic intensity using a new tool, the 'Orgasmometer', to quantitatively measure the intensity of orgasmic pleasure. Among 329 subjects attending our andrological unit for suspected PE, 257 men fulfilled the inclusion criteria. Of these, 156 (60.7%; 156/257) were affected by PE (PE group) and 101 (39.3%; 101/257) did not have any sexual dysfunction (Control group). Men were requested to fill out the Premature Ejaculation Diagnostic Tool (PEDT) and the Orgasmometer, a new visual tool recording orgasm intensity on a Likert scale. Interestingly, MANCOVA analysis revealed a statistically significant difference between the two groups (p = 0.044) in the subjective perception of orgasm intensity with the PE group scoring lower on the Orgasmometer (mean 5.8; 95% CI 5.191-6.409) than the Control group (mean 7.95; 95% CI 7.033-8.87). In addition, multiple linear regression revealed an inverse correlation between the PEDT and the Orgasmometer scores (p < 0.0001). Hence, higher PEDT scores were associated with a lower subjective perception of orgasmic intensity. The Orgasmometer was well understood, had good test-retest reliability and a high AUC in differentiating between men with high and low orgasmic pleasure intensity. The ROC curve analysis showed that a cut-off ≤6 had 87.7% sensitivity (95% CI 79.6-92.6), 95% specificity (95% CI 88.7-98.4), 95.3% positive predictive value (PPV) and 86.4% negative predictive value (NPV). Men affected by premature ejaculation perceived significantly lower orgasmic intensity than sexually healthy men. The Orgasmometer is an easy-to-perform, user-friendly tool for measuring orgasmic intensity.

Is thyroid hormones evaluation of clinical value in the work-up of males of infertile couples?

STUDY QUESTION: Is thyroid hormones (TH) evaluation of clinical value in the work-up of males of infertile couples? STUDY ANSWER: Our results suggest that TH evaluation is not mandatory in the work-up of male infertility. WHAT IS KNOWN ALREADY: A few previous studies performed on a limited series of subjects reported a negative impact of hyper- and hypo-thyroidism on semen volume, sperm concentration, progressive motility and normal morphology. No previous study has systematically evaluated associations between TH variation, semen parameters and ultrasound characteristics of the male genital tract. STUDY DESIGN, SIZE AND DURATION: Cross-sectional analysis of a consecutive series of 172 subjects seeking medical care for couple infertility from September 2010 to November 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: Of the entire cohort, 163 men (age 38.9 ± 8.0 years) free of genetic abnormalities were studied. All subjects underwent a complete andrological and physical examination, biochemical and hormonal assessment, scrotal and transrectal colour-Doppler ultrasound (CDUS) and semen analysis (including seminal interleukin 8 levels, sIL-8) evaluation within the same day. MAIN RESULTS AND THE ROLE OF CHANCE: Among the patients studied, 145 (88.9%) showed euthyroidism, 6 (3.7%) subclinical hyper- and 12 (7.4%) subclinical hypo-thyroidism. No subjects showed overt hyper- or hypo-thyroidism. At univariate analysis, no associations among thyroid-stimulating hormone (TSH) or TH levels and sperm parameters were observed. Conversely, we observed positive associations among free triiodothyronine (fT3) and free thyroxine (fT4) levels, ejaculate volume and seminal fructose levels. In a multivariate model, after adjusting for confounders such as age, body mass index, smoking habit, sexual abstinence, calculated free testosterone, prolactin and sIL-8 levels, only the associations found for fT3 levels were confirmed. When CDUS features were investigated, using the same multivariate model, we found positive associations between fT3 levels and seminal vesicles (SV) volume, both before and after ejaculation (adj. r = 0.354 and adj. r = 0.318, both P < 0.0001), as well as with SV emptying (ΔSV volume; adj. r = 0.346, P < 0.0001) and echo-texture inhomogeneity. In addition, after adjusting for confounders, negative associations between fT4 levels and epididymal body and tail diameters were found. No significant associations between TSH or TH levels and CDUS features of other organs of the male genital tract, including testis and prostate, were found. Finally, when the features of subjects with euthyroidism, subclinical hypo- and hyper-thyroidism were compared, no significant differences in seminal or hormonal parameters were found. Conversely, evaluating CDUS parameters, subjects with subclinical hyperthyroidism showed a higher difference between the SV longitudinal diameters measured before and after ejaculation when compared with that of subclinical hypothyroid men, even after adjusting for confounders (P < 0.007). All the other male genital tract CDUS characteristics did not differ among groups. LIMITATIONS, REASONS FOR CAUTION: First, the number of patients investigated is relatively small and those with (subclinical) thyroid dysfunctions are an even smaller number; hence, it is therefore difficult to draw firm conclusions. Moreover, the present results are derived from patients consulting an Italian Andrology Clinic for couple infertility, and could have different characteristics from the male general population or from those males consulting general practitioners for reasons other than couple infertility. Finally, due to the cross-sectional nature of the study, neither a causality hypothesis nor mechanistic models can be inferred. WIDER IMPLICATIONS OF THE FINDINGS: Although no associations between TH and sperm parameters were observed, present data support a positive effect of TH on SV size and a permissive role on the ejaculatory machinery, likely through an action on SV and epididymal contractility. This is the first study reporting such evidence. However, in contrast with the view that TH assessment is important for female fertility, our results do not support a systematic evaluation of thyroid function in males of infertile couples. How TH abnormalities impact male fertility needs to be addressed by further studies. STUDY FUNDING/COMPETING INTERESTS: No funding was received for the study. None of the authors have any conflict of interest to declare.

