The impact of preovulatory versus midluteal serum progesterone level on live birth rates during fresh embryo transfer.

BACKGROUND: Conflicting evidence still prevails concerning the effect of preovulatory elevated progesterone (EP4) on reproductive outcomes in fresh embryo transfer (ET). However, few studies have analyzed the effect of EP4 on the likelihood of pregnancy using multivariate regression approach. The potential confounding factors tested in these studies were limited to either patient's characteristics or to stimulation related parameters. Yet, several studies have shown that postovulatory parameters such as midluteal progesterone (P4) level may be considered as a proxy variable of endometrial receptivity as well. OBJECTIVE: The aim of the present study was to estimate the independent effect of preovulatory P4 effect, if any, on the probability of live birth (LB) by considering the midluteal endocrine profile when controlling for the potential confounding factors. METHODS: This is a secondary data analysis of a cohort of fresh IVF/ICSI cycles triggered with GnRH agonist (n = 328) performed in a single IVF center during the period 2014-2016. Patients contributed only one cycle and were stratified into four groups according to preovulatory P4 quartiles. We assessed the association between preovulatory P4 and the odds of LB calculated by logistic regression analysis after controlling for the most clinically relevant confounders. The primary outcome measure: Live birth rates (LBR). RESULTS: Both preovulatory and midluteal P4 were significantly correlated with the ovarian response. Logistic regression analysis showed that preovulatory serum P4 did not have a significant impact on LBR. In contrast, midluteal serum P4 level was an important independent factor associated with LBR. The optimal chance of LBR was achieved with midluteal serum P4 levels of 41-60 ng/ml, [OR: 2.73 (1.29-5.78); p< 0.008]. CONCLUSION: The multivariate analysis suggests that the midluteal P4 level seems to impact LBR more than the preovulatory P4 level in women undergoing IVF treatment followed by fresh ET.

Genetic analyses of a large cohort of infertile patients with globozoospermia, DPY19L2 still the main actor, GGN confirmed as a guest player.

Globozoospermia is a rare phenotype of primary male infertility inducing the production of round-headed spermatozoa without acrosome. Anomalies of DPY19L2 account for 50-70% of all cases and the entire deletion of the gene is by far the most frequent defect identified. Here, we present a large cohort of 69 patients with 20-100% of globozoospermia. Genetic analyses including multiplex ligation-dependent probe amplification, Sanger sequencing and whole-exome sequencing identified 25 subjects with a homozygous DPY19L2 deletion (36%) and 14 carrying other DPY19L2 defects (20%). Overall, 11 deleterious single-nucleotide variants were identified including eight novel and three already published mutations. Patients with a higher rate of round-headed spermatozoa were more often diagnosed and had a higher proportion of loss of function anomalies, highlighting a good genotype phenotype correlation. No gene defects were identified in patients carrying < 50% of globozoospermia while diagnosis efficiency rose to 77% for patients with > 50% of globozoospermia. In addition, results from whole-exome sequencing were scrutinized for 23 patients with a DPY19L2 negative diagnosis, searching for deleterious variants in the nine other genes described to be associated with globozoospermia in human (C2CD6, C7orf61, CCDC62, CCIN, DNAH17, GGN, PICK1, SPATA16, and ZPBP1). Only one homozygous novel truncating variant was identified in the GGN gene in one patient, confirming the association of GGN with globozoospermia. In view of these results, we propose a novel diagnostic strategy focusing on patients with at least 50% of globozoospermia and based on a classical qualitative PCR to detect DPY19L2 homozygous deletions. In the absence of the latter, we recommend to perform whole-exome sequencing to search for defects in DPY19L2 as well as in the other previously described candidate genes.

Low LH Level on the Day of GnRH Agonist Trigger Is Associated With Reduced Ongoing Pregnancy and Live Birth Rates and Increased Early Miscarriage Rates Following IVF/ICSI Treatment and Fresh Embryo Transfer.

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.

Effect of Spermatic Nuclear Quality on Live Birth Rates in Intracytoplasmic Sperm Injection.

BACKGROUND: Our study defines the clinical role of sperm DNA damage in the assisted reproductive technology procedure. AIM: To investigate if the compaction of chromatin explored added to the analysis of the sperm DNA fragmentation allows obtaining a new indicator for sperm genome quality linked to live birth rate (LBR). DESIGN: This was a prospective study, undergoing 101 cycles in the intracytoplasmic sperm injection (ICSI) program. MATERIALS AND METHODS: The sperm DNA fragmentation index (DFI) has been measured with sperm chromatin dispersion examination. The sperm decondensation index (SDI) of chromatin has been measured with aniline blue procedure; with these indexes, a new parameter has been created: DFI × SDI. STATISTICAL ANALYSIS: Pearson's correlation coefficient, Student's t-test, and Chi-square test were used. The quantitative variables were described as mean ± standard deviation. Multivariate logistic regressions were performed with live birth as outcome. RESULTS: The sperm concentration, motility, and normal morphology were lower when the DFI was high (P = 0.001). The fertilization rates and the number of obtained embryos were not statistically significant different according to the DFI groups. The SDI does not appear to be linked either with the spermatic parameters or with the ICSI parameters. A low DFI seems to be a beneficial factor to obtain a live birth in ICSI procedure (P = 0.064). In case of high DFI, a high SDI allows to obtain a higher LBR than a low SDI. CONCLUSION: The DFI is a good prognostic for a delivery rate in ICSI procedure, and the SDI could be added to DFI to create a new parameter of sperm nuclear quality. This new parameter seems to be linked to LBR.

Impact of Mid-Luteal Phase GnRH Agonist Administration on Reproductive Outcomes in GnRH Agonist-Triggered Cycles: A Randomized Controlled Trial.

OBJECTIVE: To explore whether the addition of a mid-luteal bolus of GnRH agonist (GnRHa) improves the implantation rate (IR) in in vitro fertilization (IVF) cycles. DESIGN: A randomized controlled trial. SETTING: Private IVF center. PATIENTS: 328 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). INTERVENTIONS: In addition, the study group received a bolus of GnRHa 6 days after OPU, whereas the control group did not. MAIN OUTCOME MEASURE: Implantation rate. SECONDARY OUTCOME MEASURES: Ongoing pregnancy (OP) and live birth (LB) rates. RESULTS: Although 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]. CONCLUSION: Although 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. NCT: 02053779.

Mutations of the aurora kinase C gene causing macrozoospermia are the most frequent genetic cause of male infertility in Algerian men.

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.

The Aurora Kinase C c.144delC mutation causes meiosis I arrest in men and is frequent in the North African population.

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.