Rescue in vitro maturation using ovarian support cells of human oocytes from conventional stimulation cycles yields oocytes with improved nuclear maturation and transcriptomic resemblance to in vivo matured oocytes.

PURPOSE: Determine if the gene expression profiles of ovarian support cells (OSCs) and cumulus-free oocytes are bidirectionally influenced by co-culture during in vitro maturation (IVM). METHODS: Fertility patients aged 25 to 45 years old undergoing conventional ovarian stimulation donated denuded immature oocytes for research. Oocytes were randomly allocated to either OSC-IVM culture (intervention) or Media-IVM culture (control) for 24-28 h. The OSC-IVM culture condition was composed of 100,000 OSCs in suspension culture with human chorionic gonadotropin (hCG), recombinant follicle stimulating hormone (rFSH), androstenedione, and doxycycline supplementation. The Media-IVM control lacked OSCs and contained the same supplementation. A limited set of in vivo matured MII oocytes were donated for comparative evaluation. Endpoints consisted of MII formation rate, morphological and spindle quality assessment, and gene expression analysis compared to in vitro and in vivo controls. RESULTS: OSC-IVM resulted in a statistically significant improvement in MII formation rate compared to the Media-IVM control, with no apparent effect on morphology or spindle assembly. OSC-IVM MII oocytes displayed a closer transcriptomic maturity signature to IVF-MII controls than Media-IVM control MII oocytes. The gene expression profile of OSCs was modulated in the presence of oocytes, displaying culture- and time-dependent differential gene expression during IVM. CONCLUSION: The OSC-IVM platform is a novel tool for rescue maturation of human oocytes, yielding oocytes with improved nuclear maturation and a closer transcriptomic resemblance to in vivo matured oocytes, indicating a potential enhancement in oocyte cytoplasmic maturation. These improvements on oocyte quality after OSC-IVM are possibly occurring through bidirectional crosstalk of cumulus-free oocytes and ovarian support cells.

Effect of postthaw change in embryo score on single euploid embryo transfer success rates.

OBJECTIVE: To assess whether the change in embryo morphology from precryopreservation to postthaw is associated with the embryo transfer success rates in single euploid embryo transfer cycles. DESIGN: Retrospective cohort study. SETTING: Academic affiliated fertility clinic. PATIENT(S): Patients who underwent a single euploid embryo transfer cycle from September 2016 to April 2022 were included. A decision support tool was used to assign each embryo a reproductive potential score on the basis of the day of biopsy, expansion, and grade of trophectoderm and inner cell mass at the time of cryopreservation and after thaw. Embryos were divided into 4 groups: group 1 included embryos with the same score after thaw (reference); group 2 included those with a higher score; group 3 included those with a lower score; and group 4 included those that did not re-expand after thaw. INTERVENTION(S): No interventions administered. MAIN OUTCOME MEASURE(S): The primary outcome was the live birth rates (LBRs) per embryo transfer. The secondary outcomes included the chemical pregnancy, clinical pregnancy, and clinical pregnancy loss rates. Comparative statistics and univariate analyses were performed using the Kruskal-Wallis and χ2tests. Multivariate logistic regression fitted with generalized estimating equation was performed to compare the odds of live birth between groups. RESULT(S): A total of 7,750 embryo transfers performed for 4,613 patients met inclusion criteria: 5,331 in group 1; 486 in group 2; 1,726 in group 3; and 207 in group 4. In the univariate analysis, there was a statistically significant difference in the LBR between groups 1, 2, 3, and 4 (55.8% vs. 51.4%, 47.5%, and 26.6%). Logistic regression controlling for oocyte age, antimüllerian hormone, body mass index, endometrial thickness, year of embryo transfer, time from thaw to final grading, and embryo score before cryopreservation showed significantly lower odds of live birth when the embryo was downgraded (odds ratio [OR], 0.70; confidence interval [CI], 0.62-0.79) or did not re-expand (OR, 0.36; CI, 0.26-0.51) than those with no change in score. When controlling for all variables, there was a significant increase in the odds of live birth between embryos that had a higher score after thaw and those without a change (OR, 1.42; CI, 1.14-1.76). There was no significant difference in the clinical pregnancy loss rate among the 4 groups. CONCLUSION(S): The change in the quality of the embryo after thaw is an important factor in embryo transfer success. In an adjusted analysis, the chemical and clinical pregnancy rates and LBR per embryo transfer all significantly decrease in embryos that were downgraded or did not expand on the day of single euploid embryo transfer. Embryos that re-expand and have improved quality after thaw have the highest odds of live birth.

Single Euploid Embryo Transfer Outcomes After Uterine Septum Resection.

