Suppression of ERß signaling via ERß knockout or antagonist protects against bladder cancer development.

Epidemiological studies showed that women have a lower bladder cancer (BCa) incidence, yet higher muscle-invasive rates than men, suggesting that estrogen and the estrogen receptors, estrogen receptor alpha (ERα) and estrogen receptor beta (ERß), may play critical roles in BCa progression. Using in vitro cell lines and an in vivo carcinogen N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced mouse BCa model, we found that ERß plays a positive role in promoting BCa progression. Knockdown of ERß with ERß-shRNA in ERß-positive human BCa J82, 647v and T24 cell lines led to suppressed cell growth and invasion. Mice lacking ERß have less cancer incidence with reduced expression of the proliferation marker Ki67 in BBN-induced BCa. Consistently, our results show that non-malignant urothelial cells with ERß knockdown are more resistant to carcinogen-induced malignant transformation. Mechanism dissection found that targeting ERß suppressed the expression of minichromosome maintenance complex component 5 (MCM5), a DNA replication licensing factor that is involved in tumor cell growth. Restoring MCM5 expression can partially reverse ERß knockdown-mediated growth reduction. Supportively, treating cells with the ERß-specific antagonist, 4-[2-Phenyl-5,7-bis(trifluoromethyl) pyrazolo[1,5-a]pyrimidin-3-yl]phenol (PHTPP), reduced BCa cell growth and invasion, as well as MCM5 expression. Furthermore, we provide the first evidence that BCa burden and mortality can be controlled by PHTPP treatment in the carcinogen-induced BCa model. Together, these results demonstrate that ERß could play positive roles in promoting BCa progression via MCM5 regulation. Targeting ERß through ERß-shRNA, PHTPP or via downstream targets, such as MCM5, could serve as potential therapeutic approaches to battle BCa.

Microsurgical varicocelectomy for infertile couples with advanced female age: natural history in the era of ART.

Varicocele represents the most common cause of male infertility, and most reports indicate that varicocelectomy has a beneficial effect on male fertility and pregnancy outcome. Assisted reproductive technologies (ARTs) are an alternative to varicocelectomy for the management of couples with a varicocele. The age of the female partner is important in the decision-making process; however, the true influence of female age on pregnancy outcome following varicocelectomy or ART in these couples is unknown. We evaluated the outcomes of 2 cohorts of infertile men with a varicocele and a female partner 35 years of age or older; one group selected varicocelectomy and the other a nonsurgical approach. We reviewed a group of consecutive infertile men who underwent microsurgical varicocelectomy and whose partners are 35 years of age or older (n = 110). We also reviewed a consecutive group of men with varicoceles who elected not to have surgery and whose partners are 35 years of age or older (n = 94). The outcome measures included changes in semen parameters, pregnancy rates (assisted and unassisted), and use of ART. The surgical and nonsurgical groups had comparable semen parameters and female ages. Mean sperm concentration and motility increased significantly after varicocelectomy (P < .05). At a mean of 30 months follow-up, 35% of couples in the surgical group achieved a spontaneous pregnancy and an additional 6% achieved a pregnancy via ART (20% of this group attempted ART). In the nonsurgical group, 25% achieved a spontaneous pregnancy and an additional 16% achieved a pregnancy with ART (40% of this group attempted ART). This study on the natural history of infertile men with varicocele and advanced female age suggests that the surgical and nonsurgical approaches offer comparable pregnancy outcome (combined assisted and unassisted pregnancy rates are about 40%). Overall, these data suggest that varicocelectomy is an acceptable option for couples with advanced female age, but other female factors must be considered in the decision-making process.

Erectile dysfunction and andropause symptoms in infertile men.

PURPOSE: We evaluated the prevalence of andropause symptoms and erectile dysfunction in our infertile population. MATERIALS AND METHODS: A total of 302 consecutive men presenting for infertility evaluation and 60 consecutive men with proven fertility seeking vasectomy (controls) were administered the Androgen Deficiency in the Aging Male and Sexual Health Inventory for Men (SHIM) questionnaires. Information regarding other clinical parameters, including seminal parameters, was collected by review of patient charts. RESULTS: Of the 302 infertile men screened, 38% reported significant andropause symptoms and 28% had abnormal SHIM scores. Of the subgroup of infertile men with nonobstructive azoospermia, 25% reported andropause symptoms and 27% had an abnormal SHIM score. In the fertile group 21% reported andropause symptoms and only 11% had an abnormal SHIM score. The prevalence of erectile dysfunction in infertile men was significantly higher than in the fertile controls (p = 0.007). CONCLUSIONS: Andropause symptoms and erectile dysfunction are common among infertile men, affecting approximately 38% of this population. This finding suggests that the population of infertile men should be carefully screened to identify and treat those with erectile dysfunction.