Multicentric, prospective observational data show sperm capacitation predicts male fertility, and cohort comparison reveals a high prevalence of impaired capacitation in men questioning their fertility.

RESEARCH QUESTIONS: Can a previously defined relationship between sperm capacitation and the probability of a man generating pregnancy within three cycles, prospectively predict male fertility in diverse clinical settings? A second study asked, what is the prevalence of impaired sperm fertilizing ability in men questioning their fertility (MQF), and does this relate to traditional semen analysis metrics? DESIGN: In the multicentric, prospective observational study, data (n = 128; six clinics) were analysed to test a published relationship between the percentage of fertilization-competent, capacitated spermatozoa (Cap-Score) and probability of generating pregnancy (PGP) within three cycles of intrauterine insemination. Logistic regression of total pregnancy outcomes (n = 252) assessed fit. In the cohort comparison, Cap-Scores of MQF (n = 2155; 22 clinics) were compared with those of 76 fertile men. RESULTS: New outcomes (n = 128) were rank-ordered by Cap-Score and divided into quintiles (25-26 per group); chi-squared testing revealed no difference between predicted and observed pregnancies (P = 0.809). Total outcomes (n = 252; 128 new + 124 previous) were pooled and the model recalculated, yielding an improved fit (P < 0.001). Applying the Akaike information criterion found that the optimal model used Cap-Score alone. Cap-Scores were performed on 2155 men (with semen analysis data available for 1948). To compare fertilizing ability, men were binned by PGP (≤19%, 20-29%, 30-39%, 40-49%, 50-59%, ≥60%). Distributions of PGP and the corresponding Cap-Scores were significantly lower in MQF versus fertile men (P < 0.001). Notably, 64% of MQF with normal volume, concentration and motility (757/1183) had PGP of 39% or less (Cap-Scores ≤31), versus 25% of fertile men. CONCLUSIONS: Sperm capacitation prospectively predicted male fertility. Impaired capacitation affects many MQF with normal semen analysis results, informing diagnosis versus idiopathic infertility.

The dual trigger study: Rationale and study design of a prospective double-blind randomized clinical trial comparing pregnancy rates after co-administration of low dose hCG at the time of GnRH agonist trigger or 35 h later for the prevention of OHSS.

Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication of controlled ovarian stimulation. The use of gonadotropin releasing hormone (GnRH) agonist for the trigger of oocyte maturation is effective in the prevention of OHSS although it may result in a lower pregnancy rate. The use of adjuvant low dose human chorionic gonadotropin (hCG) at the time of trigger or at the time of oocyte retrieval may improve pregnancy rates. The goal of this dual trigger study is to evaluate the safety and efficacy of the use of low dose hCG administered at the time of GnRH agonist trigger or 35 h later as well as the potential impact on pregnancy rates. The population will consist of 82 women undergoing IVF treatment who are at risk of developing OHSS. This study will be a single center prospective randomized double-blind placebo controlled trial. The randomization schedule will be administered by the Investigational Drug Services of the University. After controlled ovarian stimulation, induction of oocyte maturation will be achieved using a GnRH agonist and patients will be randomized to receive either low dose hCG 1000 IU at the time of trigger and placebo at oocyte retrieval (Study group) or placebo at the time of trigger and hCG 1500 IU at the time of oocyte retrieval (Control group). The main outcomes will be live birth rates and incidence of OHSS. Two ancillary studies will include a quality of life survey and serum assessment of independent corpus luteum function.

Single-Nucleotide Polymorphism-Microarray Ploidy Analysis of Paraffin-Embedded Products of Conception in Recurrent Pregnancy Loss Evaluations.

OBJECTIVE: To compare the analysis of chromosome number from paraffin-embedded products of conception using single-nucleotide polymorphism (SNP) microarray with the recommended screening for the evaluation of couples presenting with recurrent pregnancy loss who do not have previous fetal cytogenetic data. METHODS: We performed a retrospective cohort study including all women who presented for a new evaluation of recurrent pregnancy loss over a 2-year period (January 1, 2012, to December 31, 2013). All participants had at least two documented first-trimester losses and both the recommended screening tests and SNP microarray performed on at least one paraffin-embedded products of conception sample. Single-nucleotide polymorphism microarray identifies all 24 chromosomes (22 autosomes, X, and Y). RESULTS: Forty-two women with a total of 178 losses were included in the study. Paraffin-embedded products of conception from 62 losses were sent for SNP microarray. Single-nucleotide polymorphism microarray successfully diagnosed fetal chromosome number in 71% (44/62) of samples, of which 43% (19/44) were euploid and 57% (25/44) were noneuploid. Seven of 42 (17%) participants had abnormalities on recurrent pregnancy loss screening. The per-person detection rate for a cause of pregnancy loss was significantly higher in the SNP microarray (0.50; 95% confidence interval [CI] 0.36-0.64) compared with recurrent pregnancy loss evaluation (0.17; 95% CI 0.08-0.31) (P=.002). Participants with one or more euploid loss identified on paraffin-embedded products of conception were significantly more likely to have an abnormality on recurrent pregnancy loss screening than those with only noneuploid results (P=.028). The significance remained when controlling for age, number of losses, number of samples, and total pregnancies. CONCLUSION: These results suggest that SNP microarray testing of paraffin-embedded products of conception is a valuable tool for the evaluation of recurrent pregnancy loss in patients without prior fetal cytogenetic results. Recommended recurrent pregnancy loss screening was unnecessary in almost half the patients in our study. LEVEL OF EVIDENCE: II.

Ovulation rate and cycle characteristics in a subsequent clomiphene citrate cycle after stair-step protocol.

OBJECTIVE: To determine the ovulation rate after ovulation induction with clomiphene citrate (CC) in women who had previously been ovulatory after a stair-step (CC-SS) ovulation induction. DESIGN: Retrospective cohort. SETTING: University-based tertiary fertility center. PATIENT(S): 61 anovulatory patients <40 years of age with polycystic ovary syndrome who underwent ovulation induction with a CC-SS protocol and a subsequent CC cycle. INTERVENTION(S): Ovulation induction with CC. MAIN OUTCOME MEASURE(S): Ovulation rates and cycle characteristics. RESULT(S): Of 61 patients who underwent a subsequent CC cycle, 15 (25%) failed to ovulate at the previously ovulatory dose. Of those 15 patients, 13 (86.7%) ovulated after an increase in dose. The total number of follicles ≥15 mm (2.8 ± 1.2 vs. 1.6 ± 0.7) and peak estradiol (E2) levels (604 ± 272 pg/mL vs. 447 ± 218 pg/mL) were statistically significantly higher in the CC-SS cycle compared with the subsequent CC cycle, respectively. The endometrial lining was statistically significantly thinner in the CC-SS than the CC cycle (7.8 ± 1.8 vs. 9.2 ± 2.7, respectively). CONCLUSION(S): The majority of patients who ovulate after a CC-SS protocol will ovulate after taking the previously ovulatory CC dose in a subsequent cycle. Those who do not ovulate will likely ovulate with a further increase in CC dose.

Maternal and neonatal outcomes after gonadotropin-releasing hormone agonist trigger for final oocyte maturation in patients undergoing in vitro fertilization.

OBJECTIVE: To compare the rate of congenital anomalies, obstetrical complications, and neonatal complications in antagonist cycles where either GnRH agonist (GnRHa) or hCG was used for final oocyte maturation. DESIGN: Retrospective cohort study. SETTING: University-based tertiary fertility center. PATIENT(S): Three hundred ninety-two women under 40 years of age who underwent controlled ovarian stimulation using a GnRH antagonist protocol and who had final oocyte maturation triggered with either a GnRHa or hCG that resulted in pregnancy and delivery after 16 weeks' gestation. INTERVENTION(S): GnRHa versus hCG trigger of final oocyte maturation. MAIN OUTCOME MEASURE(S): Congenital anomaly rates, obstetrical complications, and neonatal complications. RESULT(S): There were no significant differences in the rate of congenital anomalies between GnRHa and hCG trigger (6.6 vs. 9.2%). There were also no differences in the maternal complications (27.6 vs. 20.8%) or neonatal complications (19.7 vs. 20.0%) between the GnRHa trigger and hCG trigger groups. CONCLUSION(S): GnRHa trigger does not affect the rate of congenital anomalies or obstetrical or neonatal complications and remains a viable option in the prevention of ovarian hyperstimulation syndrome.

Dual trigger with gonadotropin-releasing hormone agonist and standard dose human chorionic gonadotropin to improve oocyte maturity rates.

