Comparison of testosterone fractions between Framingham Heart Study participants and Japanese participants

Objectives: To determine testosterone fractions in Japanese men and to compare these values with those of Framingham Heart Study participants. Methods: We enrolled 498 healthy Japanese men. Total testosterone was assayed by liquid chromatography tandem mass spectrometry, sex hormone-binding globulin was assayed by immunoassay and free testosterone was calculated by a laboratory at the Boston Medical Center. Analog-based free testosterone and immunoassay-based total testosterone were determined by immunoassay. We compared mass spectrometry assay-based total testosterone and calculated free testosterone values in the Japanese participants with values in the American Framingham Heart Study third generation cohort. Results: The mean serum mass spectrometry assay-based total testosterone, sex hormone-binding globulin, and calculated free testosterone values were 439.4±167ng/dL, 65.34±30.61nmol/L, and 58.75±20.0pg/mL, respectively. The correlation coefficients with age for mass spectrometry assay-based total testosterone, sex hormone-binding globulin, and calculated free testosterone were 0.0010, 0.5041, and -0.496, respectively. There were no age-related changes in mass spectrometry assay-based total testosterone values in healthy men (P=0.981), whereas sex hormone-binding globulin and calculated free testosterone levels showed similar age-related changes (P<0.0001). Serum analog-based free testosterone levels (8.24±2.9pg/mL) showed age-related changes (P<0.0001) regardless of immunoassay-based total testosterone levels (P=0.828). Serum immunoassay-based total testosterone values (486.1±162.5ng/dL) correlated with serum mass spectrometry assay-based total testosterone values (r=0.740, 95% confidence interval 0.6965-0.7781, P<0.0001). Similarly, analog-based free testosterone and calculated free testosterone values showed a highly significant correlation (r=0.706, 95% confidence interval 0.6587-0.7473, P<0.0001). The analog-based free testosterone values were approximately 10% of the calculated free testosterone values. Conclusions: In contrast to the Framingham Heart Study cohort, total testosterone values in Japanese men are not associated with advancing age; thus, they cannot be used to diagnose late-onset hypogonadism in Japan. The analog-based free testosterone value can be considered instead as a suitable biochemical determinant for diagnosing late-onset hypogonadism syndrome. © 2014 The Japanese Urological Association

Chronological urodynamic evaluation of changing bladder and urethral functions after robot-assisted radical prostatectomy

Objective To examine chronological changes in urethral and bladder functions before, immediately after, and 1 year after robot-assisted radical prostatectomy (RARP), urodynamic studies were prospectively performed. Methods Sixty-three consecutive patients underwent pressure-flow studies, urethral pressure profiles, and abdominal leak point pressure (ALPP) tests 1-2 days before, immediately after, and 1 year after RARP. Results The mean bladder compliance was 28.3 mL/cm H2O before RARP; it worsened to 16.3 mL/cm H2O immediately after RARP and recovered to 27.1 mL/cm H2O at 1 year. The mean detrusor pressure at maximum flow rate was 61.9 cm H2O before RARP; it decreased to 34.3 cm H2O immediately after RARP and remained at 35.6 cm H2O at 1 year. The mean maximum urethral closure pressure was 84.2 cm H2O before RARP; it decreased to 33.4 cm H2O immediately after RARP and recovered to 63.0 cm H2O at 1 year. Intrinsic sphincter deficiency (ISD) evaluated by the ALPP test was observed in 53 patients immediately after RARP, although no patient showed ISD before RARP. ISD remained in 7 patients at 1 year. Both ALPP and maximum urethral closure pressure at 1 year were significant factors for continence in multivariate analysis. Conclusion Urethral sphincter and bladder function worsen immediately after RARP and recover over time. The bladder storage function after RARP returns to almost the same level before RARP, and the voiding function improves compared with the condition before RARP; however, the urethral sphincter function does not return to its preoperative level. Urethral sphincter dysfunction is considered the main factor for urinary incontinence after RARP. © 2015 Elsevier Inc.Embargo Period 12 month

