ResearchPad - male-reproductive-health-throughout-the-lifespan Default RSS Feed en-us © 2020 Newgen KnowledgeWorks <![CDATA[OR02-01 Gene Dosage Changes in RBFOX-2 Can Affect Upper and Lower Tract Genitourinary Development]]> Searching for genetic and genomic alterations in patients with genitourinary (GU) birth defects can aid in the identification of genes that are important for normal GU development. Using data in DECIPHER, RBFOX-2, located at 22q12 was identified as one such candidate gene and the effect of haploinsufficiency in humans and a mouse model (Rbfox-2α/+) assessed. RBFOX2 is an RNA-binding protein regulating alternative splicing. It also impacts steroid receptor transcriptional activity. RBFOX family members are thought to affect different developmental programs via isoform-specific localization and splicing activities. RBFOX-2 plays a vital role in multiple developmental processes including heart, brain, muscle and testis development. “Non-syndromic” patients with congenital GU anomalies were more likely to harbor RBFOX-2 CNVs (2.4%; hypospadias, 21% cryptorchidism, 29% vesicoureteral reflux and 29% ureteropelvic junction obstruction) relative to the general population (0.11%) indicating that 22q12 is a hotspot genetic locus for GU anomalies. CNVs (microdeletions and microduplications) spanning RBFOX-2 were identified in twenty-seven humans with a wide range of birth defects(intellectual disability, CNS, cardiac, genitourinary, facial, hearing, vision, growth and stature anomalies) and the phenotype of the haploinsufficient Rbfox-2α/+mouse model closely correlated with the human phenotype, although Rbfox-2α/+ andRbfox-2α/α are neonatal lethal. By E18.5 day of development 100% of the Rbfox-2α/+ and null fetuses exhibited hypospadias, megacystis (50%) and bilateral hydroureteronephrosis. RNA Seq was performed on genital tubercles from three Rbfox2fl/fl, Gdf9 icre+ and three Rbfox2fl/fl P1 males. 377 genes were differentially expressed between the two groups including 212 genes which were upregulated and 165 genes which were downregulated. Hallmark gene set analysis revealed downregulation of Wnt/β-catenin signaling and hedgehog signaling, both pathways which are well defined in genital development. Gene ontology (GO) analysis further defined downregulation of pathways (fibroblast growth factor, retinoic, androgen, estrogen and G-protein receptor signaling) including those involving negative regulation of embryonic development, epithelial development, morphogenesis of epithelial tube, renal, ureter, limb and several other developmental pathways. These results support the hypothesis that loss of Rbfox2 during development leads to hypospadias through impaired development of the urethral epithelium.

<![CDATA[OR02-06 Sexual Symptoms Predict All-Cause Mortality Independently of Sex Steroids in Ageing Men]]> Background: The association between low testosterone (T) and higher mortality in men remains controversial. Most studies focus only on the association between total T (TT) and mortality. While TT declines with age, free T (FT) shows a greater fall, due to the rise in SHBG. Moreover, higher LH as well as sexual dysfunction, often co-existing with low T, have also been associated with mortality in ageing men.

Objective: To study the interrelationships between sex steroids, gonadotrophins and sexual symptoms with all-cause mortality in a large prospective cohort of European men.

Methods: 1913 community-dwelling men, aged 40-79, participated in the European Male Ageing Study (EMAS) between 2003-2005. Sexual symptoms were assessed via a validated questionnaire (EMAS-SFQ). Sex steroids were measured by mass spectrometry. In 5 of 8 EMAS centres, survival status was available until 1 April 2018. Cox proportional hazard models were used to study the association between hormones, sexual symptoms and mortality. Because of the wide age range at study entry, age was used as time-scale, instead of years since inclusion adjusting for age. Results were expressed as hazard ratios (HR) with 95% confidence intervals, adjusted for centre, BMI and smoking.

Results: 483 (25.3%) men died during a mean follow-up of 12.4±3.3 years. Men who died had a higher BMI (p=0.002), but smoking status did not differ. TT levels were similar in both groups, but FT was lower in those who died (mean±SD: 312±86 pmol/L vs 270±84, p<0.001) and LH was higher (5.7±3.3 U/L vs 7.8±5.8, p<0.001). Men in the lowest FT quartile had higher mortality risk compared to men in the highest quartile (HR 1.43 (1.06-1.95); p=0.021). Also men in the highest FSH quartile had increased mortality risk (HR 1.38 (1.02-1.88); p=0.036). However, there was no association with TT, E2 or LH. Men with 3 sexual symptoms had a higher mortality risk compared to men with no sexual symptoms (HR 1.77 (1.28-2.41); p<0.001). In particular erectile dysfunction and poor morning erections, but not lower libido, were associated with increased mortality (HR 1.40 (1.15-1.73); p=0.001; HR 1.30 (1.06-1.60); p=0.012; HR 1.14 (0.93-1.40); p=0.203 respectively). Further adjusting for TT and FT did not influence the observed HRs. Also in men with normal TT (>12 nmol/L), the presence of sexual symptoms increased mortality risk (HR 1.51 (1.15-1.97); p=0.003). Finally, men with TT<8 nmol/L and sexual symptoms had a higher mortality risk compared to men with normal TT and no sexual symptoms (HR 1.92 (1.05-3.52); p=0.035).

Conclusions: Men with the lowest FT and highest FSH levels have an increased mortality risk. Sexual symptoms, in particular erectile dysfunction, predict all-cause mortality independently of T levels. As both vascular disease and low T can influence erectile function, sexual symptoms can be an early sign for increased cardiovascular risk and mortality, as well as a sequela of low T.

<![CDATA[OR02-02 Possible Age and Time-Of-Day Differences in the Hypothalamo-Pituitary-Testicular, and Adrenal, Response to Total Overnight Sleep Restriction]]> <![CDATA[OR02-03 Role of Phosphorylated Gonadotropin-Regulated Testicular RNA Helicase (GRTH/DDX25) in the Regulation of Germ Cell Specific MRNAs in Chromatoid Bodies During Spermiogenesis]]> <![CDATA[OR02-05 Effect of Testosterone Replacement Therapy Added to Intensive Lifestyle Intervention on Cognitive Functions in Frail, Older Veterans with Hypogonadism and Obesity: A Randomized Clinical Trial]]>