Current smoking is associated with lower seminal vesicles and ejaculate volume, despite higher testosterone levels, in male subjects of infertile couples.

STUDY QUESTION: What is the impact of smoking behaviour on seminal, hormonal and male genital tract ultrasound parameters in subjects seeking medical care for couple infertility? STUDY ANSWER: In males of infertile couples, current smokers (CS), when compared with non-smokers, show lower ejaculate and ultrasound-derived seminal vesicles (SV) volume, despite higher testosterone levels. WHAT IS KNOWN ALREADY: Data on the effects of smoking on male fertility are conflicting. A correlation between smoking and reduced semen parameters has been reported, however, with a high heterogeneity among studies. An association between smoking behaviour and higher testosterone levels in men has been described in several, but not all, the previous studies. No study has systematically evaluated the impact of smoking on the male genital tract ultrasound characteristics. STUDY DESIGN, SIZE AND DURATION: Retrospective cross-sectional analysis of a consecutive series of 426 subjects seeking medical care for couple infertility from January 2010 to July 2013. PARTICIPANTS/MATERIALS, SETTING, METHODS: From the entire cohort, 394 men (age 36.0 ± 8.0 years) free of genetic abnormalities were selected. All subjects underwent a complete andrological and physical examination, biochemical and hormonal assessment, scrotal and transrectal colour-Doppler ultrasound and semen analysis (including seminal interleukin-8 levels, sIL-8) within the same day. MAIN RESULTS AND THE ROLE OF CHANCE: Among the patients evaluated, 229 were never smokers (NS), 56 past smokers (PS) and 109 CS. When CS were compared with the rest of the sample (non-smokers, NS + PS), in a multivariate model (analysis of covariance, ANCOVA) adjusted for age, lifestyle (including alcohol, cannabis and physical activity), BMI and sex hormone-binding globulin, significantly higher androgen (total testosterone, P = 0.001; calculated free testosterone, P < 0.005) and lower FSH (P < 0.05) levels were observed in CS. However, when total testosterone was also included in the multivariate model as a further covariate, the difference in FSH levels was not confirmed. In a similar model, a lower ejaculate volume (P < 0.01) and a higher prevalence of normal sperm morphology (P < 0.02) were also detected in CS in comparison with the rest of the sample. However, when total testosterone was also included in the multivariate model as a further covariate, only the difference in ejaculate volume between CS and non-smokers was confirmed (-0.61 ± 0.23 ml, P < 0.01). Finally, CS showed lower total SV volume, before and after ejaculation, even after adjusting for confounders (P = 0.02 and <0.01, respectively). Similar results were observed when the reported number of cigarettes smoked or the number of pack-years was considered separately. LIMITATIONS, REASONS FOR CAUTION: The present results are derived from patients consulting an Andrology Clinic for couple infertility, who could have different characteristics from the general male population or males consulting general practitioners for reasons other than couple infertility. In addition, we did not have a true control group composed of age-matched, apparently healthy, fertile men, and therefore true normative data of sonographic parameters cannot be inferred. Due to the cross-sectional nature of our study, neither a causality hypothesis nor mechanistic models can be drawn. Finally, this is a retrospective study, and further prospective studies are required. WIDER IMPLICATIONS OF THE FINDINGS: We report an apparent paradox in CS: lower SV volume despite higher testosterone levels. Our data suggest that smoking may negatively affect SV volume in an independent manner, as the difference between CS and non-smokers retained significance after adjusting for confounders including testosterone. This is the first study reporting such ultrasound evidence. How this new smoking-related alteration, along with low semen volume, impacts male fertility needs to be addressed by further studies. STUDY FUNDING/COMPETING INTERESTS: No funding was received for the study. None of the authors have any conflict of interest to declare.