STUDY OBJECTIVE: To study pregnancy outcomes after single euploid embryo transfer (SEET) in patients who underwent prior uterine septum resection to those with uteri of normal contour, without Müllerian anomalies or uterine abnormalities including polyps or fibroids, and without a history of prior uterine surgeries. DESIGN: Retrospective cohort study. SETTING: Single academic affiliated center. PATIENTS: 60 cycles of patients with prior hysteroscopic uterine septum resection who underwent an autologous SEET between 2012 and 2020 were used as the investigational cohort. A 3:1 ratio propensity score matched control cohort of 180 single euploid embryo transfer cycles from patients without a history of uterine septa were used as the control group. INTERVENTIONS: No interventions administered. MEASUREMENTS AND MAIN RESULTS: Pregnancy, clinical pregnancy loss, ongoing clinical pregnancy, and live birth rates in patients with a history of uterine septum resection compared with matched patients without Müllerian anomalies or uterine surgeries. Patients with a prior uterine septum had significantly lower rates of chemical pregnancy (58.33% vs 77.2%, p = .004), implantation (41.67% vs 65.6%, p = .001), and live birth (33.33% vs 57.8%, p = .001) per transfer. No statistical difference in clinical pregnancy loss rates was found when comparing septum patients with controls (8.33% vs 7.8%, p = .89). CONCLUSION: Patients with a history of hysteroscopic resection who undergo in vitro fertilization are more susceptible to suboptimal clinical outcomes compared with patients with normal uteri. Early pregnancy loss rates in patients with a uterine septum are higher than in those without; however, after resection, the rates are comparable. Patients born with septate uteri require assessment of surgical intervention prior to SEET, and to optimize their reproductive outcomes.

Correlation of self-reported racial background to euploidy status and live birth rates in assisted reproductive technology cycles.

PURPOSE: To determine whether the embryonic euploidy rate and live birth outcomes following single, euploid embryo transfer (SEET) differ among women of self-reported racial and ethnic backgrounds. METHODS: This retrospective cohort study included all infertile patients of different self-reported racial backgrounds who underwent In vitro fertilization (IVF) with preimplantation genetic testing for aneuploidy (PGT-A) and an autologous single euploid embryo transfer (SEET) from December 2015 to December 2019 at a single private and academic assisted reproduction technology center. Primary outcome measures included ploidy rates among different racial groups. Secondary outcomes included clinical pregnancy, clinical pregnancy loss, and live birth rates. RESULTS: Five thousand five hundred sixty-two patients who underwent an IVF cycle with ICSI-PGT-A were included. A total of 24,491 blastocysts were analyzed. White participants had on average more euploid embryos and higher euploidy rates when compared to their counterparts (p ≤ 0.0001). However, after controlling for confounding factors, there was no association between race and the odds of having  a higher euploidy rate (aOR 1.31; 95% CI 0.63-2.17, p = 0.42). A total of 4949 patients underwent SEET. Pregnancy outcomes did not differ among patients of varying self-reported races. CONCLUSIONS: Euploidy rates and pregnancy outcomes were comparable among patients of different racial backgrounds who underwent a SEET.

In Vitro Fertilization and Early Pregnancy Outcomes After Coronavirus Disease 2019 (COVID-19) Vaccination.

OBJECTIVE: To assess whether coronavirus disease 2019 (COVID-19) mRNA vaccination is associated with controlled ovarian hyperstimulation or early pregnancy outcomes. METHODS: This retrospective cohort study included patients who underwent controlled ovarian hyperstimulation or single euploid frozen-thawed embryo transfer at a single academic center. Patients fully vaccinated with a COVID-19 mRNA vaccine were compared with unvaccinated patients who cycled during the same time period. The primary outcome was the fertilization rate for controlled ovarian hyperstimulation and the clinical pregnancy rate for frozen-thawed embryo transfer. Secondary outcomes for controlled ovarian hyperstimulation included eggs retrieved, mature oocytes retrieved, mature oocytes ratio, blastulation rate, and euploid rate. Secondary outcomes for frozen-thawed embryo transfer included pregnancy rate, ongoing pregnancy rate, biochemical pregnancy loss rate, and clinical pregnancy loss rate. RESULTS: Among 222 vaccinated patients and 983 unvaccinated patients who underwent controlled ovarian hyperstimulation cycles between February and September 2021, there was no association on adjusted analysis between COVID-19 vaccination and fertilization rate (ß=0.02±0.02, P=.20) or any of the secondary outcomes assessed: eggs retrieved (ß=0.01±0.57, P=.99), mature oocytes retrieved (ß=0.26±0.47, P=.58), mature oocytes ratio (ß=0.02±0.01, P=.12), blastulation rate (ß=0.02±0.02, P=.27), or euploid rate (ß=0.05±0.03, P=.08). Among 214 vaccinated patients and 733 unvaccinated patients undergoing single euploid frozen-thawed embryo transfer, adjusted analysis demonstrated no significant association between vaccination and clinical pregnancy (adjusted odds ratio [aOR] 0.79, 95% CI 0.54-1.16) or any of the secondary outcomes: pregnancy (aOR 0.88, 95% CI 0.58-1.33), ongoing pregnancy (aOR 0.90, 95% CI 0.61-1.31), biochemical pregnancy loss (aOR 1.21, 95% CI 0.69-2.14), or clinical pregnancy loss (aOR 1.02, 95% CI 0.51-2.06). CONCLUSION: Administration of COVID-19 mRNA vaccines was not associated with an adverse effect on stimulation or early pregnancy outcomes after IVF. Our findings contribute to the growing body of evidence regarding the safety of COVID-19 vaccination in women who are trying to conceive.

