A positive ReceptivaDx result for BCL6 does not correlate with abnormal ERA results or decreased expression of receptivity-associated markers: two sides of the endometrial receptivity coin in fertility evaluation and treatment.

OBJECTIVE: To investigate if a positive result on ReceptivaDx for evaluation of B-cell lymphoma 6 (BCL6), a proposed marker of progesterone resistance associated with impaired uterine receptivity, correlates with a suboptimal profile of receptivity-associated markers in the window of implantation using the endometrial receptivity array and single-nucleus transcriptomic analysis DESIGN: Retrospective clinical cohort study; pilot study of single-nucleus RNA sequencing of prospectively collected window of implantation endometrium undergoing ReceptivaDx BCL6 evaluation SETTING: Academic center SUBJECTS: Patients with infertility who underwent endometrial biopsy for concurrent endometrial receptivity array analysis (ERA®; Igenomix) and BCL6 immunostaining (ReceptivaDx™; Cicero Diagnostics, Inc.) EXPOSURE: Positive BCL6 result on ReceptivaDx™ (histologic score 'HSCORE' >1.4) MAIN OUTCOME MEASURES: Pre-receptive ERA result; relative expression levels of endometrial receptivity-associated epithelial genes by single-nucleus sequencing RESULTS: One hundred and seventy-two patients with concurrent ERA and ReceptivaDx evaluation were included in the analysis: 40 were BCL6-positive and 132 were BCL6-negative. One patient (2.5%) in the BCL6-positive group had a pre-receptive ERA result, compared to 29 patients (22.0%) in the BCL6-negative group (p<0.01). BCL6 positivity was associated with decreased odds of a pre-receptive ERA result (OR 0.09 95%CI [0.01-0.69], p=0.02). Single-nucleus transcriptomic analysis of 5,718 epithelial cell nuclei from four individuals showed significant cell type-specific transcriptomic changes associated with a positive ReceptivaDx BCL6 result in both natural cycle (NC) and programmed cycle (PC) endometrium: there were 2,801 significantly differentially expressed genes (DEGs) comparing NC BCL6-positive to -negative, and 1,062 DEGs comparing PC BCL6-positive to -negative. Of the 34 receptivity-associated epithelial markers evaluated, 16 were significantly upregulated in NC BCL6-positive versus -negative endometrium epithelial nuclei. In PC epithelial nuclei, 12 of the 34 receptivity-associated genes were significantly upregulated, while only 1 was significantly downregulated in BCL6-positive versus -negative endometrium. CONCLUSIONS: A positive ReceptivaDx BCL6 result does not correlate with a pre-receptive ERA. Epithelial cells from BCL6-positive endometrium did not show significantly decreased expression in most of the receptivity markers evaluated. These findings demonstrate discordance between the interpretation of "endometrial receptivity" by ReceptivaDx and ERA, and highlight the need for further validation of endometrial evaluation methods in fertility treatment.

How ingroup norms of multiculturalism (and tolerance) affect intergroup solidarity: The role of ideology.

Multiculturalism and tolerance, as two sets of normative beliefs about how to deal with intergroup diversity, have been recognized as effective at reducing outgroup negativity among majority group members. However, whether majority group members' normative beliefs regarding them might motivate their solidarity-based collective actions and how their political ideology might qualify this influence remained unclear. To answer these questions, we conducted two pre-registered experimental studies (N = 626), both zooming in on the multiculturalism issues in the context of the relationships between native Dutch citizens and citizens with a Moroccan background within Dutch university campuses (Study 1) and broader Dutch society (Study 2). In both studies, we found an ingroup norm of tolerance (vs. control) undermined majority group members' engagement in collective actions in support of ethnic minorities. Additionally, ideological leftists were more sensitive to norms than rightists: Study 1 showed a facilitative effect of the multiculturalism norm (vs. control) on solidarity-based collective action intentions particularly among leftists, whilst Study 2 revealed a dampening effect of the tolerance norm (vs. control) on these intentions particularly among leftists.

Unraveling Image and Justice Concerns: A Social Identity Account on Appraisals and Emotional Drivers of High-Status Transgressor Group Members' Solidarity With Low-Status Groups.