A novel y chromosome microdeletion with the loss of an endogenous retrovirus related, testis specific transcript in AZFb region

Purpose: We identified the endogenous retroviruses associated with TTYs (testis specific transcripts linked to the Y) in the AZFb region. We evaluated the relationship between endogenous retroviruses, and TTY expression patterns and function in spermatogenesis. Materials and Methods: We identified family members of TTYs in the AZFb region using computational screening. After investigating the relationship between the endogenous retrovirus genome and TTY expression patterns we screened genomic polymerase chain reaction products from TTY13 amplified from 790 Japanese men, including 275 with azoospermia, 285 with oligozoospermia and 230 who were fertile. Results: Computational screening revealed that 3 members of the TTY family, TTY9, 10 and 13, were regulated by endogenous retroviruses in the AZFb region. Homologous recombination between long terminal repeat of the TTY13 associated human endogenous retrovirus-K14C resulted in TTY13 deletion events. These deletions were more common in patients with azoospermia and oligozoospermia than in fertile males. Specifically 15.63% of the azoospermia group, 10.88% of the oligozoospermia group and 0% of fertile controls had only the deletion variant, indicating an association between the homologous recombination rate and the severity of spermatogenesis failure that was statistically significant (p <0.05). Conclusions: Because of the finding of what are to our knowledge novel microdeletions due to endogenous retrovirus in the AZFb region, our study raises the possibility that specific variations in genomic structure may contribute to some forms of human idiopathic male infertility. © 2011 American Urological Association Education and Research, Inc

Use of preoperative factors including urodynamic evaluations and nerve-sparing status for predicting urinary continence recovery after robot-assisted radical prostatectomy: Nerve-sparing technique contributes to the reduction of postprostatectomy incontinence

Aims: To examine which preoperative factors, including urodynamic evaluations, and operative procedures could predict continence status after robot-assisted radical prostatectomy (RARP) in this study. Materials and Methods: Univariate and multivariate logistic regression analyses of preoperative factors such as age, body mass index, prostate-specific antigen level before biopsy, prostate size before surgery, membranous urethral length measured using magnetic resonance imaging (MRI), bladder compliance and maximum urethral closure pressure (MUCP) measured by urodynamic study (UDS), and nerve-sparing (NS) status predicting 24-hr pad test >2 g/day at 1 year after RARP were examined in 111 patients enrolled in this study. Results: The number of patients with incontinence at 1 year after RARP was 39 (35.1%). The only predictive factor for urinary continence was NS grades. To investigate the contribution of NS to urinary continence, 84 patients underwent UDS three times; before, immediately after, and 1 year after RARP. Chronological UDS revealed that recovery patterns of storage and voiding functions were the same among non-NS, unilateral-NS, and bilateral-NS groups, and that higher degrees of NS contributed to lesser decreases in MUCP and longer functional urethral length (FUL) after RARP. Conclusion: Preoperative factors, including the results of UDS, could not predict continence 1 year after RARP. The NS procedure contributed to continence status. NS favorably affected MUCP and FUL; however, it did not affect bladder function after RARP. Neurourol. Urodynam. 35:1034–1039, 2016. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.Embarogo Period 12 month

Efficacy of two-time prophylactic intravenous administration of tazobactam/piperacillin for transrectal ultrasound-guided needle biopsy of the prostate