The association between prior cesarean delivery and subsequent in vitro fertilization outcomes in women undergoing autologous, frozen-thawed single euploid embryo transfer.

BACKGROUND: The rates of cesarean deliveries continue to increase worldwide. Previous work suggests an association between a previous cesarean delivery and reduced fertility in natural conception and in vitro fertilization treatment cycles. To our knowledge, there is no published research that explored the relationship between a previous cesarean delivery and the clinical outcomes after in vitro fertilization and the subsequent transfer of a single frozen-thawed euploid embryo. OBJECTIVE: This study aimed to investigate the relationship between the previous mode of delivery and subsequent pregnancy outcomes in patients undergoing a single frozen-thawed euploid embryo transfer after in vitro fertilization. STUDY DESIGN: A retrospective cohort study was performed at a single academic fertility center from January 2012 to April 2020. All women with a history of a live birth undergoing autologous, frozen-thawed single euploid embryo transfers were identified. Cases included patients with a single previous cesarean delivery; controls included patients with a single previous vaginal delivery. Only the first embryo transfer cycle was included. The primary outcome was the implantation rate. Secondary outcomes included ongoing pregnancy and live birth rates, biochemical pregnancy rate, and clinical miscarriage rate. RESULTS: A total of 525 patients met the inclusion criteria and were included in the analysis. Patients with a previous cesarean delivery had a higher body mass index (24.5±4.5 vs 23.4±4.1; P=.004) than those in the vaginal delivery cohort; the rest of the demographic data were otherwise similar. In a univariate analysis, the implantation rate was significantly lower in patients with a previous cesarean delivery (111/200 [55.5%] vs 221/325 [68.0%]; P=.004). After adjusting for the relevant covariates, a previous cesarean delivery was associated with a 48% reduction in the odds of implantation (adjusted odds ratio, 0.52; 95% confidence interval, 0.34-0.78; P=.002). In addition, after adjusting for the same covariates, a previous cesarean delivery was significantly associated with a 39% reduction in the odds of an ongoing pregnancy and live birth (adjusted odds ratio, 0.61; 95% confidence interval, 0.41-0.90; P=.01). There were no differences in the biochemical pregnancy rates or clinical miscarriage rates. CONCLUSION: This study demonstrated a marked reduction in implantation and ongoing pregnancy and live birth associated with a previous cesarean delivery in patients undergoing a single euploid embryo transfer. Our work stresses the importance of reducing the primary cesarean delivery rates at a national level and elucidating the mechanisms behind the substantially lower implantation rates after a cesarean delivery.

Fertility preservation for cancer patients: treatment gaps and considerations in patients' choices.

PURPOSE: Women with cancer may desire fertility preservation (FP) prior to initiating cancer treatment, but undergoing FP may result in treatment delays. This study sought to determine whether such delays existed in our population and which factors were associated with patients' decision to proceed with FP. METHODS: This was a historical cohort study performed at Montefiore Medical Center's Institute for Reproductive Medicine and Health. Reproductive age women diagnosed with cancer and consulted for FP were included. The main outcome measure was the number of days between FP consultation and cancer treatment initiation. Factors associated with patients' decisions to proceed with FP were also analyzed. RESULTS: Thirty out of 51 women in our study underwent FP including embryo cryopreservation, oocyte cryopreservation, ovarian tissue cryopreservation (OTC), both oocyte and embryo cryopreservation, or GnRH agonist treatment. The majority of women who underwent FP chose embryo cryopreservation (36.7%), followed by oocyte cryopreservation (33.3%). Of the 20 patients with partners who underwent FP, 13 (65%) froze embryos. Only 4 of the 30 women who underwent FP had all, or a portion of their services, covered by insurance. The mean treatment delay was 18 days (p = 0.007), with a mean consultation to oncologic treatment gap of 23 ± 16.8 and 41.4 ± 25.9 days in the non-FP and FP groups, respectively. CONCLUSION: Women with cancer diagnosis who underwent FP prior to initiating cancer treatment experienced a statistically significant delay in initiating cancer treatment. However, the clinical significance of this finding is unknown since FP treatments have not been associated with increased recurrence or mortality.

A workflow for simultaneous DNA copy number and methylome analysis of inner cell mass and trophectoderm cells from human blastocysts.

OBJECTIVE: To establish a workflow for isolating single trophectoderm (TE) and inner cell mass (ICM) cells and to simultaneously evaluate these cells for copy number variation (CNV) as well as methylome development. DESIGN: Experimental. SETTING: Academic medical center. PATIENT(S): Donated genetically abnormal blastocysts. INTERVENTION(S): Single cells were isolated, followed by bisulfite conversion and sequencing to identify CNV and methylome profiles. MAIN OUTCOME MEASURE(S): CNV and methylation profiling. RESULT(S): Two embryos were dissociated, isolating 46 single cells, with 17 ICM and 12 TE cells selected for further downstream analysis. Chromosome ploidies and embryo sex were concordant with the results from conventional aneuploidy testing. In 3 of the 29 cells, additional aneuploidies were discovered, indicating possible mosaicism undetected by routine preimplantation genetic testing for aneuploidy. CpG methylation frequency was higher in ICM cells compared with TE cells (44.3% vs. 32.4%), respectively, while non-CpG methylation frequency was similar among both cell types. CpG methylation levels accurately distinguished ICM from TE cells epigenetically. CONCLUSION(S): We describe an effective workflow for isolating and sequencing single ICM and TE cells from human blastocysts. The use of methylation profiling can help distinguish these two cell populations better then morphologic identification alone. TE cells had significantly lower levels of DNA methylation, which may be explained in part by the fact that these cells have begun the process of differentiation and are transcriptionally more active than ICM. This approach may be used to explore the genetic complexities within human embryos, specifically among the two primary cell types seen at this stage of development.

Presence of endometrial nucleolar channel systems at the time of frozen embryo transfer in hormone replacement cycles with successful implantation.

OBJECTIVE: To detect nucleolar channel systems (NCSs) in cells in endometrial aspirations obtained immediately before embryo transfer during blastocyst hormone replacement therapy-frozen embryo transfer (HRT-FET) cycles without affecting implantation. DESIGN: Prospective case series. SETTING: University-affiliated fertility clinic. PATIENTS: Five patients who underwent an HRT-FET cycle consented to lower uterine segment aspiration using an open-tip embryo transfer catheter during a routine mock transfer performed immediately before embryo transfer. INTERVENTIONS: Exfoliated cells in the aspirated endometrial secretions were analyzed for the presence of NCSs using indirect immunofluorescence and, in one case, electron microscopy for unambiguous identification. MAIN OUTCOME MEASURES: On the basis of a previous study, positive NCS status was defined as the presence of NCSs in at least 3 endometrial epithelial cells (EECs). The effect of endometrial aspiration on implantation and pregnancy outcomes was assessed. RESULTS: Biochemical pregnancy, as evidenced by positive ß-human chorionic gonadotropin, was seen in 5 of 5 patients, and clinical pregnancy was seen in 2 of 5 patients. NCSs were detected in exfoliated EECs of uterine secretions in 4 of 5 patient samples and could not be unequivocally identified in 1 of 5 patient samples, which was designated as indeterminate. CONCLUSIONS: This is the first report of NCS detection in HRT-FET cycles in the absence of follicular development and ovulation. NCS status can be determined in exfoliated EECs of uterine secretions obtained at the time of embryo transfer while maintaining implantation. Our study furthers the goal of establishing whether individualized point of care testing of NCS status in HRT-FET cycles can determine optimal endometrial receptivity and improve pregnancy outcomes.

Differential impact of controlled ovarian hyperstimulation on live birth rate in fresh versus frozen embryo transfer cycles: a Society for Assisted Reproductive Technology Clinic Outcome System study.