High-status group members typically respond defensively when their ingroup members transgress against low-status groups. However, when they identify highly with transgressor groups, they sometimes also engage in solidarity with victimized low-status groups due to ingroup-focused motives. Yet, the response of low-identified transgressor group members, who can prioritize victims' plight over ingroup interests, remains underexplored. To address this gap, we conducted three preregistered studies (Ntotal = 886) concerning education-based transgressions in the Netherlands and the United Kingdom, employing cross-sectional (Study 1) and experimental designs (Studies 2-3). Supporting previous research, we found that high-identifiers engage in nonradical solidarity driven by ingroup image concerns and image-related emotions. Low-identifiers, however, engage in both nonradical and radical solidarity through perceived injustice and justice-related emotions. Our findings provide insights into the roots of high-status group collective action on behalf of low-status groups against intergroup transgressions. Theoretical and societal implications were discussed.

Miscarriage risk assessment: a bioinformatic approach to identifying candidate lethal genes and variants.

PURPOSE: Miscarriage, often resulting from a variety of genetic factors, is a common pregnancy outcome. Preconception genetic carrier screening (PGCS) identifies at-risk partners for newborn genetic disorders; however, PGCS panels currently lack miscarriage-related genes. In this study, we evaluated the potential impact of both known and candidate genes on prenatal lethality and the effectiveness of PGCS in diverse populations. METHODS: We analyzed 125,748 human exome sequences and mouse and human gene function databases. Our goals were to identify genes crucial for human fetal survival (lethal genes), to find variants not present in a homozygous state in healthy humans, and to estimate carrier rates of known and candidate lethal genes in various populations and ethnic groups. RESULTS: This study identified 138 genes in which heterozygous lethal variants are present in the general population with a frequency of 0.5% or greater. Screening for these 138 genes could identify 4.6% (in the Finnish population) to 39.8% (in the East Asian population) of couples at risk of miscarriage. This explains the cause of pregnancy loss in approximately 1.1-10% of cases affected by biallelic lethal variants. CONCLUSION: This study has identified a set of genes and variants potentially associated with lethality across different ethnic backgrounds. The variation of these genes across ethnic groups underscores the need for a comprehensive, pan-ethnic PGCS panel that includes genes related to miscarriage.

Preconception Genetic Carrier Screening for Miscarriage Risk Assessment: A Bioinformatic Approach to Identifying Candidate Lethal Genes and Variants.

Purpose: Miscarriage, due to genetically heterogeneous etiology, is a common outcome of pregnancy. Preconception genetic carrier screening (PGCS) identifies at-risk partners for newborn genetic disorders; however, PGCS panels currently lack miscarriage-related genes. Here we assessed the theoretical impact of known and candidate genes on prenatal lethality and the PGCS among diverse populations. Methods: Human exome sequencing and mouse gene function databases were analyzed to define genes essential for human fetal survival (lethal genes), identify variants that are absent in a homozygous state in healthy human population, and to estimate carrier rates for known and candidate lethal genes. Results: Among 138 genes, potential lethal variants are present in the general population with a frequency of 0.5% or greater. Preconception screening for these 138 genes would identify from 4.6% (Finnish population) to 39.8% (East Asian population) of couples that are at-risk for miscarriage, explaining a cause for pregnancy loss for ∼1.1-10% of conceptions affected by biallelic lethal variants. Conclusion: This study identified a set of genes and variants potentially associated with lethality across different ethnic backgrounds. The diversity of these genes amongst the various ethnic groups highlights the importance of designing a pan-ethnic PGCS panel comprising miscarriage-related genes.

B-cell lymphoma 6 expression significantly differs by the uterine preparation method used for frozen embryo transfer.