High prevalence of circulating autoantibodies against thyroid hormones in vitiligo and correlation with clinical and historical parameters of patients.

BACKGROUND: Autoantibodies against thyroid hormones (THAbs) directed towards triiodothyronine (T3-Ab) and/or thyroxine (T4-Ab) are very rare in the general population. They are increased in some nonthyroidal autoimmune diseases, where they seem to predict autoimmune thyroid disorders (ATDs). So far, their presence in patients with vitiligo has not been evaluated, but it might have a possible predictive role. OBJECTIVES: To assess the prevalence of THAbs in a group of vitiligo patients and to correlate their presence with clinical and historical parameters. METHODS: In total 79 patients with nonsegmental vitiligo and 100 controls were examined. Clinical characteristics of vitiligo and family and personal medical history were evaluated. Antinuclear autoantibodies, thyroid hormones and thyroid autoantibodies were measured. IgM T3-Ab, IgG T3-Ab, IgM T4-Ab and IgG T4-Ab were assayed by a radioimmunoprecipitation technique. Fisher's test, Student's t-test and χ(2)-test were used for statistical analysis. RESULTS: Overall 77 of 79 patients (97%) had at least one type of THAb (11 T3-Ab, 10 T4-Ab, 56 both). In the control group, only one person (1%) had THAbs. In patients with vitiligo, T3-Abs were significantly associated with leucotrichia (IgM+IgG, P = 0.033; IgG, P = 0.039; IgM, P = 0.005) and thyroglobulin autoantibodies (IgM+IgG, P = 0.031; IgG, P = 0.058), while the absence of T3-Ab was related to personal history of cancer (IgM+IgG, P = 0.021; IgG, P = 0.039). T4-Abs were significantly associated with vitiligo activity (IgM+IgG, P < 0.001; IgM, P = 0.037) and duration (IgG, P = 0.013). CONCLUSIONS: The surprisingly high prevalence of THAb in patients with vitiligo and their associations suggest a possible pathogenetic role in the disease and stress the tight link between vitiligo and ATDs. Further evaluation in a larger group of patients and an adequate follow-up are needed to define their potential predictive role.

Seminal, clinical and colour-Doppler ultrasound correlations of prostatitis-like symptoms in males of infertile couples.

'Prostatitis-like symptoms' (PLS) are a cluster of bothersome conditions defined as 'perineal and/or ejaculatory pain or discomfort and National Institutes of Health-Chronic Prostatitis Symptom Index (NIH-CPSI) pain subdomain score ≥4' (Nickel's criteria). PLS may originate from the prostate or from other portions of the male genital tract. Although PLS could be associated with 'prostatitis', they should not be confused. The NIH-CPSI is considered the gold-standard for assessing PLS severity. Although previous studies investigated the impact of prostatitis, vesiculitis or epididymitis on semen parameters, correlations between their related symptoms and seminal or scrotal/transrectal colour-Doppler ultrasound (CDU) characteristics have not been carefully determined. And no previous study evaluated the CDU features of PLS in infertile men. This study was aimed at investigating possible associations among NIH-CPSI (total and subdomain) scores and PLS, with seminal, clinical and scrotal/transrectal CDU parameters in a cohort of males of infertile couples. PLS of 400 men (35.8 ± 7.2 years) with a suspected male factor were assessed by the NIH-CPSI. All patients underwent, during the same day, semen analysis, seminal plasma interleukin 8 (sIL-8, a marker of male genital tract inflammation), biochemical evaluation, urine/seminal cultures, scrotal/transrectal CDU. PLS was detected in 39 (9.8%) subjects. After adjusting for age, waist and total testosterone (TT), no association among NIH-CPSI (total or subdomain) scores or PLS and sperm parameters was observed. However, we found a positive association with current positive urine and/or seminal cultures, sIL-8 levels and CDU features suggestive of inflammation of the epididymis, seminal vesicles, prostate, but not of the testis. The aforementioned significant associations of PLS were further confirmed by comparing PLS patients with age-, waist- and TT-matched PLS-free patients (1 : 3 ratio). In conclusion, NIH-CPSI scores and PLS evaluated in males of infertile couples, are not related to sperm parameters, but mainly to clinical and CDU signs of infection/inflammation.

Clinical implications of measuring prolactin levels in males of infertile couples.

