Purpose Implantation failure is a major limiting factor of successful in vitro fertilization (IVF). The objective of this study was to determine if endometrial mechanical stimulation (EMS) by endometrial biopsy in the luteal phase of the cycle prior to embryo transfer (ET) improves clinical outcomes in an unselected subfertile population. Methods Double-blind, randomized controlled trial of EMS versus sham biopsy and odds of clinical pregnancy after IVF and embryo transfer. Secondary outcomes included spontaneous miscarriage and live birth. Results One hundred women enrolled and were randomized from 2013 to 2017. Enrollment was terminated after futility analysis showed no difference in clinical pregnancy between EMS versus control, 47.2% vs 61.7% (OR 0.55, 95% CI 0.25-1.23, p = 0.15). There were no significant differences between women who underwent EMS and those who did not in terms of positive pregnancy test 54.7% vs 63.8% (OR 0.69, 95% CI 0.31-1.53, p = 0.36), miscarriage 7.5% vs 2.1% (OR 3.76 95% CI 0.41-34.85, p = 0.22), or live birth 43.4% vs 61.7% (OR 0.48 95% CI 0.21-1.06, p = 0.07). Conclusions EMS in the luteal phase of the cycle preceding embryo transfer does not improve clinical outcomes in an unselected subfertile population and may result in a lower live birth rate. We caution the routine use of EMS in an unselected population.

III.

NIH K12 HD063086 (ESJ, MGT), NIH T32 HD0040135-11 (KAR), F32 HD040135-10 NIH (KRO), 5K12HD000849-25 (PTJ). No competing interests.

De novo mutations are known to play a prominent role in sporadic disorders with reduced fitness. We hypothesize that de novo mutations play an important role in severe male infertility and explain a portion of the genetic causes of this understudied disorder. To test this hypothesis, we utilize trio-based exome sequencing in a cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare (MAF < 0.1%) protein-altering de novo mutations are classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of loss-of-function de novo mutations in loss-of-function-intolerant genes (p-value = 1.00 × 10−5) in infertile men compared to controls. Additionally, we detected a significant increase in predicted pathogenic de novo missense mutations affecting missense-intolerant genes (p-value = 5.01 × 10−4) in contrast to predicted benign de novo mutations. One gene we identify, RBM5, is an essential regulator of male germ cell pre-mRNA splicing and has been previously implicated in male infertility in mice. In a follow-up study, 6 rare pathogenic missense mutations affecting this gene are observed in a cohort of 2,506 infertile patients, whilst we find no such mutations in a cohort of 5,784 fertile men (p-value = 0.03). Our results provide evidence for the role of de novo mutations in severe male infertility and point to new candidate genes affecting fertility.

Non-obstructive azoospermia (NOA) is the most severe form of male infertility and typically incurable. Defining the genetic basis of NOA has proven challenging, and the most advanced classification of NOA subforms is not based on genetics, but simple description of testis histology. In this study, we exome-sequenced over 1000 clinically diagnosed NOA cases and identified a plausible recessive Mendelian cause in 20%. We find further support for 21 genes in a 2-stage burden test with 2072 cases and 11,587 fertile controls. The disrupted genes are primarily on the autosomes, enriched for undescribed human “knockouts”, and, for the most part, have yet to be linked to a Mendelian trait. Integration with single-cell RNA sequencing data shows that azoospermia genes can be grouped into molecular subforms with synchronized expression patterns, and analogs of these subforms exist in mice. This analysis framework identifies groups of genes with known roles in spermatogenesis but also reveals unrecognized subforms, such as a set of genes expressed across mitotic divisions of differentiating spermatogonia. Our findings highlight NOA as an understudied Mendelian disorder and provide a conceptual structure for organizing the complex genetics of male infertility, which may provide a rational basis for disease classification.

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Objective To study and describe the use of social networking websites among SART member clinics Design Cross-sectional study Setting University Based Practice Patients Not Applicable Interventions Not Applicable Main Outcome Measure Prevalence of social networking websites among SART member clinics and evaluation of content, volume and location (i.e mandated state, region) using multivariate regression analysis Results 384 SART registered clinics and 1,382 social networking posts were evaluated. Of the clinics, 96% have a website and 30% link to a social networking website. The majority of clinics (89%) with social networking websites were affiliated with non-academic centers. Social networking posts mostly provide information (31%) and/or advertise (28%), while the remaining offer support (19%) or are irrelevant (17%) to the target audience. Only 5% of posts involved patients requesting information. Clinic volume correlates with the presence of a clinic website and a social networking website (p<0.001). Conclusion Almost all SART member clinics have a website. Nearly one-third of these clinics host a social networking website like Facebook, Twitter and/or a Web-log (“blog”). Larger volume clinics commonly host social networking websites. These sites provide new ways to communicate with patients, but clinics should maintain policies on the incorporation of social networks into practice.

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