金沢大学大学院医学系研究科泌尿器集学的治療学 / Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical SciencesBackground Prevalence of fluoroquinolone (FQ)-resistant Escherichia coli has been recently increasing worldwide. We analyzed the incidence and characteristics of acute bacterial prostatitis after transrectal ultrasound-guided needle prostate biopsy (TRUSP-Bx) with prophylactic tazobactam/piperacillin (TAZ/PIPC) treatment as an alternative regimen. Methods A total of 391 patients who underwent TRUSP-Bx were included in the study. All patients received intravenous TAZ/PIPC (4.5 g) 30 minutes before and 6 hours after TRUSP-Bx. Results Acute bacterial prostatitis developed in six patients (1.5%); the frequency of its occurrence was significantly higher in patients in whom rectal disinfection was not performed (P < 0.05). These six patients developed clinical symptoms of acute bacterial prostatitis a median of 24 hours after the biopsy. Escherichia coli was isolated in urine or blood bacterial cultures in four cases, and Klebsiella pneumoniae in two cases. All of the isolated organisms showed excellent sensitivity to TAZ/PIPC. Conclusions The incidence rate of acute prostatitis with prophylactic TAZ/PIPC was consistent with those reported previously with FQ-based regimens, despite the favorable sensitivity of isolated organisms. Two-time regimen of TAZ/PIPC may not always prevent the post-TRUSP-Bx infection, possibly due to the pharmacokinetic characteristics of TAZ/PIPC. However, if each case was considered individually to select the best setting and frequency of dosage of TAZ/PIPC, this can be an optimal prophylaxis in the era of widespread FQ-resistant microorganisms. Copyright © 2015 Asian Pacific Prostate Society, Published by Elsevier. All rights reserved

Tumor-associated macrophages promote prostate cancer migration through activation of the CCL22-CCR4 axis

Previous studies have found that tumor-associated macrophages (TAMs) promote cancer progression. We previously reported that TAMs promote prostate cancer metastasis via activation of the CCL2-CCR2 axis. The CCR4 (receptor of CCL17 and CCL22) expression level in breast cancer was reported to be associated with lung metastasis. The aim of this study was to elucidate the role of CCR2 and CCR4 in prostate cancer progression. CCR2 and CCR4 were expressed in human prostate cancer cell lines and prostate cancer tissues. In vitro co-culture of prostate cancer cells and macrophages resulted in increased CCL2 and CCR2 levels in prostate cancer cells. The addition of CCL2 induced CCL22 and CCR4 production in prostate cancer cells. The migration and invasion of prostate cancer cells via enhanced phosphorylation of Akt were promoted by CCL17 and CCL22. CCR4 may be a potential candidate for molecular-targeted therapy

Serum chemokine (CC motif) ligand 2 level as a diagnostic, predictive, and prognostic biomarker for prostate cancer

Prostate-specific antigen (PSA) is regarded as the most sensitive biomarker for prostate cancer. Although androgen/androgen receptor (AR) signaling promotes prostate cancer progression, suppression of AR signaling induces chemokine (CC motif) ligand 2 (CCL2), which enables prostate cancer cells to gain metastatic potential. AR-controlled PSA alone may be an unreliable biomarker for patients receiving androgen deprivation therapy. Therefore, we investigated the validity of CCL2 as a complementary biomarker to PSA for prostate cancer. Our in vitro approach of enriching for prostate cancer cells with higher migration potential showed that CCL2 activated cellular migration. Importantly, we found that CCL2 levels were significantly different between men (n = 379) with and without prostate cancer. Patients with CCL2 ≥ 320 pg/mL had worse overall survival and prostate cancer -specific survival than those with CCL2 < 320 pg/mL. A novel risk classification was developed according to the risk factors CCL2 ≥ 320 pg/mL and PSA ≥ 100 ng/mL, and scores of 2, 1, and 0 were defined as poor, intermediate, and good risk, respectively, and clearly distinguished patient outcomes. CCL2 may serve as a novel biomarker for prostate cancer. The novel risk classification based on combining CCL2 and PSA is more reliable than using either alone