Although in females of infertile couples abnormal prolactin (PRL) has a definitive role in the medical flowchart, its role in males is less clear. Animal models suggest that PRL does not play a major role in male reproduction, although its trophic action on male accessory glands was often observed. Studies in humans are scanty. We systematically evaluated possible clinical and ultrasound correlates of PRL in males of infertile couples. Of 288 consecutive males of infertile couples, 269 (36.6 ± 4.4 years) without genetic abnormalities were studied. All men underwent physical, biochemical, seminal evaluation and scrotal and transrectal ultrasound before and after ejaculation. Ejaculatory and erectile functions were assessed by Premature Ejaculation Diagnostic Tool (PEDT) and International Index of Erectile Function (IIEF)-15 respectively; prostate-related symptoms by National Institutes of Health-Chronic Prostatitis Symptom Index and International Prostate Symptom Score; psychological symptoms by Middlesex Hospital Questionnaire. Among semen parameters, only the positive association between PRL and ejaculate volume was significant, even adjusting for age, total testosterone and thyroid-stimulating hormone (adj. r = 0.126, p < 0.05). In a logistic ordinal model, adjusting for the aforementioned confounders and ejaculate volume, PRL was negatively associated with delaying ejaculation according to PEDT#1 score (Wald = 4.65, p < 0.05). In an age- and ejaculate volume-adjusted, iterative binary logistic model, low PRL was associated with a fivefold risk of any failure in controlling ejaculation (HR = 5.15 [1.15-23], p < 0.05). Among scrotal and transrectal ultrasound features, we found a significant positive association between PRL and seminal vesicles (SV) volume and inhomogeneity, before and after ejaculation, and with deferential ampullas diameter. Associations with PRL were confirmed in nested 1 : 1 case-control analysis. No significant associations were found between PRL and other clinical parameters. For the first time, this study extends the concept of a trophic effect of PRL on male accessory glands from animals to humans. We report a positive association among PRL and ejaculate and SV volume, before and after ejaculation. Low PRL is associated with a lessened ability to control ejaculation.

Seminal vesicles and diabetic neuropathy: ultrasound evaluation after prolonged treatment with a selective phosphodiesterase-5 inhibitor.

We have previously reported that infertile patients with diabetes mellitus (DM) have a particular ultrasound features of the seminal vesicles (SV) characterized by higher fundus-to-body ratio and lower pre- and post-ejaculatory difference in body antero-posterior diameter (APD). Based on these premises the aim of the present study was to investigate possible ultrasound SV changes in infertile patients with DM and diabetic neuropathy (DN), after prolonged administration of tadalafil (TAD) (a specific phosphodiesterase-5 inhibitor). To accomplish this, 20 infertile patients with symptomatic DN and erectile dysfunction were selected and arbitrarily divided into two groups which were assigned to: daily administration of 5 mg TAD for 3 months (Group A) (n = 10) and administration of placebo (Group B) (n = 10). All patients underwent to scrotal and prostate-vesicular transrectal ultrasound evaluation and semen analysis (Laboratory Manual for the Examination and Processing of Human Semen, WHO, 2010) before and after treatment. The following SV US parameters were recorded: (i) body APD; (ii) fundus APD; (iii) parietal thickness of the right and left SVs; and (iv) number of polycyclic areas within both SVs. We then calculated the following parameters: (i) fundus/body (F/B) ratio; (ii) difference of the parietal thickness between the right and the left SV and (iii) pre- and post-ejaculatory APD difference. In addition, we also evaluated the SV ejection fraction. Group A patients showed a significant reduction in F/B ratio and higher pre- and post-ejaculatory body SV APD difference compared with baseline or Group B after 3 months. These patients showed also a significant increase in SV ejection fraction and a significant improvement of the total sperm count, progressive motility, seminal levels of fructose, leucocytes and ejaculate volume. In conclusion, these results suggest that infertile DM patients with DN and erectile dysfunction had an improvement of ultrasound features suggestive of diabetic neuropathy after daily treatment with low doses of TAD.

Seminal, ultrasound and psychobiological parameters correlate with metabolic syndrome in male members of infertile couples.