OBJECTIVE: To study the impact of both controlled ovarian hyperstimulation (COH) length and total gonadotropin (GN) dose individually and in concert on live birth rates (LBR) in both fresh and freeze-all in vitro fertilization embryo transfer (IVF-ET) cycles. DESIGN: Historical cohort study. SETTING: Not applicable. PATIENT(S): The U.S. national database from the Society of Assisted Reproductive Technology Clinic Outcome Reporting System from 2014 to 2015 was used to identify patients undergoing autologous GN stimulation IVF cycles with the use of GnRH antagonist-based suppression protocols where a single embryo transfer was performed as part of a fresh IVF-ET cycle (fresh, n = 14,866) or the first frozen embryo transfer after a freeze-all cycle (frozen, n = 2,964), and not including preimplantation genetic testing cycles. The patients' demographic and cycle characteristics, duration of COH, total GN dose, and pregnancy outcomes were extracted. Binomial regression models estimated trend and relative risk of live birth with respect to days of stimulation and total GN dose singularly, and after adjustment for a priori confounders including age, parity, body mass index, diagnosis, and maximum follicle-stimulating hormone in both fresh and frozen embryo transfer cycles. Both days of stimulation and total GN dose were then added to the multivariate model to show whether they were independently associated with LBR. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Live birth rate. RESULTS: In both fresh and frozen cycles, length of COH was significantly associated with total GN dose. On univariate analysis, LBR decreased significantly with increasing length of stimulation and increasing total GN dose in both fresh and frozen cycles. On multivariable analysis including both days of stimulation and total GN dose, days of stimulation was no longer significantly correlated with LBR, whereas total GN dose remained significantly correlated with LBR in fresh cycles only. When total GN doses ranging from <2,000 IU through 5,000 IU to >5,000 IU were compared, a significant improvement in live birth rate was noted with lower total GN doses. Specifically, GN doses <2,000 IU had a 27% higher rate of live birth compared with GN dose >5,000 IU. For GN dose groups up to 4,000 IU, the estimated effect on LBR was similar. There was a marginal improvement (13%) in LBR with GN doses of 4,000 IU to 5,000 IU compared with >5,000 IU. When the multivariate model was applied to the frozen cycles, neither total GN dose nor days of stimulation was significantly associated with LBR. CONCLUSIONS: High total GN dose but not prolonged COH is associated with decreasing LBRs in fresh cycles, whereas neither factor significantly affects LBR in frozen cycles. Consideration should be given to minimizing the total GN dose when possible in fresh autologous cycles, either by decreasing the daily dose or by limiting the length of stimulation to improve LBRs. In freeze-all cycles, the use of higher GN doses does not seem to adversely affect the LBR of the first frozen embryo transfer. High total GN dose likely exerts a negative impact on the endometrium and/or oocyte/embryo unrelated to the length of stimulation. The differential effect of total GN dose on LBR in fresh and frozen cycles may imply a greater impact exerted on the endometrium rather than the oocyte.

Length of ovarian stimulation does not impact live birth rate in fresh donor oocyte cycles: a SART CORS study.

PURPOSE: To evaluate the effect of controlled ovarian hyperstimulation length and total gonadotropin (GN) dose on recipient live birth rate (LBR) in fresh donor oocyte cycles. METHODS: Data was obtained from SART CORS on all fresh donor oocyte GnRH antagonist cycles (n = 1049) between 2014 and 2015 which resulted in a single embryo transferred. Donor and recipient demographic information and cycle characteristics were extracted. Binomial regression was used to estimate LBR with respect to days of stimulation (DOS) and total GN dose. Multivariate analysis was performed to evaluate these relationships after controlling for confounders. RESULTS: Overall LBR in fresh donor oocyte cycles was 57%. Average stimulation length was 14.3 ± 4.9 days, and total GN dose was 2464 ± 1062 IU. On univariate analysis, neither days of stimulation (p = 0.5) nor total GN dose (p = 0.57) was independently correlated with LBR. However, in prolonged stimulations (> 15 days) with high total GN dose (> 3000 IU), as both the cycle length and total GN dose increased, LBR significantly decreased from 63.81 to 48.15% (p = 0.02) and from 67.61 to 48.15% (p = 0.01), respectively. Multivariate analysis showed no significant effect of either DOS or total GN dose on LBR. CONCLUSIONS: LBR is significantly decreased in fresh donor oocyte cycles when cycles are prolonged with high total GN dose. However, after controlling for confounders neither DOS nor total GN dose significantly affects LBR.

Monocyte chemotactic protein-1 plays a role in ovarian dysfunction related to high-fat diet-induced obesity.

Obesity, known to cause a systemic elevation in monocyte chemotactic protein-1 (MCP-1), adversely affects normal ovarian function. The aim of this study was to determine whether MCP-1 plays a role in ovarian dysfunction that is related to obesity induced by high-fat (HF) diet intake. Wild type (WT) C57BL/6J mice were fed either normal chow (NC) (Group 1, control group) or HF diet (Group 2). To assess whether MCP-1 is involved in HF-diet-induced ovarian dysfunction, MCP-1 knock-out mice were fed HF diet (Group 3). Body weight, body fat composition, number of oocytes collected following ovarian superovulation with gonadotropins, ovarian macrophage markers and expression of genes important in folliculogenesis and steroidogenesis were quantified in the 3 groups of animals. Animals in Group 2 gained significant body weight and body mass, produced the fewest number of oocytes following superovulation, and had significant alterations in ovarian genes involved in folliculogenesis and steroidogenesis as well as genes involved in inflammation. Although animals in Group 3 had the highest body weight and body fat composition, they produced similar number of oocytes compared to animals in Group 1 but had different ovarian gene expression compared to Group 2. These findings suggest that MCP-1 gene knockout could reverse some of the adverse effects of obesity induced by HF diet intake. Future studies assessing ovarian histology in MCP-1 knock out mouse model will confirm our findings. MCP-1 inhibition could represent a future therapeutic target to protect ovarian health from the adverse effects of HF diet ingestion.

Dietary Advanced Glycation End Products (AGEs) could alter ovarian function in mice.

Nutrition is an important source of exogenous AGEs and thermally processed foods present in western-style diets contain a large amount of these pro-inflammatory AGEs. Additionally, the intake of dietary AGEs could upregulate ovarian gene expression of inflammatory macrophage markers. The objective of this study was to investigate the effect of diet rich in AGEs on estrous cyclicity and ovarian function in a mouse model. Six-week old C57BL/6 J female mice were randomly subjected to either a diet low in AGEs (L-AGE) or a diet high in AGEs (H-AGE) for a total of 13 weeks. Experiments performed included daily vaginal smears to assess estrous cyclicity, ovarian superovulation with gonadotropins to assess the number of oocytes released, whole ovarian tissue mRNA quantification by RT-PCR to quantify genes involved in folliculogenesis, steroidogenesis, and macrophage markers, and ovarian morphology for follicle count. Outcome measures included estrous cyclicity, number of oocytes following superovulation, expression of genes involved in folliculogenesis, steroidogenesis, and macrophage infiltration as well as the number of primordial, primary, secondary, antral follicles and corpora lutea. Compared to mice on L-AGE diet, mice on H-AGE spent significantly longer time in the diestrus phase, had similar number of oocytes released following ovarian superovulation, and showed significant alterations in genes involved in steroidogenesis (increase in Star mRNA expression levels) and folliculogenesis (increase in Gdf-9 and Fshr mRNA expression levels). Mouse macrophage marker F4/80 mRNA expression was upregulated in mice on H-AGE diet compared to mice on L-AGE diet. Finally, mice on H-AGE diet had significantly fewer corpora lutea in their ovaries. These results indicate that the ingestion of high amounts of dietary AGEs could disrupt folliculogenesis and steroidogenesis that might lead to abnormal estrous cyclicity. Intake of dietary AGEs could also upregulate ovarian gene expression of inflammatory macrophage markers.

Role of adiponectin in ovarian follicular development and ovarian reserve.

Adiponectin levels are associated with anti-Müllerian hormone (AMH) and kisspeptin levels in non-ovarian tissues. The objective of the present study was to investigate the association between adiponectin and the genes important for ovarian follicular development and ovarian reserve, specifically AMH and kisspeptin, and their corresponding receptors. In the first experiment, the mRNA levels of anti-Müllerian hormone (amh) and its receptor (Amhr2), as well as those of kisspeptin (Kiss1) and its receptor (Kiss1r), were quantified by reverse transcription-polymerase chain reaction analysis in the ovaries of two groups of mice [adiponectin-knockout (KO) vs. control] that underwent oophorectomy. The second experiment measured follicular phase serum AMH and follicular fluid adiponectin levels in 25 women who underwent controlled ovarian hyperstimulation for in vitro fertilization. Compared with the control mice, adiponectin-KO mice had 6.5 times lower Kiss1 mRNA levels (P=0.009) and a tendency for lower ovarian Kiss1r mRNA expression levels (P=0.06). However, adiponectin-KO mice had significantly higher Amhr2 mRNA levels (P=0.01). In all women participants, there was a positive correlation between serum AMH and follicular fluid adiponectin concentrations (r=0.54, P=0.006). The findings of the present study indicate that adiponectin may play a role in ovarian physiology through its impact on genes crucial for ovarian follicular development and ovarian reserve, such as kisspeptin and AMH. Understanding the role of adiponectin in ovarian function may improve our knowledge of the pathophysiology underlying ovulatory dysfunction in obese women, who usually have low adiponectin levels, and overcome reproductive barriers.

The impact of using donor sperm in assisted reproductive technology cycles on perinatal outcomes.