Association of TUSC1 and DPF3 gene polymorphisms with male infertility

Purpose Recently, a genome-wide association studies of a Hutterite population in the USA revealed that five single nucleotide polymorphisms (SNPs) with a significant association with sperm quality and/or function in ethnically diverse men from Chicago were significantly correlated with family size. Of these, three SNPs (rs7867029, rs7174015, and rs12870438) were found to be significantly associated with the risk of azoospermia and/or oligozoospermia in a Japanese population. In this study, we investigated whether the rs10966811 (located in an intergenic region between the TUSC1 and IZUMO3 genes) and rs10129954 (located in the DPF3 gene) SNPs, previously related to family size, are associated with male infertility. In addition, we performed association analysis between rs12348 in TUSC1 and rs2772579 in IZUMO3 and male infertility. Methods We genotyped 145 patients with infertility (including 83 patients with azoospermia, and 62 with oligozoospermia) and 713 fertile controls by PCR-RFLP technique for polymorphism. Because rs10966811 has no restriction sites, the SNP rs12376894 with strong linkage disequilibrium was selected as an alternative to rs10966811. Results There was a statistically significant association between rs12376894 proxy SNP of rs10966811, and oligozoospermia. A statistically significant association between rs10129954 and azoospermia, and oligozoospermia were observed. When we assessed the relationship between rs12348 in TUSC1 and rs2772579 in IZUMO3 and male infertility traits, we found that rs12348 in TUSC1 was significantly associated with azoospermia and oligozoospermia, but rs2772579 in IZUMO3 was not associated with male infertility. Conclusion We found that the polymorphisms in TUSC1 and DPF3 displayed strong associations with male infertility

An independent validation study of three single nucleotide polymorphisms at the sex hormone-binding globulin locus for testosterone levels identified by genome-wide association studies

STUDY QUESTION: Are the single nucleotide polymorphisms (SNPs) rs2075230, rs6259 and rs727428 at the sex hormone-binding globulin (SHBG) locus, which were identified by genome-wide association studies (GWASs) for testosterone levels, associated with testosterone levels in Japanese men? SUMMARY ANSWER: The SNP rs2075230, but not rs6259 and rs727428, is significantly associated with testosterone levels in Japanese men. WHAT IS ALREADY KNOWN: Previous GWASs have revealed that rs2075230 is associated with serum testosterone levels in 3495 Chinese men and rs6259 and rs727428 are associated with serum testosterone levels in 3225 men of European ancestry. STUDY DESIGN, SIZE, AND DURATION: This is an independent validation study of 1687 Japanese men (901 in Cohort 1 and 786 in Cohort 2). PARTICIPANTS/MATERIALS, SETTING AND METHOD: Cohort 1 (20.7 ± 1.7 years old, mean ± SD) and Cohort 2 (31.2 ± 4.8 years) included samples obtained from university students and partners of pregnant women, respectively. The three SNPs were genotyped using either TaqMan probes or restriction fragment length polymorphism PCR. Blood samples were drawn from the cubital vein of the study participants in the morning, and total testosterone and SHBG levels were measured using a time-resolved immunofluorometric assay. Association between each SNP and testosterone levels was evaluated by meta-analysis of the two Japanese male cohorts. MAIN RESULTS AND THE ROLE OF CHANCE: The age of the two cohorts was significantly different (P < 0.0001). We found that rs2075230 was significantly associated with serum testosterone levels (βSTD = 0.15, P = 7.2 × 10−6); however, rs6259 and rs727428 were not (βSTD = 0.17, P = 0.071; βSTD = 0.082, P = 0.017, respectively), after adjusting for multiple testing in a combined analysis of two Japanese male cohorts. Moreover, rs2075230, rs6259 and rs727428 were significantly associated with high SHBG levels (βSTD = 0.22, P = 3.4 × 10−12; βSTD = 0.23, P = 6.5 × 10−6 and βSTD = 0.21, P = 3.4 × 10−10, respectively). LARGE SCALE DATA: Not applicable. LIMITATIONS, REASONS FOR CAUTION: This study had differences in the age and background parameters of participants compared to those observed in previous GWASs. In addition, the average age of participants in the two cohorts in our study also differed from one another. Therefore, the average testosterone levels, which decrease with age, between studies or the two cohorts were different. WIDER IMPLICATIONS OF THE FINDINGS: The three SNPs have a considerable effect on SHBG levels and hence may indirectly affect testosterone levels. STUDY FUNDING/COMPETING INTERESTS: This study was supported partly by the Ministry of Health and Welfare of Japan (1013201) (to T.I.), Grant-in-Aids for Scientific Research (C) (26462461) (to Y.S.) and (23510242) (to A.Ta.) from the Japan Society for the Promotion of Science, the European Union (BMH4-CT96-0314) (to T.I.) and the Takeda Science Foundation (to A.Ta.). There are no conflicts of interest to declare