Metabolic syndrome (MetS) is a diagnostic category which identifies subjects at high risk for diabetes and cardiovascular diseases, erectile dysfunction (ED) and male hypogonadism. However, MetS impact on male infertility has been poorly studied. We systematically evaluated possible associations between MetS and clinical characteristics in men with couple infertility. Out of 367 consecutive subjects, 351 men without genetic abnormalities were studied. MetS was defined according to the International Diabetes Federation&American Heart Association/National Heart,Lung, and Blood Institute classification. All men underwent physical, hormonal, seminal and scrotal ultrasound evaluation. Erectile and ejaculatory functions were assessed by International Index of Erectile Function-15 erectile function domain (IIEF-15-EFD) and Premature Ejaculation Diagnostic Tool (PEDT), respectively, while psychological symptoms by Middlesex Hospital Questionnaire. Out of 351 patients, 27 (7.7%) fulfilled MetS criteria. Among ultrasound features, in an age-adjusted logistic model, only testis inhomogeneity was significantly associated with increasing MetS factors (HR = 1.36 [1.09-1.70]; p < 0.01). In an age-adjusted model, MetS was associated with a stepwise decline in total testosterone (TT) (B = -1.25 ± 0.33; p < 0.0001), without a concomitant rise in gonadotropins. At univariate analysis, progressive motility and normal morphology were negatively related to the number of MetS components (both p < 0.0001), but when age and TT were introduced in a multivariate model, only sperm morphology retained a significant association (B = -1.418 ± 0.42; p = 0.001). The risk of ED (IIEF-15-EFD score <26) increased as a function of the number of MetS factors, even after adjusting for age and TT (HR = 1.45[1.08-1.95]; p < 0.02). No association between PEDT score and MetS was observed. Finally, after adjusting for age and TT, somatization and depressive symptoms were associated with increasing MetS components (B = 0.66 ± 0.03, p < 0.05; B = 0.69 ± 0.03, p < 0.02; respectively). In conclusion, in men with couple infertility, MetS is associated with hypogonadism, poor sperm morphology, testis ultrasound inhomogeneity, ED, somatization and depression. Recognizing MetS could help patients to improve not only fertility but also sexual and overall health.

BMI in relation to sperm count: an updated systematic review and collaborative meta-analysis.

BACKGROUND The global obesity epidemic has paralleled a decrease in semen quality. Yet, the association between obesity and sperm parameters remains controversial. The purpose of this report was to update the evidence on the association between BMI and sperm count through a systematic review with meta-analysis. METHODS A systematic review of available literature (with no language restriction) was performed to investigate the impact of BMI on sperm count. Relevant studies published until June 2012 were identified from a Pubmed and EMBASE search. We also included unpublished data (n = 717 men) obtained from the Infertility Center of Bondy, France. Abstracts of relevant articles were examined and studies that could be included in this review were retrieved. Authors of relevant studies for the meta-analysis were contacted by email and asked to provide standardized data. RESULTS A total of 21 studies were included in the meta-analysis, resulting in a sample of 13 077 men from the general population and attending fertility clinics. Data were stratified according to the total sperm count as normozoospermia, oligozoospermia and azoospermia. Standardized weighted mean differences in sperm concentration did not differ significantly across BMI categories. There was a J-shaped relationship between BMI categories and risk of oligozoospermia or azoospermia. Compared with men of normal weight, the odds ratio (95% confidence interval) for oligozoospermia or azoospermia was 1.15 (0.93-1.43) for underweight, 1.11 (1.01-1.21) for overweight, 1.28 (1.06-1.55) for obese and 2.04 (1.59-2.62) for morbidly obese men. CONCLUSIONS Overweight and obesity were associated with an increased prevalence of azoospermia or oligozoospermia. The main limitation of this report is that studied populations varied, with men recruited from both the general population and infertile couples. Whether weight normalization could improve sperm parameters should be evaluated further.

Autoimmune signals in non-segmental vitiligo patients are associated with distinct clinical parameters and toxic exposures.

BACKGROUND: Although non-segmental vitiligo is commonly considered an autoimmune disease, the possible differences between non-segmental vitiligo patients with and without autoimmune signals have not been clearly established. OBJECTIVE: To perform a comparison of non-segmental vitiligo patients with autoimmune signals (AIS) vs. those without autoimmune signals (NAIS) in regards to clinical characteristics and toxic/drug exposure. METHODS: 112 vitiligo patients were selected for a sex and age matched (1 : 1) case control study at an university based dermatology outpatient hospital specialized in pigmentary disorders. Medical assessment was performed by dermatologists using the modified Vitiligo European Task Force form and serological and clinical signs of autoimmunity were evaluated. RESULTS: Disease duration, age of onset, patient history of cardiovascular disease, past smoking history, use of drugs, and consummation of goitrogenic foods were all significantly increased in the AIS group using McNemar's test for matched pairs. In our conditional regression model, the simultaneous presence of disease duration, use of prescription drugs, and consummation of goitrogenic foods were the best predictors of AIS vitiligo patients. CONCLUSION: The evaluation of non-segmental vitiligo patients according to the presence vs. the absence of autoimmune signals allows us to correlate patients exhibiting autoimmune phenomenon with certain clinical characteristics, namely long disease duration, use of prescription drugs, and consumption of goitrogenic substances. In the presence of the aforementioned clinical profile, we suggest an evaluation of autoimmune signals.