OBJECTIVE: To assess the impact of using donor sperm in assisted reproductive technology (ART) cycles on perinatal outcomes. DESIGN: Historical cohort study. SETTING: US national database from the Society of Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) from 2012 to 2013. PATIENT(S): Patients undergoing the first fresh autologous ART cycle using either donor or partner sperm. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Miscarriage, preterm birth, low birthweight rates. RESULTS: A total of 134,710 fresh autologous ART cycles were evaluated from the SART CORS database. Following exclusion criteria and after restricting to the first cycle, 2,123 donor sperm and 42,799 partner sperm ART cycles were included in the final analyses. After adjusting for all confounding variables (including maternal age, race, body mass index, smoking status, gravidity, history of preterm birth, highest follicle stimulating hormone count, blastocyst transfer percentage, total embryo transferred, and etiology of infertility), no statistically significant differences in miscarriage rates, preterm births, very preterm births, low birthweight, and very low birthweight were observed. Birthweight was significantly lower in the partner sperm group than in the donor sperm group (3,292 ± 601 and 3,233 ± 592 g in donor and partner sperm groups, respectively, adjusted P value 0.003); however, this small absolute difference (adjusted effect estimate 42 g, 95% CI 14.7-70.9) does not carry clinical significance. CONCLUSIONS: The use of donor sperm in fresh autologous ART cycles was not associated with increased miscarriage, preterm births, or low birthweights, as compared to cycles using partner sperm. This information can be used in patient counseling to reassure patients using donor sperm in ART cycles.

Comparison of perinatal outcomes following frozen embryo transfer cycles using autologous versus donor oocytes in women 40 to 43 years old: analysis of SART CORS data.

OBJECTIVE: To study the differences in perinatal outcomes after frozen embryo transfer cycles using autologous or donor oocytes in women of advanced maternal age. DESIGN: Historical cohort study. SETTING: US national database from the Society of Assisted Reproductive Technology Clinic Outcome Reporting System (SART CORS) from 2009 to 2013. PATIENT(S): Women at 40-43 years of age undergoing autologous frozen embryo transfers (a-FET) or donor oocyte frozen embryo transfers (d-FET) resulting in singleton pregnancies that were entered in the SART CORS database from 2009 to 2013. RESULTS: a-FET resulted in 4402 singleton live births whereas d-FET resulted in 2703 singleton live births. d-FET resulted in a higher risk of preterm births (< 37 weeks), with adjusted odds ratio (aOR) 1.33 (95% CI 1.02-1.75), but similar risk of small for gestational age (SGA), with aOR 1.75 (95% CI 0.85-3.7), when compared to a-FET. However, when only single blastocyst transfer cycles are considered, d-FET and a-FET showed no difference in preterm births or other adverse perinatal outcomes. CONCLUSIONS: Singletons resulting from d-FET are at increased risk for perinatal morbidity. However, the risk was diminished in single blastocyst transfer cycles. Our study supports the current American Society for Reproductive Medicine (ASRM) guidelines of transferring a single blastocyst in d-FET cycles.

Counseling patients on reproductive aging and elective fertility preservation-a survey of obstetricians and gynecologists' experience, approach, and knowledge.

PURPOSE: What are the experience, approach, and knowledge of US Obstetricians and Gynecologists' (ob-gyn) towards counseling patients on reproductive aging (RA) and elective fertility preservation (EFP). METHODS: A cross-sectional survey emailed by the American College of Obstetricians and Gynecologists (ACOG) to 5000 ACOG fellows consisting of 9 demographic and 28 questions relating to counseling patients on RA and EFP. RESULTS: Seven hundred and eighty-four responders completed the survey. Although 82.8% agreed that conversations relating to RA should take place with patients desiring future childbearing and delaying due to social reasons, only 27.6% stated that they frequently counsel these women aged 18-34 years old, compared to 75.8% aged 35-44 years old (P < 0.01). Limited time (75.8%) and limited knowledge (41.4%) were amongst the most frequent reported barriers towards counseling patients on RA. Fifty-eight percent stated that they have been asked about EFP by patients. Although 74.8% agreed that conversations should take place related to EFP in women desiring future childbearing and delaying due to social reasons, only 27.6% stated that they frequently counsel these patients on EFP (P < 0.01). Limited time (75%) and limited knowledge (59.9%) were amongst the most frequent barriers towards counseling on EFP. CONCLUSIONS: In the USA, methods to improve patient counseling and provider knowledge on RA and EFP are warranted and further studies are needed to address optimal methods to improve counseling and knowledge related to these topics.

Role of hormonal and inflammatory alterations in obesity-related reproductive dysfunction at the level of the hypothalamic-pituitary-ovarian axis.