OBJECTIVE: To evaluate the percentage (%) of mature oocytes retrieved in patients with a previous history of >25% immature oocytes retrieved who were triggered with gonadotropin-releasing hormone agonist (GnRH-a) and human chorionic gonadotropin (hCG) to induce oocyte maturation. DESIGN: Retrospective cohort study. SETTING: A university-based tertiary fertility center. PATIENT(S): Patients with a history of >25% immature oocytes retrieved in a prior in vitro fertilization cycle who were triggered with GnRH-a and hCG 5,000 IU or 10,000 IU in a subsequent cycle from January 2008 through February 2012. INTERVENTION(S): Dual trigger of GnRH-a and hCG 5,000 or 10,000 IU. MAIN OUTCOME MEASURE(S): Percent of mature oocytes retrieved and fertilization rate. RESULT(S): The proportion of mature oocytes retrieved was significantly higher with a dual trigger compared with the subject's previous cycle (75.0%, interquartile range 55.6%-80.0% vs. 38.5%, interquartile range 16.7%-55.6%). The odds of a mature oocyte retrieved for patients who received a dual trigger was 2.51 times higher after controlling for stimulation protocol, hCG dose, gonadotropin dose, and oocyte retrieval time interval (odds ratio 2.51; confidence interval 1.06-5.96). The implantation, clinical, and ongoing pregnancy rates for the dual trigger were 11.8%, 26.1%, and 17.4%, respectively. CONCLUSION(S): In patients with a low percentage of mature oocytes retrieved who are triggered with a combination of GnRH-a and hCG, the % of mature oocytes retrieved improved. in vitro fertilization outcomes, however, remain poor, suggesting an underlying oocyte dysfunction.

Reactivation of maternal SNORD116 cluster via SETDB1 knockdown in Prader-Willi syndrome iPSCs.

Prader-Willi syndrome (PWS), a disorder of genomic imprinting, is characterized by neonatal hypotonia, hypogonadism, small hands and feet, hyperphagia and obesity in adulthood. PWS results from the loss of paternal copies of the cluster of SNORD116 C/D box snoRNAs and their host transcript, 116HG, on human chromosome 15q11-q13. We have investigated the mechanism of repression of the maternal SNORD116 cluster and 116HG. Here, we report that the zinc-finger protein ZNF274, in association with the histone H3 lysine 9 (H3K9) methyltransferase SETDB1, is part of a complex that binds to the silent maternal but not the active paternal alleles. Knockdown of SETDB1 in PWS-specific induced pluripotent cells (iPSCs) causes a decrease in the accumulation of H3K9 trimethylation (H3K9me3) at 116HG and corresponding accumulation of the active chromatin mark histone H3 lysine 4 dimethylation (H3K4me2). We also show that upon knockdown of SETDB1 in PWS-specific iPSCs, expression of maternally silenced 116HG RNA is partially restored. SETDB1 knockdown in PWS iPSCs also disrupts DNA methylation at the PWS-IC where a decrease in 5-methylcytosine is observed in association with a concomitant increase in 5-hydroxymethylcytosine. This observation suggests that the ZNF274/SETDB1 complex bound to the SNORD116 cluster may protect the PWS-IC from DNA demethylation during early development. Our findings reveal novel epigenetic mechanisms that function to repress the maternal 15q11-q13 region.

Dual trigger of oocyte maturation with gonadotropin-releasing hormone agonist and low-dose human chorionic gonadotropin to optimize live birth rates in high responders.

OBJECTIVE: To compare live birth rates after dual trigger of oocyte maturation with GnRH agonist (GnRHa) and low-dose hCG versus GnRHa alone in high responders with peak E(2) <4,000 pg/mL at risk of ovarian hyperstimulation syndrome (OHSS). DESIGN: Retrospective cohort study. SETTING: University-based tertiary-care fertility center. PATIENT(S): Patients <40 years old with peak E(2) <4,000 pg/mL at risk of OHSS who underwent IVF/intracytoplasmic sperm injection with GnRH antagonist protocol and triggered with GnRHa alone or GnRHa plus 1,000 IU hCG (dual trigger) for oocyte maturation. INTERVENTION(S): GnRHa alone versus dual trigger. MAIN OUTCOME MEASURE(S): Live birth, implantation, and clinical pregnancy rates and OHSS. RESULT(S): The dual-trigger group had a significantly higher live birth rate (52.9% vs. 30.9%), implantation rate (41.9% vs. 22.1%), and clinical pregnancy rate (58.8% vs. 36.8%) compared with the GnRHa trigger group. One case of mild OHSS occurred in the dual-trigger group, and there were no cases of OHSS in the GnRHa trigger group. CONCLUSION(S): Dual trigger of oocyte maturation with GnRHa and low-dose hCG in high responders with peak E(2) <4,000 pg/mL improves the probability of conception and live birth without increasing the risk of significant OHSS.