Lower prostate cancer risk in Swedish men with the androgen receptor E213 A-allele.

BACKGROUND: In a previous population-based study on 3369 European men with self-reported prostate cancer (PCa), it was shown that androgen receptor (AR) haplotype designated H2 was associated with high levels of serum PSA (prostate-specific antigen) concentration, and, at the same time, with low risk for PCa. The aim of this study was to replicate this finding in other cohorts, with registry-based cancer diagnosis. METHODS: Using data from two population-based cohorts; the Malmö Diet and Cancer Study (MDCS, n = 12,121) and the Swedish Osteoporotic fractures in men study (MrOS, n = 1,120), 628 men with PCa and 1,374 controls were identified and genotyped. PCa data were collected from the Swedish national cancer registry. PCa odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for carriers of the particular AR haplotype, tagged by the rs6624304 T-allele. RESULTS: The 15% of men who were carriers of the AR haplotype H2 had approximately one-third lower risk for PCa diagnosis compared to those with the most common H1 variant (OR 0.65; 95% CI 0.45-0.94; p = 0.021). The same trend, although not statistically significant (OR 0.75; 95% CI 0.47-1.24; p = 0.275), was observed in MrOS Sweden. When both cohorts were merged, an even more significant result was observed (OR 0.68; 95% CI 0.51-0.90; p = 0.008). CONCLUSIONS: Swedish men with the variant AR haplotype H2, tagged by rs6624304, have significantly lower risk of PCa compared to those with the more common variant.

Male infertility and prostate cancer risk: a nested case-control study.

The pathogenesis of prostate cancer is unclear, although experimental evidence implicates androgens as playing an important role. Infertile men frequently suffer from some degree of hypogonadism and may hence be hypothesized to be at lower risk of developing prostate cancer than fertile men. To test this hypothesis, we conducted a case-control study nested within "the Malmö Diet and Cancer Study" cohort in Sweden, inviting 661 prostate cancer cases and 661 age-matched controls to participate. Of the 975 (74%) respondents, we excluded 84 childless men with unknown fertility status. Thus, 891 men were included, providing 445 prostate cancer cases and 446 controls. Of these, 841 (94%) men were biological fathers and 50 (6%) men were infertile. Logistic regression showed that the infertile men were at significantly lower risk of being diagnosed with prostate cancer than the fertile men (odds ratio, 0.45; 95% confidence interval, 0.25-0.83). Conditional and unconditional multivariate models, adjusting for socioeconomic, anthropometric, and health-status-related factors, provided similar estimates. We conclude that enduring male infertility is associated with a reduced prostate cancer risk, thus corroborating the theory that normal testicular function, and hence most probably sufficient steroidogenesis, is an important contributing factor to the later development of this malignancy.

Imaging modalities and treatment of paediatric upper tract urolithiasis: A systematic review and update on behalf of the EAU urolithiasis guidelines panel.

BACKGROUND: Prompt diagnosis and treatment of paediatric urolithiasis are required to avoid long term sequelae of renal damage. OBJECTIVE: To systematically review the literature regarding the diagnostic imaging modalities and treatment approaches for paediatric urolithiasis. STUDY DESIGN: PubMed, Science Direct, Scopus and Web of Science were systematically searched from January 1980-January 2019. 76 full-text articles were included. RESULTS: Ultrasound and Kidney-Ureter-Bladder radiography are the baseline diagnostic examinations. Non-contrast Computed Tomography (CT) is the second line choice with high sensitivity (97-100%) and specificity (96-100%). Magnetic Resonance Urography accounts only for 2% of pediatric stone imaging studies. Expectant management for single, asymptomatic lower pole renal stones is an acceptable initial approach, especially in patients with non-struvite, non-cystine stones<7 mm. Limited studies exist on medical expulsive therapy as off-label treatment. Extracorporeal shock wave lithotripsy (SWL) is the first-line treatment with overall stone free rates (SFRs) of 70-90%, retreatment rates 4-50% and complication rates up to 15%. Semi-rigid ureteroscopy is effective with SFRs of 81-98%, re-treatment rates of 6.3-10% and complication rates of 1.9-23%. Flexible ureteroscopy has shown SFRs of 76-100%, retreatment rates of 0-19% and complication rates of 0-28%. SFRs after first and second-look percutaneous nephrolithotomy (PNL) are 70.1-97.3% and 84.6-97.5%, respectively with an overall complication rate of 20%. Open surgery is seldom used, while laparoscopy is effective for stones refractory to SWL and PNL. Limited data exist for robot-assisted management. CONCLUSIONS: In the initial assessment of paediatric urolithiasis, US is recommended as first imaging modality, while non-contrast CT is the second option. SWL is recommended as first line treatment for renal stones <20 mm and for ureteral stones<10 mm. Ureteroscopy is a feasible alternative both for ureteral stones not amenable to SWL as well as for renal stones <20 mm (using flexible). PNL is recommended for renal stones >20 mm.