BACKGROUND: Besides being a risk factor for multiple metabolic disorders, obesity could affect female reproduction. While increased adiposity is associated with hormonal changes that could disrupt the function of the hypothalamus and the pituitary, compelling data suggest that obesity-related hormonal and inflammatory changes could directly impact ovarian function. OBJECTIVE: To review the available data related to the mechanisms by which obesity, and its associated hormonal and inflammatory changes, could affect the female reproductive function with a focus on the hypothalamic-pituitary-ovarian (HPO) axis. METHODS: PubMed database search for publications in English language until October 2017 pertaining to obesity and female reproductive function was performed. RESULTS: The obesity-related changes in hormone levels, in particular leptin, adiponectin, ghrelin, neuropeptide Y and agouti-related protein, are associated with reproductive dysfunction at both the hypothalamic-pituitary and the ovarian levels. The pro-inflammatory molecules advanced glycation end products (AGEs) and monocyte chemotactic protein-1 (MCP-1) are emerging as relatively new players in the pathophysiology of obesity-related ovarian dysfunction. CONCLUSION: There is an intricate crosstalk between the adipose tissue and the inflammatory system with the HPO axis function. Understanding the mechanisms behind this crosstalk could lead to potential therapies for the common obesity-related reproductive dysfunction.

Not all twins are monozygotic after elective single embryo transfer: analysis of 32,600 elective single embryo transfer cycles as reported to the Society for Assisted Reproductive Technology.

OBJECTIVE: To study the incidence and risk factors of multiple pregnancies after elective single ET. DESIGN: Historic cohort. SETTING: Not applicable. PATIENT(S): Women <35 years of age undergoing elective single ET entered in the SART CORS database from 2010 to 2013. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE(S): Rate of sex discordant pregnancies. Rate of same sex pregnancies and risk factors for both same sex and sex discordant pregnancies. RESULT(S): A total of 32,600 cycles were reported to SART CORS during this time period. There were 15,143 pregnancies from which 14,888 were singletons (98.3%), 23 sex discordant (0.15%) multiple pregnancies, 226 (1.5%) sex concordant multiple pregnancies, and 6 (0.01%) pregnancies without sex information. When Weinberg's differential rule was applied, the rate of dizygotic pregnancies was calculated to be 18%. Unexplained infertility was found to be the biggest risk factor for sex discordant multiple pregnancies (adjusted odds ratio 4.33, 95% confidence interval 1.4-13.1), followed by elevated body mass index (BMI). The only risk factor found for sex concordant pregnancies was undergoing a fresh transfer (adjusted odds ratio 1.4, 95% confidence interval 1.02-1.95). CONCLUSION(S): Elective single ET improves, but does not completely eliminate the risk of multiple pregnancies. Patients should be counseled that there might be up to a ∼2% risk of multiple pregnancies, of which up to 18% can be dizygotic. Patients with elevated BMI and unexplained fertility may be at higher risk for sex discordant multiple pregnancies and patients undergoing fresh cycles may be at higher risk for sex concordant multiple pregnancies.

Status of nucleolar channel systems in uterine secretions accurately reflects their prevalence-a marker for the window of implantation-in simultaneously obtained endometrial biopsies.

OBJECTIVE: To assess whether nucleolar channel systems (NCSs) can be detected in exfoliated endometrial epithelial cells (EECs) of uterine secretions and whether such noninvasively determined NCS status is associated with significant NCS prevalence in simultaneously obtained endometrial biopsies. DESIGN: Prospective study (December 2015-February 2017). SETTING: University-affiliated and private fertility clinics. PATIENT(S): Luteal-phase patients of reproductive age requiring endometrial biopsy for medical indications. INTERVENTION(S): Uterine secretion aspiration before endometrial biopsy. Cells in uterine secretions were spun onto slides and fixed. NCSs were identified and quantified in cells and paraffin-embedded tissue sections by indirect immunofluorescence. MAIN OUTCOME MEASURE(S): Comparison of NCS status of uterine secretions with NCS prevalence in biopsies. Based on NCS detection, uterine secretions were assigned a status of NCS-positive (n = 15) or NCS-negative (n = 7). NCS prevalence in biopsies was expressed as a percentage of NCSs per EECs. RESULT(S): NCSs can be detected in exfoliated EECs of uterine secretions. Median NCS prevalence in endometrial biopsies from patients with NCS-positive secretions was 41.9% (interquartile range [IQR], 21.1-53.9) versus 2.0% (IQR, 0-6.9) when secretions were NCS-negative. The NCS status of secretions identified a significant difference in NCS prevalence of simultaneously obtained biopsies. CONCLUSION(S): NCS status of secretions accurately reflects NCS prevalence of biopsies, a marker for the implantation window. As secretion aspiration is compatible with same-day ET, our study provides proof of principle for a minimally invasive approach to determine endometrial receptivity for timing frozen ET.