OBJECTIVE: To determine whether B-cell lymphoma 6 (BCL6), an endometriosis-associated marker postulated to predict poor pregnancy outcomes, is differentially expressed in the window of implantation with various uterine preparation regimens commonly used for frozen embryo transfers. DESIGN: A retrospective cohort study. SETTING: An academic center. PATIENT(S): Patients with infertility who underwent endometrial biopsy for BCL6 evaluation INTERVENTION(S): Exogenous estradiol and/or progesterone. MAIN OUTCOME MEASURE(S): Endometrial BCL6 histological score (HSCORE) and overexpression (HSCORE >1.4) RESULT(S): Two hundred and forty-four patients were included in the analysis: 76 patients were sampled in a natural menstrual cycle without exogenous hormone exposure (NC), 25 under a modified natural cycle embryo transfer protocol with choriogonadotropin alfa injection followed by luteal phase vaginal progesterone supplementation (mNC), and 143 under a programmed cycle embryo transfer protocol, with estradiol administration followed by addition of intramuscular progesterone-in-oil injections (PC). Median HSCORE (interquartile range) was the highest in NC (3.0 [1.8-3.6]). BCL6 expression was significantly lower in mNC (1.1 [0.4-2.1]) and PC groups (0.8 [0.3-1.3]) compared with NC. In addition, BCL6 overexpression (HSCORE >1.4) was observed in 80.3% of NC, 40.0 % of mNC, and 23.1 % of PC. After adjusting for covariates, the endometrium exposed to exogenous progesterone had significantly lower odds of BCL6 overexpression than that of a natural menstrual cycle (adjusted odds ratio, 0.12 [95% CI 0.04-0.35] for mNC; and odds ratio, 0.08 [95% CI 0.04-0.17] for PC). CONCLUSION(S): BCL6 expression differs by the type of uterine preparation method, with lower levels observed with exogenous progesterone exposure. The validity and utility of BCL6 testing under medicated endometrial state warrants further investigation.

Leveraging electronic health records to identify risk factors for recurrent pregnancy loss across two medical centers: a case-control study.

Recurrent pregnancy loss (RPL), defined as 2 or more pregnancy losses, affects 5-6% of ever-pregnant individuals. Approximately half of these cases have no identifiable explanation. To generate hypotheses about RPL etiologies, we implemented a case-control study comparing the history of over 1,600 diagnoses between RPL and live-birth patients, leveraging the University of California San Francisco (UCSF) and Stanford University electronic health record databases. In total, our study included 8,496 RPL (UCSF: 3,840, Stanford: 4,656) and 53,278 Control (UCSF: 17,259, Stanford: 36,019) patients. Menstrual abnormalities and infertility-associated diagnoses were significantly positively associated with RPL in both medical centers. Age-stratified analysis revealed that the majority of RPL-associated diagnoses had higher odds ratios for patients <35 compared with 35+ patients. While Stanford results were sensitive to control for healthcare utilization, UCSF results were stable across analyses with and without utilization. Intersecting significant results between medical centers was an effective filter to identify associations that are robust across center-specific utilization patterns.

Triggering with 1,500 IU of human chorionic gonadotropin plus follicle-stimulating hormone compared to a standard human chorionic gonadotropin trigger dose for oocyte competence in in vitro fertilization cycles: a randomized, double-blinded, controlled noninferiority trial.

OBJECTIVE: To assess if triggering with 1,500 IU of human chorionic gonadotropin (hCG) with 450 IU of follicle-stimulating hormone (FSH) induces noninferior oocyte competence to a standard dose of hCG trigger used in in vitro fertilization (IVF). The alternative trigger will be considered noninferior if it is at least 80% effective in promoting oocyte competence. DESIGN: Randomized, double-blinded, controlled noninferiority trial. SETTING: Academic infertility practice. PATIENTS: Women aged 18-41 undergoing IVF with antral follicle count ≥8, body mass index ≤30 kg/m2, and no history of ≥2 IVF cycles canceled for poor response were enrolled. Participants with a serum estradiol >5,000 pg/mL on the day of trigger were excluded because of high risk of ovarian hyperstimulation syndrome. INTERVENTIONS: Participants were randomized to receive an alternative trigger of 1,500 IU of hCG plus 450 IU of FSH or a standard trigger dose of hCG (5,000 or 10,000 IU) for final oocyte maturation. MAIN OUTCOME MEASURES: The primary outcome was total competent proportion, defined as the probability of 2 pronuclei from an oocyte retrieved. The alternative trigger will be considered noninferior to the standard trigger if a 1-sided 95% confidence interval (CI) of the relative risk (RR) is not <0.8. Secondary outcomes included oocyte recovery and maturity, intracytoplasmic sperm injection fertilization, embryo quality, pregnancy rates, as well as serum and follicular hormones. Secondary outcomes were compared using a 2-sided superiority test. Outcomes were analyzed by intention-to-treat and per-protocol. RESULTS: A total of 105 women undergoing IVF were randomized from May 2015 to June 2018. The probability of the primary outcome was 0.59 with the alternative trigger and 0.65 with the standard trigger, with a RR of 0.91 and a 1-sided 95% CI of 0.83. Noninferiority of the alternative trigger was demonstrated. Live birthrate from all fresh transfers in the alternative trigger group vs. standard trigger was 46.9 vs. 46.4% (RR, 1.01; 95% CI, 0.62-1.62), respectively. Live birthrate per randomized participant was 48.1% in the alternative trigger group vs. 62.7% with the standard trigger (RR, 0.73; 95% CI, 0.48-1.11). No participants had a failed retrieval. CONCLUSION: Triggering with 1,500 IU of hCG plus 450 IU of FSH promoted noninferior oocyte competence compared to a standard hCG trigger dose. TRIAL REGISTRATION: NCT02310919.

When is the right time to stop autologous in vitro fertilization treatment in poor responders?

Declining oocyte quality and quantity with age are the main limiting factors in female reproductive success. Age of the female partner, ovarian reserve, the patient's previous fertility treatment outcomes, and the fertility center's pregnancy success data for specific patient profiles are used to predict live birth rates with in vitro fertilization (IVF) treatment. The chance of finding a euploid blastocyst or achieving live birth after the age of 45 is close to zero. Therefore, any IVF cycle using autologous oocytes after the age of 45 can be accepted as futile and should be discouraged. The number of mature eggs retrieved and the number of embryos available for transfer are the second most important predictors of pregnancy and live birth after female age. For patients aged ≤45 years, the recommendation for attempting IVF should be given considering the patient's age and the expected ovarian response. Before the start of the IVF cycle, patients with a very poor prognosis must be fully informed of the prognosis, risks, costs, and alternatives, including using donor oocytes. Alternative treatments to improve oocyte quality and decrease aneuploidy have the potential to change how clinicians treat poor responders. However, these treatments are not yet ready for clinical use.

Back-to-back random-start ovarian stimulation prior to chemotherapy to maximize oocyte yield.

PURPOSE: To evaluate the feasibility of utilizing back-to-back random-start ovarian stimulation to increase oocyte yield for fertility preservation prior to cancer treatment. METHODS: A case series of 15 patients who underwent back-to-back random-start stimulation cycles prior to chemotherapy. RESULTS: Of the 15 back-to-back random-start stimulation cases, 13 had breast cancer and 2 had other cancers. The average age was 38 years (range 30-43) and average AFC was 8 (range 3-14). Fourteen of the 15 women (93%) who underwent two ovarian stimulation cycles completed both of them. The average time to complete back-to-back random-start ovarian stimulation was 33 days (range 13-43 days). The average time between the first cycle completion and the second cycle start in our back-to-back random-start stimulations was 9 days (range 0-14 days). Two of the women underwent back-to-back random-start ovarian stimulation prior to starting neoadjuvant chemotherapy for breast cancer. Eleven of our 15 women at least doubled their oocyte or embryo yield relative to their first cycle. Only 1 of the 15 second cycles was canceled. The mature oocyte rate, fertilization rate, and embryo yield were similar among the first and second cycles. CONCLUSIONS: Back-to-back random-start ovarian stimulation may be an effective way to maximize fertility preservation, even in time-limited settings.

Large Differences in Small RNA Composition Between Human Biofluids.

Extracellular microRNAs (miRNAs) and other small RNAs are implicated in cellular communication and may be useful as disease biomarkers. We systematically compared small RNAs in 12 human biofluid types using RNA sequencing (RNA-seq). miRNAs and tRNA-derived RNAs (tDRs) accounted for the majority of mapped reads in all biofluids, but the ratio of miRNA to tDR reads varied from 72 in plasma to 0.004 in bile. miRNA levels were highly correlated across all biofluids, but levels of some miRNAs differed markedly between biofluids. tDR populations differed extensively between biofluids. Y RNA fragments were seen in all biofluids and accounted for >10% of reads in blood plasma, serum, and cerebrospinal fluid (CSF). Reads mapping exclusively to Piwi-interacting RNAs (piRNAs) were very rare, except in seminal plasma. These results demonstrate extensive differences in small RNAs between human biofluids and provide a useful resource for investigating extracellular RNA biology and developing biomarkers.

