The UGT1 locus is a determinant of prostate cancer recurrence after prostatectomy.

The prognostic significance of common deletions in uridine diphospho-glucuronosyltransferase 2B (UGT2B) genes encoding sex steroid metabolic enzymes has been recently recognized in localized prostate cancer (PCa) after radical prostatectomy (RP). However, the role of germline variations at the UGT1 locus, encoding half of all human UGTs and primarily involved in estrogen metabolism, remains unexplored. We investigated whether variants of UGT1 are potential prognostic markers. We studied 526 Caucasian men who underwent RP for clinically localized PCa. Genotypes of patients for 34 haplotype-tagged single-nucleotide polymorphisms (htSNPs) and 11 additional SNPs across the UGT1 locus previously reported to mark common variants including functional polymorphisms were determined. The risk of biochemical recurrence (BCR) was estimated using adjusted Cox proportional hazards regression and Kaplan-Meier analysis. We further investigated whether variants are associated with plasma hormone levels by mass spectrometry. In multivariable models, seven htSNPs were found to be significantly associated with BCR. A greater risk was revealed for four UGT1 intronic variants with hazard ratios (HRs) of 1.59-1.88 (P<0.002) for htSNPs in UGT1A10, UGT1A9, and UGT1A6. Conversely, decreased BCR was associated with three htSNPs in introns of UGT1A10 and UGT1A9 (HR=0.56-058; P≤0.01). An unfavorable UGT1 haplotype comprising all risk alleles, with a frequency of 14%, had a HR of 1.68 (95% CI=1.13-2.50; P=0.011). Significant alteration in circulating androsterone levels was associated with this haplotype, consistent with changes in hormonal exposure. This study provides the first evidence, to our knowledge, that germline polymorphisms of UGT1 are potential predictors of recurrence of PCa after prostatectomy.

Testicular sperm aspiration for nonazoospermic men: sperm retrieval and intracytoplasmic sperm injection outcomes.

OBJECTIVE: To evaluate testicular sperm aspiration (TESA) sperm retrieval rates and intracytoplasmic sperm injection outcomes in nonazoospermic men. MATERIALS AND METHODS: Data were collected retrospectively from 54 consecutive, nonazoospermic, infertile men who underwent TESA between March 2007 and September 2012. Sperm retrieval rates and clinical pregnancy outcomes were recorded. Patients were subgrouped based on clinical diagnosis: group 1, anejaculation (primary, situational); group 2, idiopathic severe oligoasthenozoospermia; and group 3, severe oligoasthenozoospermia after vasovasostomy. RESULTS: Mean (± standard deviation) paternal and maternal ages were 39 ± 7 and 35 ± 5 years, respectively. Using TESA, sperm recovery was successful in 94% (51 of 54) of the men overall and in 100% (17 of 17) of the men in group 1, 90% (28 of 31) in group 2, and 100% (6 of 6) in group 3. Overall, 35% of the couples achieved a clinical pregnancy using TESA sperm (with a mean of 1.7 ± 0.9 embryos transferred per cycle). The clinical pregnancy rates were 40% in group 1, 33% in group 2, and 33% in group 3 with no significant difference in paternal or maternal age between groups. CONCLUSION: The data indicate that TESA yields high sperm retrieval rates in select groups of nonazoospermic infertile men, and this approach results in acceptable pregnancy rates regardless of the male infertility etiology. Randomized controlled trials comparing ejaculated vs testicular sperm are needed to assess the true benefit of TESA-intracytoplasmic sperm injection in these couples.

Deletions of the androgen-metabolizing UGT2B genes have an effect on circulating steroid levels and biochemical recurrence after radical prostatectomy in localized prostate cancer.

CONTEXT: The prognostic relevance of inherited variations in hormone-related genes in the context of prostate cancer (PCa) progression has not been well studied. Of these, UDP-glucuronosyltransferase (UGT) gene products lead to inactivation of steroids. OBJECTIVE: Our objective was to determine whether polymorphisms in five UGT genes, involved in steroid metabolism, are associated with the risk of biochemical recurrence after radical prostatectomy (RP) and to examine their relationship with hormonal exposure. DESIGN: The study included 526 Caucasian and 320 Asian men who underwent RP for clinically localized PCa. The relationship between genotypes and biochemical recurrence were assessed with multivariate Cox proportional hazard models. Plasma steroids were measured using specific and sensitive mass spectrometry-based methods. RESULTS: The presence of at least two deleted copies of UGT2B17 and UGT2B28 genes resulted in a hazard ratio of 2.26 (95% confidence interval = 1.41-3.61; P = 0.0007) for Caucasians and 2.16 (95% confidence interval = 1.24-3.73; P = 0.006) for Asians. A positive association was observed only between UGT2B17 deletion and the Gleason score in Asians, whereas no other interaction was shown with prostate-specific antigen, Gleason score, and TNM (tumor node metastasis) staging. Patients carrying UGT2B17 deletions and those with three deleted UGT2B copies had significantly lower androgen glucuronides, in support of an altered androgen metabolism. CONCLUSION: This study is the first to recognize the prognostic significance of common deletions in steroid inactivation pathways in localized PCa after RP. Alteration of circulating steroid levels associated with UGT2B gene deletions further support the notion that such inherited genomic deletions have the potential to modify hormonal exposure and risk of recurrence.