An association study of four candidate loci for human male fertility traits with male infertility

STUDY QUESTION Are the four candidate loci (rs7867029, rs7174015, rs12870438 and rs724078) for human male fertility traits, identified in a genome-wide association study (GWAS) of a Hutterite population in the USA, associated with male infertility in a Japanese population? SUMMARY ANSWER rs7867029, rs7174015 and rs12870438 are significantly associated with the risk of male infertility in a Japanese population. WHAT IS KNOWN ALREADY Recently, a GWAS of a Hutterite population in the USA revealed that 41 single-nucleotide polymorphisms (SNPs) were significantly correlated with family size or birth rate. Of these, four SNPs (rs7867029, rs7174015, rs12870438 and rs724078) were found to be associated with semen parameters in ethnically diverse men from Chicago. STUDY DESIGN, SIZE, DURATION This is a case-control association study in a total of 917 Japanese subjects, including 791 fertile men, 76 patients with azoospermia and 50 patients with oligozoospermia. PARTICIPANTS/MATERIALS, SETTING, METHODS Azoospermia was diagnosed on the basis of semen analysis (the absence of sperm in ejaculate), serum hormone levels and physical examinations. Oligozoospermia was defined as a sperm concentration of <20 × 106/ml. We excluded patients with any known cause of infertility (i.e. obstructive azoospermia, varicocele, cryptorchidism, hypogonadotropic hypogonadism, karyotype abnormalities or complete deletion of AZF a, b or c). The SNPs rs7867029, rs7174015, rs12870438 and rs724078 were genotyped using DNA from peripheral blood samples and either restriction fragment length polymorphism PCR or TaqMan probes. Genetic associations between the four SNPs and male infertility were assessed using a logistic regression analysis under three different comparative models (additive, recessive or dominant). MAIN RESULTS AND THE ROLE OF CHANCE The genotypes of all four SNPs were in Hardy-Weinberg equilibrium in the fertile controls. The SNPs rs7867029 and rs7174015 are associated with oligozoospermia [rs7867029: odds ratio (OR) = 1.70, 95% confidence interval (CI) = 1.07-2.68, P = 0.024 (log-additive); rs7174015: OR = 6.52, 95% CI = 1.57-27.10, P = 0.0099 (dominant)] and rs12870438 is associated with azoospermia (OR = 10.90, 95% CI = 2.67-44.60, P = 0.00087 (recessive)] and oligozoospermia [OR = 8.54, 95% CI = 1.52-47.90, P = 0.015 (recessive)]. The association between rs7174015 and oligozoospermia under a dominant model and between rs12870438 and azoospermia under additive and recessive models remained after correction for multiple testing. There were no associations between rs724078 and azoospermia or oligozoospermia. LIMITATIONS, REASONS FOR CAUTION Even though the sample size of case subjects was not very large, we found that three SNPs were associated with the risk of male infertility in a Japanese population. WIDER IMPLICATIONS OF THE FINDINGS The three infertility-associated SNPs may be contributing to a quantitative reduction in spermatogenesis. STUDY FUNDING/COMPETING INTEREST(S) This study was supported in part by the Ministry of Health and Welfare of Japan (1013201) (to T.I.), Grant-in-Aids for Scientific Research (C) (23510242) (to A.Ta.) from the Japan Society for the Promotion of Science, the European Union (BMH4-CT96-0314) (to T. I.) and the Takeda Science Foundation (to A.Ta.). None of the authors has any competing interests to declare. © 2015 The Author. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved