High estradiol levels in fresh embryo transfer cycles are not associated with detrimental impact on birth outcomes.

PURPOSE: There is an unclear relationship between estradiol levels and fresh embryo transfer (ET) outcomes. We determined the relationship between estradiol on the day of trigger, in fresh ET cycles without premature progesterone elevation, and good birth outcomes (GBO). METHODS: We identified autologous fresh ET cycles from 2015 to 2021 at multiple clinics in the USA. Patients with recurrent pregnancy loss, uterine factor, and elevated progesterone on the day of trigger (progesterone > 2 ng/mL or 3-day area under the curve > 4.5 ng/mL) were excluded. The primary outcome was GBO (singleton, term, live birth with appropriate weight). Log-binomial generalized estimating equations determined the likelihood of outcomes. RESULTS: Of 17,608 fresh ET cycles, 5025 (29%) yielded GBO. Cycles with estradiol ≥ 4000 pg/mL had a greater likelihood of GBO compared to cycles < 1000 pg/mL (aRR = 1.32, 95% CI 1.13-1.54). Pairwise comparisons of estradiol between < 1000 pg/mL versus 1000-1999 pg/mL and 1000-1999 pg/mL versus 2000-2999 pg/mL revealed a higher likelihood of GBO with higher estradiol (aRR 0.83, 95% CI 0.73-0.95; aRR 0.91, 95% CI 0.85-0.97, respectively). Comparisons amongst more elevated estradiol levels revealed that the likelihood of GBO remained similar between groups (2000-2999 pg/mL versus 3000-3999 pg/mL, aRR 1.04, 95% CI 0.97-1.11; 3000-3999 pg/mL versus ≥ 4000 pg/mL, aRR 0.96, 95% CI 0.9-1.04). CONCLUSION: In fresh ET cycles, higher estradiol levels were associated with an increased prevalence of GBO until estradiol 2000-2999 pg/mL, thereafter plateauing. In fresh ET candidates, elevated estradiol levels should not preclude eligibility though premature progesterone rise, and risk of ovarian hyperstimulation syndrome must still be considered.

Effects of pulsatile intravenous follicle-stimulating hormone treatment on ovarian function in women with obesity.

OBJECTIVE: To establish conditions for effective hypothalamic suppression in women with normal and high body mass index (BMI) and test the hypothesis that intravenous (IV) administration of pulsatile recombinant follicle-stimulating hormone (rFSH) can overcome the clinically evident dysfunctional pituitary-ovarian axis in women with obesity. DESIGN: Prospective interventional study. SETTING: Academic medical center. PATIENT(S): Twenty-seven normal-weight women and 27 women with obesity, who were eumenorrheic and aged 21-39 years. INTERVENTION(S): Two-day frequent blood sampling study, in early follicular phase, before and after cetrorelix suppression of gonadotropins and exogenous pulsatile IV rFSH administration. MAIN OUTCOME MEASURE(S): Serum inhibin B and estradiol (E2) levels (basal and rFSH stimulated). RESULT(S): A modified gonadotropin-releasing hormone antagonism protocol effectively suppressed production of endogenous gonadotropins in women with normal and high BMIs, providing a model to address the functional role of FSH in the hypothalamic-pituitary-ovarian axis. The IV rFSH treatment resulted in equivalent serum levels and pharmacodynamics in normal-weight women and those with obesity. However, women with obesity exhibited reduced basal levels of inhibin B and E2 and a significantly decreased response to FSH stimulation. The BMI was inversely correlated with serum inhibin B and E2. In spite of this observed deficit in ovarian function, pulsatile IV rFSH treatment in women with obesity resulted in E2 and inhibin B levels comparable with those in normal-weight women, in the absence of exogenous FSH stimulation. CONCLUSION(S): Despite normalization of FSH levels and pulsatility by exogenous IV administration, women with obesity demonstrate ovarian dysfunction with respect to E2 and inhibin B secretion. Pulsatile FSH can partially correct the relative hypogonadotropic hypogonadism of obesity, thereby providing a potential treatment strategy to mitigate some of the adverse effects of high BMI on fertility, assisted reproduction, and pregnancy outcomes. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov #NCT02478775.

Expression and T cell regulatory action of the PD-1 immune checkpoint in the ovary and fallopian tube.

PROBLEM: Immune cell trafficking and surveillance within the ovary and fallopian tube are thought to impact fertility and also tumorigenesis in those organs. However, little is known of how native cells of the ovary and fallopian tube interact with resident immune cells. Interaction of the Programmed Cell Death Protein-1 (PD-1/PDCD-1/CD279) checkpoint with PD-L1 is associated with downregulated immune response. We have begun to address the question of whether PD-1 ligand or its receptors (PD-L1/-L2) can regulate immune cell function in these tissues of the female reproductive tract. METHOD OF STUDY: PD-1 and ligand protein expression was evaluated in human ovary and fallopian tube specimens, the latter of which included stages of tubal cell transformation and early tumorigenesis. Ovarian expression analysis included the determination of the proteins in human follicular fluid (HFF) specimens collected during in vitro fertilization procedures. Finally, checkpoint bioactivity of HFF was determined by treatment of separately-isolated human T cells and the measurement of interferon gamma (IFNγ). RESULTS: We show that membrane bound and soluble variants of PD-1 and ligands are expressed by permanent constituent cell types of the human ovary and fallopian tube, including granulosa cells and oocytes. PD-1 and soluble ligands were present in HFF at bioactive levels that control T cell PD-1 activation and IFNγ production; full-length checkpoint proteins were found to be highly enriched in HFF exosome fractions. CONCLUSION: The detection of PD-1 checkpoint proteins in the human ovary and fallopian tube suggests that the pathway is involved in immunomodulation during folliculogenesis, the window of ovulation, and subsequent egg and embryo immune-privilege. Immunomodulatory action of receptor and ligands in HFF exosomes is suggestive of an acute checkpoint role during ovulation. This is the first study in the role of PD-1 checkpoint proteins in human tubo-ovarian specimens and the first examination of its potential regulatory action in the contexts of normal and assisted reproduction.

Anti-Müllerian Hormone and Follicle-Stimulating Hormone Are Poor Independent Predictors of Live Birth After Assisted Reproductive Technology.

To query if anti-Müllerian hormone (AMH) and/or follicle-stimulating hormone (FSH) predict live birth at the University of Colorado Advanced Reproductive Medicine (CU ARM). This was a retrospective analysis using the Society for Assisted Reproductive Technology (SART) Clinic Outcome Reporting System database at CU ARM from 2017 to 2019 to identify the pregnancy outcomes of the initial fresh or frozen embryo transfer (FET) and their corresponding AMH and FSH. Fisher's exact tests were used to identify differences in pregnancy outcome by age group, and area under the receiver operator characteristic curves was used to quantify live birth prediction. A total of 1083 records from 557 patients were reviewed. After only including the first autologous transfer, 270 cycles were analyzed. Overall live birth (L/B) rate was 58.15% (157/270), which declined with increasing age group (p ≤ 0.01). Although AMH significantly decreased with increasing age (p < 0.001), it was not associated with pregnancy outcome (3.54 ng/mL vs. 3.41 ng/mL, p = 0.56); this relationship was unchanged after controlling for age in logistic regression models (p = 0.52). FSH was also not significantly related to pregnancy outcome (7.00 IU/L vs 6.00 IU/L, p = 0.15), and this relationship did not change after controlling for age (p = 0.61). Using AUC, the only variable predictive of live birth was age (p = 0.002). AMH and FSH are not associated with the probability of live birth. Only age was significantly associated with live birth in this series. AMH and FSH should therefore be used cautiously when counseling patients about ART outcomes.

Minimal Stimulation Using Gonadotropin-Releasing Hormone Antagonist is Associated with Higher Live Birth Rates: A National Study of 13,050 Cycles.

Background: The optimal protocol for minimal stimulation in vitro fertilization (IVF) has yet to be established. This study aims to determine if the use of gonadotropin-releasing hormone (GnRH) antagonist during minimal stimulation improves outcomes. Materials and Methods: All cycles designated as minimal stimulation from 2014 to 2016 from the Society for Assisted Reproductive Technology Clinic Online Reporting System were identified. Cycles in which GnRH antagonist was administered (n = 5984) were compared to those that did not receive it (n = 7066). Wilcoxon's rank-sum test and chi-square test were used to analyze continuous and categorical variables. Results: A total of 6750 patients undergoing 13,050 cycles were included. GnRH antagonist use was associated with a significantly higher total gonadotropin dosage (median 975.0 [interquartile range, IQR, 600.0, 1575.0] vs. median 660.0 [IQR 375.0, 975.0], p < 0.001), lower cycle cancelation rate (11.3% vs. 13.6%, p < 0.001; OR 1.24, 95% CI 1.12-1.38, p < 0.001), and higher live birth rate (4.3% vs. 2.1%, p < 0.001; OR 0.47, 95% CI 0.39-0.58, p < 0.001). GnRH antagonist use was associated with a significantly higher live birth rate in women ≥35 years of age (2.7% vs. 0.9%, p < 0.001; OR 0.34, 95% CI 0.25-0.47, p < 0.001) and antimullerian hormone <1 (4.9% vs. 2.6%, p = 0.004; OR 0.52, 95% CI 0.33-0.81, p = 0.004). Conclusion: The use of GnRH antagonist suppression during minimal stimulation IVF is associated with an improved live birth rate, especially in older women and in women with diminished ovarian reserve. Although GnRH antagonist use may increase costs, it significantly decreases cancelation rate, increases number of embryos cryopreserved, and should be encouraged for minimal stimulation IVF.

Preconception ovarian reserve and placenta-mediated pregnancy complications among infertile women.

RESEARCH QUESTION: Are preconception ovarian reserve markers, such as Anti-Mullerian hormone and antral follicle count, associated with preeclampsia and placenta mediated pregnancy complications among women with unexplained infertility who conceive with superovulation? DESIGN: This is a secondary analysis of women with unexplained infertility who had a singleton live birth after enrollment in the Analysis of Multiple Intrauterine Gestations after Ovarian Stimulation (AMIGOS) trial that randomized couples to superovulation with letrozole, clomiphene, or gonadotropins with insemination for up to 4 cycles. RESULTS: Compared to controls (N = 156), women who developed preeclampsia (N = 17) had lower Anti-Mullerian hormone levels (2.24 ± 1.20 vs. 2.89 ± 2.32, p = 0.07) and lower antral follicle count (18 ± 7.67 vs. 21 ± 11.43, p = 0.16); though these differences were not statistically significant. There was no relationship between Anti-Mullerian hormone (OR: 1.00, 95% CI: 0.76-1.25) or antral follicle count (OR: 0.98, 95% CI 0.93-1.04) with preeclampsia and between Anti-Mullerian hormone (OR: 1.00, 95% CI: 0.83-1.17) and antral follicle count (OR: 1.00, 95% CI: 0.97-1.04) with placenta medicated pregnancy complications after adjusting for age, BMI and race. CONCLUSIONS: Preconception ovarian reserve markers are not associated with preeclampsia and placenta mediated pregnancy complications among women with unexplained infertility who conceive with superovulation with insemination.

Racial and Ethnic Disparities in Fertility Awareness Among Reproductive-Aged Women.

Background: Despite the rising prevalence of infertility, studies have indicated that in the United States fertility awareness remains low. No published study to date, however, has investigated the impact of any racial or ethnic disparities in fertility awareness. Materials and Methods: We conducted a cross-sectional survey of people self-identifying as female, aged 18-45 years, via Amazon Mechanical Turk in August 2020. The study was approved by the institutional review board at the University of Colorado. The survey consisted of demographic questions and a validated questionnaire, the Fertility and Infertility Treatment Knowledge Score (FIT-KS). Participants were classified as non-Hispanic White (NHW) or "Minority" race/ethnicity. Results: A total of 476 women completed the survey, 405 of which were included in analysis. Of those, 54.6% self-identified as NHW and 45.4% were in the Minority group. The median FIT-KS was 51.7% (16 items answered correctly). The Minority group scored significantly lower than the NHW participants overall (58.6% vs. 48.3%, p < 0.001) and in all three subscales (p < 0.05). The Minority group was significantly more likely to underestimate the rate of miscarriage (47.3% vs. 32.6%, p = 0.003) and had a lower awareness of risk factors that can impact fertility including smoking (88.7% vs. 71.6%, p < 0.001), obesity (90.5% vs. 70.5%, p < 0.001), and/or a history of gonorrhea/chlamydia infection (83.7% vs. 64.7%, p < 0.001). Conclusions: Minority women appear to have a lower fertility awareness than their NHW counterparts. Addressing these disparities and improving fertility education in diverse communities may lead to a reduction in clinically significant infertility disparities.

Integrated stress response control of granulosa cell translation and proliferation during normal ovarian follicle development.

Mechanisms that directly control mammalian ovarian primordial follicle (PF) growth activation and the selection of individual follicles for survival are largely unknown. Follicle cells produce factors that can act as potent inducers of cellular stress during normal function. Consistent with this, we show here that normal, untreated ovarian cells, including pre-granulosa cells of dormant PFs, express phenotype and protein markers of the activated integrated stress response (ISR), including stress-specific protein translation (phospho-Serine 51 eukaryotic initiation factor 2α; P-EIF2α), active DNA damage checkpoints, and cell-cycle arrest. We further demonstrate that mRNAs upregulated in primary (growing) follicles versus arrested PFs mostly include stress-responsive upstream open reading frames (uORFs). Treatment of a granulosa cell (GC) line with the PF growth trigger tumor necrosis factor alpha results in the upregulation of a 'stress-dependent' translation profile. This includes further elevated P-eIF2α and a shift of uORF-containing mRNAs to polysomes. Because the active ISR corresponds to slow follicle growth and PF arrest, we propose that repair and abrogation of ISR checkpoints (e.g. checkpoint recovery) drives the GC cell cycle and PF growth activation (PFGA). If cellular stress is elevated beyond a threshold(s) or, if damage occurs that cannot be repaired, cell and follicle death ensue, consistent with physiological atresia. These data suggest an intrinsic quality control mechanism for immature and growing follicles, where PFGA and subsequent follicle growth and survival depend causally upon ISR resolution, including DNA repair and thus the proof of genomic integrity.

Ovarian stimulation for fertility preservation in an oncology patient with etonogestrel implant in place.

PURPOSE: To describe a case of a young woman who presented for fertility preservation and underwent ovarian stimulation with an etonogestrel implant in place. METHODS: A 24-year old, gravida 0, with an etonogestrel implant and newly diagnosed lower extremity sarcoma and DVT desiring oocyte cryopreservation prior to adjuvant chemotherapy and radiation. To avoid delay in her oncologic care and allow for continued use of contraception post-retrieval, the patient underwent controlled ovarian hyperstimulation (COH) without removal of the etonogestrel implant. RESULTS: Baseline labs included follicle-stimulating hormone 9 mIU/mL, luteinizing hormone 4.9 mIU/mL, estradiol 42 pg/mL, anti-Müllerian hormone 5.1 ng/mL, and antral follicle count greater than 40. The patient was placed on an antagonist protocol and stimulated with 125 IU Gonal-F and 75 IU Menopur. She received a total of 12 days of gonadotropin stimulation. On the day of trigger, her estradiol was 1472 pg/mL, lead follicle 21.5 mm with a total of 25 follicles measured > 12 mm. She was triggered with 5000 U hCG. She had a total of 23 oocytes retrieved, 17 of which were metaphase II and vitrified. CONCLUSIONS: COH and successful oocyte cryopreservation can be achieved in patients with an etonogestrel implant in situ without apparent detrimental effects to oocyte yield or maturity. Due to the etonogestrel implant's inhibitory effects on LH, it is recommended to use an hCG trigger for final oocyte maturation.

Birth outcomes are superior after transfer of fresh versus frozen embryos for donor oocyte recipients.

STUDY QUESTION: For donor oocyte recipients, are birth outcomes superior for fresh versus frozen embryos? SUMMARY ANSWER: Among fresh donor oocyte recipients, fresh embryos are associated with better birth outcomes when compared with frozen embryos. WHAT IS KNOWN ALREADY: Frozen embryo transfer (ET) with vitrification has been associated with improved pregnancy rates, but also increased rates of large for gestational age infants. Donor oocyte recipients represent an attractive biological model to attempt to isolate the impact of embryo cryopreservation on IVF outcomes, yet there is a paucity of studies in this population. STUDY DESIGN, SIZE, DURATION: A retrospective cohort of the US national registry, the Society for Assisted Reproductive Technology Clinic Outcome Reporting System, of IVF cycles of women using fresh donor oocytes resulting in ET between 2013 and 2015. Thawed oocytes were excluded. PARTICIPANTS/MATERIALS, SETTINGS, METHODS: Good obstetric outcome (GBO), defined as a singleton, term, live birth with appropriate for gestational age birth weight, was the primary outcome measure. Secondary outcomes included live birth, clinical pregnancy, spontaneous abortion, preterm birth, multiple births and gestational age-adjusted weight. Outcomes were modeled using the generalized estimating equation approach. MAIN RESULTS AND THE ROLE OF CHANCE: Data are from 25 387 donor oocyte cycles, in which 14 289 were fresh and 11 098 were frozen ETs. A GBO was 27% more likely in fresh ETs (26.3%) compared to frozen (20.9%) (adjusted risk ratio 1.27; 95% confidence interval (CI) 1.21-1.35; P < 0.001). Overall, fresh transfer was more likely to result in a live birth (55.7% versus 39.5%; adjusted risk ratio 1.21; 95% CI 1.18-1.26; P < 0.001). Among singleton births, there was no difference in gestational age-adjusted birth weight between groups. LIMITATION, REASONS FOR CAUTION: Our cohort findings contrast with data from autologous oocytes. Prospective studies with this population are warranted. WIDER IMPLICATIONS OF THE FINDINGS: Among donor oocyte recipients, fresh ETs may be associated with better birth outcomes. Reassuringly, given its prevalent use, modern embryo cryopreservation does not appear to result in phenotypically larger infants. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: N/A.

Preimplantation genetic testing and chances of a healthy live birth amongst recipients of fresh donor oocytes in the United States.

PURPOSE: To evaluate if preimplantation genetic testing (PGT) improves the odds of a healthy live birth amongst recipients of fresh donor oocytes. METHODS: We performed a retrospective cohort study including in vitro fertilization cycles of women using fresh donor oocytes reported to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System, between 2013 and 2015. Cycles were categorized based on PGT. Primary outcome measure was a good birth outcome (GBO), defined as a singleton, term, live birth with an average birthweight. Multivariable generalized estimating equation models were fit to analyze the effect of PGT. Interaction effect between cycle type (fresh vs frozen) and PGT was tested. RESULTS: Of 28,153 included cycles, 3708 had PGT while 24,445 did not. PGT cycles were less likely to result in an embryo transfer (ET) (64 vs 94%), but were associated with increased rates of frozen ET (70 vs 41%), single ET (67 vs 44%), and blastocyst ET (87 vs 65%). There was a significant interaction between PGT and cycle type. Cycles using PGT increased the probability of a GBO 12% in frozen cycles (RR 1.12; 95% CI 1.02, 1.22; p = 0.018), but PGT was detrimental to success in fresh cycles with a 53% reduced likelihood of GBO (RR 0.47; 9% CI 0.41, 0.54; p < 0.001). CONCLUSION: PGT, as practiced during the most recently available national data in women using fresh donor oocytes, was associated with increased probability of a healthy live birth amongst frozen cycles, but was not beneficial in fresh cycles.

Control of Murine Primordial Follicle Growth Activation by IκB/NFκB Signaling.

The transcription factor NFκB has been associated with the timing of menopause in a large human genome-wide association study. Furthermore, preclinical studies demonstrate that loss of Tumor necrosis factor alpha (Tnfα) or its receptor Tnfr2 slows primordial follicle growth activation (PFGA). Although Tnfα:receptor signaling stimulates NFκB and may mechanistically link these findings, very little is known about NFκB signaling in PFGA. Because signaling downstream of Tnfα/Tnfr2 ligand/receptor interaction has not been interrogated as relates to PFGA, we evaluated the expression of key NFκB signaling proteins in primordial and growing follicles, as well as during ovarian aging. We show that key members of the NFκB pathway, including subunits, activating kinases, and inhibitory proteins, are expressed in the murine ovary. Furthermore, the subunits p65 and p50, and the cytosolic inhibitory proteins IκBα and IκBß, are present in ovarian follicles, including at the primordial stage. Finally, we assessed PFGA in genetically modified mice (AKBI) previously demonstrated to be resistant to inflammatory stress-induced NFκB activation due to overexpression of the NFκB inhibitory protein IκBß. Consistent with the hypothesis that NFκB plays a key role in PFGA, AKBI mice exhibit slower PGFA than wild-type (WT) controls, and their ovaries contain nearly twice the number of primordial follicles as WT both at early and late reproductive ages. These data provide mechanistic insight on the control of PFGA and suggest that targeting NFκB at the level of IκB proteins may be a tractable route to slowing the rate of PFGA in women faced with early ovarian demise.

Aromatase Inhibition Ameliorates Decreased LH Output Found in Obese Women.

In obese ovulatory women, serum luteinizing Hormone (LH) and follicle stimulating hormone (FSH) are lowered compared with normal weight women. This relative hypogonadotropic hypogonadism represents a potential etiology for overall decreased fertility in obesity. The objective was to determine if administration of an aromatase inhibitor (AI) to ovulating obese women would normalize LH and FSH by interrupting estradiol negative feedback. Letrozole (2.5-5 mg) was given daily to 22 women, 12 obese and 10 normal weight, for 7 days. On the last day of administration, 8 h of blood sampling was done every 10 min before and after a bolus of GnRH at 4 h. We obtained data from 21 ovulatory women (10 normal weight and 11 obese) who had undergone a similar protocol of frequent blood sampling but no aromatase inhibitors (AI) treatment. Serum LH and FSH levels and pulse characteristics were measured. Treatment with AI only significantly affected obese women. Further, in women with obesity, LH secretion, prior to the GnRH bolus, was significantly higher in AI treated compared with non-treated (p = 0.011). AI treatment doubled LH pulse amplitude in obese women (p = 0.004). In response to aromatase inhibition, LH secretion in ovulatory women with obesity is increased and similar to levels found in untreated normal weight women. The increase in LH pulse amplitude indicates that the AI effect is mediated at the level of the pituitary. Our results suggest that the hypogonadotropic phenotype of simple obesity is subject to modulation by interruption of estradiol negative feedback.

Prevalence of a Good Perinatal Outcome With Cryopreserved Compared With Fresh Donor Oocytes.

OBJECTIVE: To compare the odds of a good perinatal outcome between cryopreserved and fresh donor oocytes. METHODS: We used the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System to conduct a retrospective cohort study of women undergoing donor oocyte in vitro fertilization (IVF) from 2012 to 2015. Cycles using cryopreserved embryos, a gestational carrier, or preimplantation genetic testing were excluded. The primary outcome was a good perinatal outcome, defined as a singleton live birth at 37 weeks of gestation or more with birth weight at or within 2,500 g and 4,000 g. Secondary outcomes included live birth, multiple birth, and prematurity. Generalized estimating equation models were used to test the effect of oocyte type on the primary outcome while accounting for covariates and the correlation induced by repeated cycles within a patient. RESULTS: Of the 36,925 cycles included in the analysis, 8,381 (22.7%) used cryopreserved and 28,544 (77.3%) used fresh oocytes. The odds of a good perinatal outcome were marginally but significantly lower with cryopreserved than with fresh oocytes before and after covariate adjustment (22.0% vs 24.1%, unadjusted odds ratio [OR] 0.90, 95% CI 0.85-0.96, adjusted OR 0.88, 95% CI 0.81-0.95). Compared with fresh oocytes, cryopreserved oocytes were associated with lower rates of live birth (39.6% vs 47.7%, OR 0.75, 95% CI 0.72-0.79), multiple birth (22.3% vs 31.2%, OR 0.63, 95% CI 0.58-0.69), and prematurity (27.6% vs 30.6%, OR 0.86, 95% CI 0.79-0.94). CONCLUSION: This retrospective national study demonstrated that the use of cryopreserved compared with fresh donor oocytes in IVF cycles is associated with marginally lower odds of a good perinatal outcome.

Embryo cryopreservation and utilization in the United States from 2004-2013.

OBJECTIVE: To evaluate the quantity and use of embryos cryopreserved at assisted reproductive technology (ART) clinics in the United States from 2004 through 2013 and to characterize trends in ART cycles in which all embryos were cryopreserved. DESIGN: Retrospective analysis. SETTING: Not applicable. PATIENTS: Registry data from the Society for Assisted Reproductive Technology. INTERVENTIONS: Historical cohort of U.S. ART cycles reported to the Society for Assisted Reproductive Technology Clinical Outcomes Reporting System between 2004 and 2013. MAIN OUTCOME MEASURES: Number of embryos cryopreserved and factors associated with having cryopreserved embryos. RESULTS: The percentage of fresh cycles in which all embryos were frozen increased dramatically each year after 2010: 15.6% (2010), 19.9% (2011), 30.7% (2012), and 40.7% (2013). During 10 years, 1,954,548 embryos were cryopreserved and 717,345 embryos were transferred. In freeze-only cycles from 2004 to 2013, there was a significant increase in the percentage of women with diminished ovarian reserve (19.9% to 34.1%) and in those who used preimplantation genetic testing (3.2% to 6.9%). During the 10-year period, there were 294,575 fresh cycles with embryo transfer and at least one embryo cryopreserved. Overall, 52.5% (n = 154,543) did not undergo a subsequent frozen embryo transfer, 29.5% (n = 40,462) were left with no frozen embryos, 50.4% (n = 68,875) had one-five embryos, and 20.0% (n = 27,396) had ≥six. Factors associated with having excess embryos included donor oocyte cycles and increased antimüllerian hormone levels. CONCLUSIONS: There has been a sharp increase in U.S. ART cycles in which all embryos are frozen and this may result in more embryos in storage.

Direct Methotrexate Injection into the Gestational Sac for Nontubal Ectopic Pregnancy: A Review of Efficacy and Outcomes from a Single Institution.

STUDY OBJECTIVE: To evaluate the efficacy of nontubal ectopic pregnancy (NTEP) management with direct methotrexate (MTX) injection into the gestational sac. DESIGN: A retrospective chart review. SETTING: A tertiary academic and teaching hospital. PATIENTS: All cases of confirmed NTEP were retrospectively identified from 2012 to 2017. INTERVENTIONS: Ultrasound-guided direct injection of MTX into the fetal pole and surrounding gestational sac and a single dose of systemic MTX with or without fetal intracardiac injection of potassium chloride. MEASUREMENTS AND MAIN RESULTS: Treatment failure, complications from treatment, operating time, and days to negative serum human chorionic gonadotropin (hCG) after treatment were measured. Fourteen women (age 34 ± 5.2 years) with NTEP underwent direct MTX injection (cesarean scar, n = 4; interstitial, n = 6; cervical, n = 4). The mean estimated gestational age was 49 ± 11, CI (43, 56 days). One patient required laparoscopic intervention with a failure rate of 1 of 14 (a double interstitial, heterotopic pregnancy). There were no other major complications. The time in the operating room was similar for all NTEP types. The average time to negative serum hCG was not different for cesarean scar (84.5 ± 36 days), cervical pregnancies (70.5 ± 19 days), or interstitial pregnancies (45.3 ± 38 days, p = .15). CONCLUSION: Direct MTX injection into the gestational sac for NTEP treatment is safe and effective. The failure rate of 7% is considerably lower than what was previously reported for a failure of systemic MTX in similar cases (25%). Resolution of serum hCG after treatment can be quite prolonged even in uncomplicated cases.

Lower antimüllerian hormone is associated with lower oocyte yield but not live-birth rate among women with obesity.

BACKGROUND: Antimüllerian hormone is produced by small antral follicles and reflects ovarian reserve. Obesity is associated with lower serum antimüllerian hormone, but it is unclear whether lower levels of antimüllerian hormone in women with obesity reflect lower ovarian reserve. OBJECTIVE: To determine whether lower antimüllerian hormone in women with obesity undergoing in vitro fertilization is associated with oocyte yield and live-birth rate. MATERIALS AND METHODS: Retrospective cohort from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System database of 13,316 women with obesity and 16,579 women with normal body mass index undergoing their first autologous in vitro fertilization with fresh transfers between 2012 and 2014. Normal body mass index was defined as body mass index 18.5-24.9 kg/m2, and obesity was defined as body mass index ≥30 kg/m2. Subjects with obesity were stratified as those with class 1 obesity (body mass index, 30.0-34.9 kg/m2), class 2 obesity (body mass index, 35.0-39.9 kg/m2), and class 3 obesity (body mass index, ≥40 kg/m2) based on the World Health Organization body mass index guidelines. Antimüllerian hormone levels were stratified as normal (>1.1 ng/mL), low (0.16-1-1 ng/mL), and undetectable (≤0.16 ng/mL). Multivariable modeling was used to assess oocyte yield using linear regression with a logarithmic transformation and odds of live birth using logistic regression. RESULTS: Women with obesity were older (36.0 ± 4.8 vs 35.5 ± 4.8, P < .001), had lower antimüllerian hormone (1.8 ± 2.0 ng/mL vs 2.1 ± 2.0 ng/mL, P < .001), and had fewer oocytes retrieved (11.9 ± 7.3 vs 12.8 ± 7.7, P < .001) than women with normal body mass index. Lower oocyte yield was observed among women with obesity and normal antimüllerian hormone levels compared to women with normal body mass index and normal antimüllerian hormone levels (13.6 ± 7.3 vs 15.8 ± 8.1, P < .001). No difference in oocyte yield was observed among women with obesity and low antimüllerian hormone levels (P = .58) and undetectabl antimüllerian hormone (P = .11) compared to women with normal BMI and similar antimüllerian hormone levels. Among women with a body mass index ≥30 kg/m2, antimüllerian hormone levels were associated with the number of oocytes retrieved (ß = 0.069; standard error, 0.005; P < .001) but not live-birth rate (odds ratio, 0.98; 95% confidence interval, 0.93-1.04, P = .57). CONCLUSION: Lower antimüllerian hormone in infertile women with obesity appears to reflect lower ovarian reserve, as antimüllerian hormone is associated with lower oocyte yield. Despite lower oocyte yield, lower antimüllerian hormone was not associated with lower live-birth rate among women with obesity.

Recommendations for assessing ovarian health and fertility potential in survivors of childhood cancer.

Most children diagnosed with cancer survive for many years after treatment. However, the fertility potential of these patients may suffer due to their oncologic therapies. Certain chemotherapies and radiation are more likely to be detrimental to gonadal function, and put patients at risk of acute or premature ovarian failure. Prepubertal cancer patients will need different follow-up and testing from their post-pubertal counterparts. This review will present evidence to help patients, family members and physicians determine who is most at risk of ovarian insufficiency and how to monitor childhood cancer survivors. It will discuss the impact of age at diagnosis and cancer therapies on reproductive outcomes, and guide caregivers and patients on monitoring gonadal function after therapy.

Reduction in FSH Throughout the Menstrual Cycle After Omega-3 Fatty Acid Supplementation in Young Normal Weight but not Obese Women.

Dietary fish oil restores ovarian function in subfertile rats, which is thought to be associated with decreased transcription of follicle-stimulating hormone (FSH) ß-subunit. We have previously demonstrated a reduction in early follicular serum FSH levels in normal weight but not obese women after treatment with omega-3 polyunsaturated fatty acids (PUFA). Herein, we report the effect of supplementation with omega-3 PUFA on urinary reproductive hormones across the whole menstrual cycle. This interventional study included 17 eumenorrheic women, aged 24-41 years. One month of daily morning urine was collected before and after 1 month of omega-3 PUFA supplementation with 4 g of eicosapentaenoic acid and docosahexaenoic acid daily. Measurements included urinary FSH, luteinizing hormone (LH) and estrogen and progesterone metabolites, plasma fatty acid composition, and markers of endoplasmic reticulum stress. Compliance with dietary supplementation was verified by significantly reduced ratios of omega-6 to omega-3 PUFA for all subjects after treatment (P < .01). After 1 month of omega-3 PUFA supplementation, urinary FSH was significantly decreased in normal weight, but not obese women, in both follicular and luteal phases (-28.4% and -12.6%, respectively, both P = .04). No significant changes were seen in LH or sex steroids for either weight group. The selective and specific decrease in FSH suggests that omega-3 PUFA supplementation merits further investigation in normal weight women with decreased fertility and/or diminished ovarian reserve.