Author Correction: A novel oocyte maturation trigger using 1500 IU of human chorionic gonadotropin plus 450 IU of follicle-stimulating hormone may decrease ovarian hyperstimulation syndrome across all in vitro fertilization stimulation protocols.

The original version of this article unfortunately contained a mistake. The middle initial of Douglas A. Mata was omitted. The original article has been corrected.

p38 Mitogen-Activated Protein Kinase is Involved in the Pathogenesis of Endometriosis by Modulating Inflammation, but not Cell Survival.

BACKGROUND: Local pro-inflammatory environment and enhanced cell survival contribute to the endometriosis development. A serine/threonine kinase p38 mitogen-activated protein kinase (MAPK) mediates intracellular signaling of cytokine production, cell proliferation, and apoptosis in different cell types. The current study compares p38 MAPK activity in normal endometrium and endometriosis, and assesses role(s) of p38 MAPK on cytokine production and cell survival in endometriosis. METHODS: Immunohistochemical levels of total and phosphorylated (active) p38 MAPK as well as its correlation with interleukin 8 (IL-8) expression, and cell proliferation and apoptosis were compared in normal human endometrium and endometriosis. The action of p38 MAPK on pro-inflammatory cytokine-induced IL-8 and monocyte chemotactic protein (MCP)-1 expression in endometriotic cells were assessed by enzyme-linked immunosorbent assay. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide cell survival, 5-bromo-2'-deoxyuridine incorporation, and Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling assays were used to determine the function of p38 MAPK in cultured human endometriotic stromal cell proliferation and apoptosis. RESULTS: p38 MAPK activity was significantly higher in both eutopic and ectopic endometria compared to normal endometria during late proliferative and early secretory phases ( P < .05). Increased p38 MAPK activity in endometriotic cells correlated with IL-8 expression (Pearson correlation coefficient r = 0.83, P < .01), but not with apoptosis in vivo. The pro-inflammatory cytokines IL-1ß and tumor necrosis factor (TNF)-α induced activation of p38 MAPK. Inhibition of p38 MAPK activity blocked IL-1ß and TNF-α-induced IL-8 and MCP-1 secretion in cultured endometriotic stromal cells ( P < .05), but did not impact on endometriotic cell survival. CONCLUSIONS: These results suggest that rather than modulating cell survival, increased p38 MAPK activity in endometriotic cells contributes to the pathogenesis of endometriosis by promoting the local inflammatory milieu.

A novel oocyte maturation trigger using 1500 IU of human chorionic gonadotropin plus 450 IU of follicle-stimulating hormone may decrease ovarian hyperstimulation syndrome across all in vitro fertilization stimulation protocols.

PURPOSE: Modification of the trigger used to induce final oocyte maturation in in vitro fertilization (IVF) is a major strategy used to reduce the risk of ovarian hyperstimulation syndrome (OHSS). A novel trigger composed of 1500 IU of human chorionic gonadotropin (hCG) plus 450 IU of follicle-stimulating hormone (FSH) has been developed to reduce OHSS risk. This study compares outcomes of the novel trigger to conventional triggers used in high-risk OHSS patients undergoing IVF. METHODS: In this retrospective cohort study, IVF cycles at high risk for OHSS based on a serum estradiol > 5000 pg/ml on trigger day conducted between January 2008 and February 2016 were evaluated. Oocyte maturation was induced with the novel trigger (1500 IU hCG plus 450 IU FSH) or a conventional trigger [3300 IU hCG, gonadotropin-releasing hormone agonist (GnRHa) alone, or GnRHa plus 1500 IU hCG]. IVF cycle outcomes were compared. Trigger strategies were examined for associations with OHSS development using logistic regression. RESULTS: Among 298 eligible IVF cycles identified, there were no differences in oocyte maturation, fertilization, embryo quality, or pregnancy outcomes among all triggers. After adjusting for serum estradiol level and number of follicles, the novel trigger was associated with lower odds of OHSS symptom development compared to the 3300 IU hCG and GnRHa plus hCG 1500 IU triggers (p = 0.007 and 0.04, respectively). CONCLUSIONS: This study suggests that 1500 IU hCG plus 450 IU FSH may be associated with decreased OHSS symptoms compared to conventional triggers, while producing similar IVF and pregnancy outcomes. More important, this novel trigger may provide a superior alternative in down-regulated cycles and in patients with hypothalamic dysfunction where GnRHa triggers cannot be utilized.

