Infertility concerns a minimum of 70 million couples worldwide. An important proportion of cases is believed to have a genetic component, yet few causal genes have been identified so far. In a previous study, we demonstrated that a homozygous mutation (c.144delC) in the Aurora Kinase C (AURKC) gene led to the production of large-headed polyploid multi-flagellar spermatozoa, a primary infertility phenotype mainly observed in North Africans. We now want to estimate the prevalence of the defect, to improve our understanding of AURKC physiopathology in spermatogenesis and assess its implication in oogenesis. A carrier frequency of 1/50 was established from individuals from the Maghrebian general population, comparable to that of Y-microdeletions, thus far the only known recurrent genetic event altering spermatogenesis. A total of 62 patients were genotyped, all who had a typical phenotype with close to 100% large-headed spermatozoa were homozygously mutated (n = 32), whereas no AURKC mutations were detected in the others. Two homozygous females were identified; both were fertile indicating that AURKC is not indispensible in oogenesis. Previous FISH results had showed a great chromosomal heterogeneity in these patient's spermatozoa. We demonstrate here by flow cytometry that all spermatozoa have in fact a homogeneous 4C DNA content and are thus all blocked before the first meiotic division. Our data thus indicate that a functional AURKC protein is necessary for male meiotic cytokinesis while its absence does not impair oogenesis.

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Objective: To examine the correlation between serum luteinizing hormone (LH) levels on the day of GnRH agonist (GnRH-a) trigger and reproductive outcomes following in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) treatment and fresh embryo transfer, and to identify a pre-trigger serum LH threshold which would be compatible with the most optimal cycle outcome.Design: This study is based on data from a previously published randomized controlled trial conducted from 2014 to 2016.Patients: A total of 322 participants were enrolled.Setting: Private IVF center. Intervention(s): GnRH-antagonist-based IVF cycles triggered with GnRH-a. For the purpose of the study, patients were stratified according to preovulatory LH quartiles (Q1-Q4). Main Outcome Measure(s): Ongoing pregnancy rates (OP), live birth rates (LB) and early pregnancy loss (EPL) rates.Results: The results of the present study showed increasing OP as well as LB rates and decreasing EPL rates with increasing pre-trigger serum LH levels (P for trend < 0.06, 0.07, and 0.02), respectively. The absolute difference between the highest LH(Q4) and the lowest LH (Q1) group was 13.4%, 12.1%, and 12% in OP, LB, and EPL rates, respectively. In multivariate regression analysis, a pre-trigger serum LH level of 1.60 mIU/ml was identified as a threshold below which reproductive outcomes decreased. The ROC curve values were statistically significant for OP, LB, and EPL; the AUC (95% CI) = [0.57 (0.50–0.63) P < 0.04; 0.57 (0.50–0.63) P < 0.05, and 0.60 (0.51–0.70) P < 0.04], respectively. A significant positive correlation was found on the day of GnRH-a trigger between serum LH, the number of follicles, serum P4, and serum E2, p < 0.03; P < 0.03; and P < 0.001, respectively.Conclusion: Low serum LH levels on the day of GnRH-a trigger is associated with reduced ongoing pregnancy and live birth rates and increased early miscarriage rates. Our findings suggest a lower threshold of serum LH values on the day of GnRH-a trigger necessary to optimize reproductive outcomes in fresh embryo transfer cycles.Clinical Trial Registration: www.ClinicalTrials.gov, Number: 02053779

ObjectiveTo explore whether the addition of a mid-luteal bolus of GnRH agonist (GnRHa) improves the implantation rate (IR) in in vitro fertilization (IVF) cycles.DesignA randomized controlled trial.SettingPrivate IVF center.Patients328 IVF/intracytoplasmic sperm injection patients were triggered with GnRHa and received 1,500 IU HCG on the day of oocyte pick-up (OPU) in addition to a standard luteal phase support (LPS).Intervention(s)In addition, the study group received a bolus of GnRHa 6 days after OPU, whereas the control group did not.Main outcome measureImplantation rate.Secondary outcome measure(s)Ongoing pregnancy (OP) and live birth (LB) rates.ResultsAlthough serum concentrations of FSH, LH, E2, and P on day OPU + 7 were significantly higher in the study group compared to the control group, the IR was not statistically different between the treatment group (27%) and the control group (23%) [odds ratio (OR) 1.2 (95% CI 0.9–1.7), P < 0.27]. Similarly, the OP rate was 37% in the treatment group and 31% in the control group [OR 1.3 (95% CI 0.8–2.0), P < 0.23]. The LB rate was 36% in the treatment group and 31% in the control group [OR: 1.3 (95% CI 0.8–2.0), P < 0.27].ConclusionAlthough a trend toward a higher IR and pregnancy rate was observed in the treatment group, this difference was not statistically significant. However, the absolute risk difference of 5% found for LB is clinically relevant, warranting further investigation.NCT02053779.

Klinefelter syndrome and Y-chromosomal microdeletion analyses were once the only two genetic tests offered to infertile men. Analyses of aurora kinase C (AURKC) and DPY19L2 are now recommended for patients presenting macrozoospermia and globozoospermia, respectively, two rare forms of teratozoospermia particularly frequent among North African men. We carried out genetic analyses on Algerian patients, to evaluate the prevalence of these syndromes in this population and to compare it with the expected frequency of Klinefelter syndrome and Y-microdeletions. We carried out a retrospective study on 599 consecutive patients consulting for couple infertility at the assisted reproduction unit of the Ibn Rochd Clinique, Constantine, Algeria. Abnormal sperm parameters were observed in 404 men. Fourteen and seven men had typical macrozoospermia and globozoospermia profiles, respectively. Molecular diagnosis was carried out for these patients, for the AURKC and DPY19L2 genes. Eleven men with macrozoospermia had a homozygous AURKC mutation (79%), corresponding to 2.7% of all patients with abnormal spermograms. All the men with globozoospermia studied (n = 5), corresponding to 1.2% of all infertile men, presented a homozygous DPY19L2 deletion. By comparison, we would expect 1.6% of the patients in this cohort to have Klinefelter syndrome and 0.23% to have Y-microdeletion. Our findings thus indicate that AURKC mutations are more frequent than Klinefelter syndrome and constitute the leading genetic cause of infertility in North African men. Furthermore, we estimate that AURKC and DPY19L2 molecular defects are 10 and 5 times more frequent, respectively, than Y-microdeletions.