Treatment of Bladder Stones in Adults and Children: A Systematic Review and Meta-analysis on Behalf of the European Association of Urology Urolithiasis Guideline Panel.

CONTEXT: Bladder stones (BS) constitute 5% of urinary stones. Currently, there is no systematic review of their treatment. OBJECTIVE: To assess the efficacy (primary outcome: stone-free rate [SFR]) and morbidity of BS treatments. EVIDENCE ACQUISITION: This systematic review was conducted in accordance with the European Association of Urology Guidelines Office. Database searches (1970-2019) were screened, abstracted, and assessed for risk of bias for comparative randomised controlled trials (RCTs) and nonrandomised studies (NRSs) with ≥10 patients per group. Quality of evidence (QoE) was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) tool. EVIDENCE SYNTHESIS: A total of 2742 abstracts and 59 full-text articles were assessed, and 25 studies (2340 patients) were included. In adults, one RCT found a lower SFR following shock wave lithotripsy (SWL) than transurethral cystolithotripsy (TUCL; risk ratio 0.88, p=0.03; low QoE). Four RCTs compared TUCL versus percutaneous cystolithotripsy (PCCL): meta-analyses demonstrated no difference in SFR, but hospital stay (mean difference [MD] 0.82d, p<0.00001) and procedure duration (MD 9.83min, p<0.00001) favoured TUCL (moderate QoE). Four NRSs comparing open cystolithotomy (CL) versus TUCL or PCCL found no difference in SFR; hospital stay and procedure duration favoured endoscopic surgery (very low QoE). Four RCTs compared TUCL using a nephroscope versus a cystoscope: meta-analyses demonstrated no difference in SFR; procedure duration favoured the use of a nephroscope (MD 22.74min, p<0.00001; moderate QoE). In children, one NRS showed a lower SFR following SWL than TUCL or CL. Two NRSs comparing CL versus TUCL/PCCL found similar SFRs; catheterisation time and hospital stay favoured endoscopic treatments. One RCT comparing laser versus pneumatic TUCL found no difference in SFR. One large NRS comparing CL techniques found a shorter hospital stay after tubeless CL in selected cases; QoE was very low. CONCLUSIONS: Current available evidence indicates that TUCL is the intervention of choice for BSs in adults and children, where feasible. Further high-quality research on the topic is required. PATIENT SUMMARY: We examined the literature to determine the most effective and least harmful procedures for bladder stones in adults and children. The results suggest that endoscopic surgery is equally effective as open surgery. It is unclear whether stone size affects outcomes. Shock wave lithotripsy appears to be less effective. Endoscopic treatments appear to have shorter catheterisation time and convalescence compared with open surgery in adults and children. Transurethral surgery, where feasible, appears to have a shorter hospital stay than percutaneous surgery. Further research is required to clarify the efficacy of minimally invasive treatments for larger stones and in young children.

Tract Sizes in Miniaturized Percutaneous Nephrolithotomy: A Systematic Review from the European Association of Urology Urolithiasis Guidelines Panel.

CONTEXT: Miniaturized instruments for percutaneous nephrolithotomy (PNL), utilizing tracts sized ≤22 Fr, have been developed in an effort to reduce the morbidity and increase the efficiency of stone removal compared with standard PNL (>22 Fr). OBJECTIVE: We systematically reviewed all available evidence on the efficacy and safety of miniaturized PNL for removing renal calculi. EVIDENCE ACQUISITION: The review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses statement. Since it was not possible to perform a meta-analysis, the data were summarized in a narrative synthesis. EVIDENCE SYNTHESIS: After screening 2945 abstracts, 18 studies were included (two randomized controlled trials [RCTs], six nonrandomized comparative studies, and 10 case series). Thirteen studies were full-text articles and five were only available as congress abstracts. The size of tracts used in miniaturized procedures ranged from 22 Fr to 4.8 Fr. The largest mean stone size treated using small instruments was 980mm2. Stone-free rates were comparable in miniaturized and standard PNL procedures. Procedures performed with small instruments tended to be associated with significantly lower blood loss, while the procedure duration tended to be significantly longer. Other complications were not notably different between PNL types. Study designs and populations were heterogeneous. Study limitations included selection and outcome reporting bias, as well as a lack of information on relevant confounding factors. CONCLUSIONS: The studies suggest that miniaturized PNL is at least as efficacious and safe as standard PNL for the removal of renal calculi. However, the quality of the evidence was poor, drawn mainly from small studies, the majority of which were single-arm case series, and only two of which were RCTs. Furthermore, the tract sizes used and types of stones treated were heterogeneous. Hence, the risks of bias and confounding were high, highlighting the need for more reliable data from RCTs. PATIENT SUMMARY: Removing kidney stones via percutaneous nephrolithotomy (PNL) using smaller sized instruments (mini-PNL) appears to be as effective and safe as using larger (traditional) instruments, but more clinical research is needed.

Linkage between cryptorchidism, hypospadias, and GGN repeat length in the androgen receptor gene.

Although sufficient androgen receptor (AR) function is crucial for normal male sexual differentiation, single-point mutations in the AR gene are infrequent in the two most common male congenital malformations, hypospadias and cryptorchidism. Because polymorphic CAG and GGN segments regulate AR function, we investigated whether there was any association between these polymorphisms and mentioned malformations. Genotyping was performed by direct sequencing of DNA from patients diagnosed with hypospadias (n = 51) and cryptorchidism (n = 23) and controls (n = 210). The subjects with hypospadias were divided into subgroups of glanular, penile, and penoscrotal hypospadias. Median GGN lengths were significantly higher (24 vs. 23) among both subjects with cryptorchidism, compared with controls (P = 0.001), and those with penile hypospadias, compared with either controls (P = 0.003) or glanular and penoscrotal hypospadias combined (P = 0.018). The frequency of cases with GGN 24 or more vs. GGN = 23, differed significantly among those with cryptorchidism (65/35%), compared with controls (31/54%) (P = 0.012), and among subjects with penile hypospadias (69/31%), compared with either controls (P = 0.035) or glanular or penoscrotal hypospadias combined (32/55%) (P = 0.056). There were no significant differences in CAG lengths between the cases and controls. Our findings indicate an association between GGN length and the risk of cryptorchidism and penile hypospadias, both conditions considered consequences of low androgenicity.

Seasonal variation in serum concentrations of reproductive hormones and urinary excretion of 6-sulfatoxymelatonin in men living north and south of the Arctic Circle: a longitudinal study.