Outcomes from a university-based low-cost in vitro fertilization program providing access to care for a low-resource socioculturally diverse urban community.

OBJECTIVE: To report on outcomes from a university-based low-cost and low-complexity IVF program using mild stimulation approaches and simplified protocols to provide basic access to ART to a socioculturally diverse low-income urban population. DESIGN: Retrospective cohort study. SETTING: Academic infertility center. PATIENT(S): Sixty-five infertile couples were enrolled from a county hospital serving a low-resource largely immigrant population. INTERVENTIONS(S): Patients were nonrandomly allocated to one of four mild stimulation protocols: clomiphene/letrozole alone, two clomiphene/letrozole-based protocols involving sequential or flare addition of low-dose gonadotropins, and low-dose gonadotropins alone. Clinical fellows managed all aspects of cycle preparation, monitoring, oocyte retrieval, and embryo transfer under an attending preceptor. Retrieval was undertaken without administration of deep anesthesia, and laboratory interventions were minimized. All embryo transfers were performed at the cleavage stage. MAIN OUTCOME MEASURE(S): Sociomedical demographics, treatment response, and pregnancy outcomes were recorded. RESULT(S): From August 2010 to June 2016, 65 patients initiated 161 stimulation IVF cycles, which resulted in 107 retrievals, 91 fresh embryo transfers, and 40 frozen embryo transfer cycles. The mean age of patients was 33.3 years, and mean reported duration of infertility was 5.3 years; 33.5% (54/161) of cycles were cancelled before oocyte retrieval, with 13% due to premature ovulation. Overall, cumulative live birth rates per retrieval including subsequent use of frozen embryos was 29.0%; 44.6% (29/65) of patients enrolled in the program achieved pregnancy. CONCLUSION(S): Use of mild stimulation protocols, simplified monitoring, and minimized laboratory handling procedures enabled access to care in a low-resource socioculturally diverse infertile population.

Long-term hormonal contraceptive use is associated with a reversible suppression of antral follicle count and a break from hormonal contraception may improve oocyte yield.

PURPOSE: Unlike infertility, patients presenting for fertility preservation (FP) are often using combined hormonal contraceptives (CHC). We studied whether long-term (≥6 months) CHC use is associated with reversible suppression of antral follicle count (AFC). METHODS: This is a longitudinal study of FP cycles from 2012 to 2016. We studied three groups: those without CHC exposure (NO CHC), those with CHC usage with a CHC break (BREAK), and without a break (NO BREAK) prior to ovarian stimulation. We assessed ovarian reserve by AFC at initial consultation and discussed the possibility of CHC suppression of AFC. Patients chose between ovarian stimulation with no CHC break versus ovarian stimulation after a CHC break. AFC was measured serially in the BREAK group. We assessed whether AFC suppression was reversed in the BREAK group. Total oocyte yield was compared among the NO CHC, BREAK, and NO BREAK groups. T tests, ANOVA, and linear/logistic regressions were used. RESULTS: Seven hundred forty-three women underwent FP. Twenty-one percent (n = 154) were taking long-term CHC (≥6 months). AFC suppression was more likely with CHC use (OR 1.6, 95% CI 1.1-2.4, P = 0.011). The BREAK group (n = 79) stopped CHC for an average of 4 months. AFC improvement started at 1 month and plateaued at approximately 6- to 7-month break. The BREAK group had approximately twice as many oocytes per initial AFC as NO BREAK (2.8 ± 3.8 vs. 1.4 ± 0.9, P < 0.001). CONCLUSIONS: When women present for FP on CHC, AFC may be suppressed. A CHC break of several months is associated with an increase in AFC and a potential improvement in overall egg yield.

Response to ovarian stimulation is not impacted by a breast cancer diagnosis.