OBJECTIVE: Seasonal variation in photoperiod or temperature may influence human reproductive biology. The present study evaluated whether seasonal changes occurred in the levels of reproductive hormones and the major melatonin metabolite, 6-sulfatoxymelatonin (aMT6s), in populations exposed to extreme variation in photoperiod and temperature. DESIGN: Two separate cohorts of Norwegian men were recruited from the general population in either of two locations: Tromsø (69.5 degrees N, n = 92) or Oslo (60 degrees N, n = 112), located north and south of the Arctic Circle (66.5 degrees N), respectively. MEASUREMENTS: Four blood and 12-h overnight urine samples were obtained on separate occasions over a 12-month period, including during the photoperiod maximum and minimum. Serum concentrations of FSH, LH, testosterone (T), oestradiol (E(2)), SHBG and the urinary excretion of aMT6s were assessed. RESULTS: Statistical analysis using generalized estimating equations indicated that LH levels were lowest during early winter in both locations (both P = 0.01). In Tromsø, free T and E(2) concentrations peaked during early winter (P = 0.02 and 0.003, respectively). In Oslo, free T levels were lowest during early winter (P = 0.06) whereas E(2) levels were lowest during late summer (P < 0.001). Urinary aMT6s concentrations were lowest during early summer in Tromsø and Oslo. Concentrations peaked during early winter in Tromsø (P < 0.001) and during late winter in Oslo (P < 0.001). CONCLUSIONS: LH levels exhibited similar changes in both locations, whereas the patterns of changes of the sex steroid concentrations differed, possibly indicating different underlying mechanisms. Excretion of aMT6s was lowest during early summer in both locations, indicating that the long natural photoperiod was sufficient to cause suppression of melatonin secretion. Whether these changes have any biological significance remains uncertain.

A frequent allele codes for a truncated variant of semenogelin I, the major protein component of human semen coagulum.

Human semen coagulum predominantly consists of high molecular mass complexes of the seminal vesicle secreted semenogelin I (SgI) and semenogelin II (SgII). Here we describe a previously unknown variant of the SgI gene that is present at an allele frequency of approximately 3% in the Swedish population. It gives rise to a protein with a molecular mass of 43 kDa, SgI(43), which compared with the 50 kDa variant, SgI(50), is lacking a tandem repeat of 60 amino acid residues that was probably deleted by homologous recombination. In spite of the size difference, SgI(43) has many properties in common with SgI(50), such as a very high iso-electric point and susceptibility to proteolytic degradation by prostate-specific antigen. Heterozygous carriers of the SgI(43) allele neither show impaired fertility nor do they significantly differ from individuals homozygous for SgI(50) with respect to sperm parameters such as semen volume, sperm count and fraction of motile spermatozoa.

Androgen receptor gene GGN and CAG polymorphisms among severely oligozoospermic and azoospermic Swedish men.

BACKGROUND: We investigated the androgen receptor gene GGN polymorphism and its relation to male infertility and receptor function. METHODS: Ninety-nine infertile patients with sperm counts < or = 5 x 10(6)/ml were screened for karyotypic abnormalities and Y-chromosome microdeletions. The GGN and CAG repeats were sequenced in those without genetic abnormalities and in 223 controls. RESULTS: Five men (5.1%) carried Y-chromosome microdeletions and five had abnormal karyotypes. Neither the distributions of GGN nor of CAG differed significantly between patients and controls. However, the < 21 CAG and GGN = 23 combination of repeats occurred more frequently in the controls (16%) compared to the entire group of patients (4%; P = 0.003) and to the subgroup of 54 patients with idiopathic infertility (4%; P = 0.02). Testicular volume and CAG lengths were higher (P = 0.04 and 0.002 respectively) among the patients with GGN = 23 compared to GGN = 24. The odds ratio (OR) of having low prostatic secretory function was higher among patients with GGN = 24 than those with GGN = 23 (OR: 3.5; 95% CI: 1.1-11.7; P = 0.04). CONCLUSIONS: The < 21 CAG and GGN = 23 combination of repeats may confer a lower risk of infertility to the carriers. Androgen sensitivity may be higher among carriers of the GGN = 23 allele compared to the GGN = 24 allele.