STUDY QUESTION: Does a breast cancer diagnosis impact ovarian function in the setting of fertility preservation? SUMMARY ANSWER: Ovarian reserve and ovarian stimulation outcomes are similar in patients with a new diagnosis of breast cancer and patients undergoing elective fertility preservation. WHAT IS KNOWN ALREADY: Prior studies, with small study populations, lack of controlling for individual differences in ovarian reserve and infertile controls, have reported conflicting outcomes for cancer patients undergoing ovarian stimulation for fertility preservation. STUDY DESIGN, SIZE, DURATION: This retrospective cohort analysis included 589 patients undergoing ovarian stimulation for fertility preservation between 2009 and 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with a recent breast cancer diagnosis (n = 191) and women desiring elective fertility preservation (n = 398) underwent ovarian stimulation with an antagonist protocol at an academic medical center. The aromatase inhibitor letrozole was administered to breast cancer patients with estrogen-sensitive disease. MAIN RESULTS AND THE ROLE OF CHANCE: Baseline antral follicle count (AFC) was not different between the breast cancer patients and controls (15.4 ± 10.4 [mean ± SD] vs 15.4 ± 10.0, P = NS), even after categorization by age. Total (19.4 ± 0.9 [mean ± SEM] vs 17.0 ± 0.5, P = NS) and mature (MII) oocytes retrieved (13.7 ± 0.7 vs 13.2 ± 0.4, P = NS), adjusted for age, BMI and total gonadotropin dose, were also similar between the two groups. Letrozole use was associated with a decreased maturity rate (MII/total oocytes retrieved) compared to elective cryopreservation (0.71 ± 0.01 vs 0.77 ± 0.01, P < 0.001), although the mature oocyte yield [MII/AFC] was comparable (1.01 ± 0.06 vs 0.93 ± 0.03, P = NS). LIMITATIONS, REASONS FOR CAUTION: The single center design may impact generalizability. Additionally, the lack of subsequent embryo and pregnancy data is an inherent weakness. WIDER IMPLICATIONS OF THE FINDINGS: In females, a breast cancer diagnosis does not impact gonadal function as measured by AFC or ovarian stimulation outcomes. Breast cancer patients should be counseled that their response to ovarian stimulation for fertility preservation is similar to that of patients undergoing elective oocyte cryopreservation. STUDY FUNDING/COMPETING INTEREST(S): None. TRIAL REGISTRATION NUMBER: N/A.

Dynamic secretion during meiotic reentry integrates the function of the oocyte and cumulus cells.

The differentiation of the female gamete into a developmentally competent oocyte relies on the protected environment of the ovarian follicle. The oocyte plays a key role in establishing this microenvironment by releasing paracrine factors that control the functions of surrounding somatic cells. Growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) are secreted during follicle growth and play pivotal roles in this local regulation. The current view is that the function of these secreted factors declines in the periovulatory period when the oocyte reenters the meiotic cell cycle. Here, we provide evidence that oocyte reentry into meiosis is instead associated with a shift in the pattern of secretion with a new set of bioactive molecules synthesized before ovulation. Using interleukin 7 (IL7) as a prototypic secreted factor, we show that its secretion is dependent on activation of mRNA translation in synchrony with the cell cycle and that its translation is under the control of somatic cells. IL7 is part of a local feedback loop with the soma because it regulates cumulus cell replication. Similar conclusions are reached when IL7 secretion is measured in human follicular fluid during in vitro fertilization cycles. IL7 concentration in the follicular fluid correlates with the oocyte ability to reach the MII stage of maturation. These findings are consistent with the hypothesis that a new set of local factors is secreted by the oocyte during ovulation. These dynamic secretions are likely critical for promoting the final stages of maturation and oocyte developmental competence.

Random-start ovarian stimulation in patients with cancer.

PURPOSE OF REVIEW: Awaiting menses to start ovarian stimulation for oocyte/embryo cryopreservation in patients with cancer may result in a significant delay of cancer treatment that may lead to patients forgoing fertility preservation. The purpose of this review is to describe the new protocols to facilitate the start of ovarian stimulation, including random-start ovarian stimulation. RECENT FINDINGS: In random-start protocols, the number of total and mature oocytes retrieved, oocyte maturity rate, mature oocyte yield and fertilization rates are similar to those in conventional (early follicular phase start) protocols. Starting ovarian stimulation in the late follicular or luteal phase did not show any superiority against the other. The presence of corpus luteum or luteal phase progesterone levels did not adversely affect synchronized follicular development, number of mature oocytes retrieved, and/or fertilization rates. SUMMARY: Random-start ovarian stimulation provides a significant advantage by decreasing total time for the IVF cycle, and in emergent settings, ovarian stimulation can be started at a random cycle date for the purpose of fertility preservation without compromising oocyte yield and maturity.