Psychological distress, vaccine, and booster acceptance in women considering or undergoing fertility treatments during the Omicron surge of the COVID-19 pandemic.

OBJECTIVE: Follow-up study to evaluate perceptions of COVID-19 vaccination and booster with psychological distress during the COVID-19 pandemic and Omicron surge in women considering or undergoing fertility treatment. MATERIALS AND METHODS: Cross-sectional anonymous survey (N = 2558) from a single academic fertility center. Five hundred forty patients completed the survey (response rate = 21.1%). Participants were randomized 1:1 to a one-page evidence-based graphic with information and benefits regarding COVID-19 vaccination. Mental health and vaccine hesitancy were assessed via the Patient Health Questionnaire Depression (PHQ-8), the Generalized Anxiety Disorder (GAD-7) scales, and the Medical Mistrust Index (MMI). RESULTS: Majority of participants were nulliparous, fully vaccinated with a booster dose, with > 1 year of infertility and mild to moderate distress. Patients with vaccine hesitancy had higher medical mistrust scores (r = .21,  p < .001). Higher MMI scores were not associated with vaccination during pregnancy. Participants that had higher PHQ-8 and GAD-7 scores were more likely to believe the omicron variant would cause delay in fertility treatments, would have impact on fertility outcome, and were more likely exhibiting medical system distrust (p < .001). Participants who received educational material were more likely to know pregnant women with COVID-19 had increased risk of death, stillbirth, and preterm birth (p < .05). CONCLUSION: The majority of women in this study were vaccinated and had received their booster dose but also with clinically significant levels of depression. Patients with higher levels of distress and greatest medical mistrust demonstrated a concern that the Omicron variant would delay treatment, lead to suboptimal fertility outcomes, and COVID-19 vaccination would impact risk of miscarriages.

Follicular fluid aids cell adhesion, spreading in an age independent manner and shows an age-dependent effect on DNA damage in fallopian tube epithelial cells.

Ovarian cancer (OC) is deadly, and likely arises from the fallopian tube epithelium (FTE). Despite the association of OC with ovulation, OC typically presents in post-menopausal women who are no longer ovulating. The goal of this study was to understand how ovulation and aging interact to impact OC progression from the FTE. Follicular fluid released during ovulation induces DNA damage in the FTE, however, the role of aging on FTE exposure to follicular fluid is unexplored. Follicular fluid samples were collected from 14 women and its effects on FTE cells was assessed. Follicular fluid caused DNA damage and lipid oxidation in an age-dependent manner, but instead induced cell proliferation in a dose-dependent manner, independent of age in FTE cells. Follicular fluid regardless of age disrupted FTE spheroid formation and stimulated attachment and growth on ultra-low attachment plates. Proteomics analysis of the adhesion proteins in the follicular fluid samples identified vitronectin, a glycoprotein responsible for FTE cell attachment and spreading.

Do Fertility Preservation Outcomes in Patients Diagnosed with Lymphoma Differ Based on Cancer Stage?

Purpose: This study aims to investigate whether oocyte stimulation outcomes in fertility preservation (FP) vary in patients with different stages of lymphoma. Methods: This is a retrospective cohort study conducted at Northwestern Memorial Hospital (NMH). Between 2006 and 2017, 89 patients were identified with a diagnosis of lymphoma who contacted the FP navigator at NMH. Anti-müllerian hormone (AMH) levels and FP ovarian stimulation outcomes were collected for analysis. The data were analyzed using chi-squared and analysis of variance tests. A regression analysis was also done to adjust for potential confounding variables. Results: Of the 89 patients who contacted the FP navigator, there were 12 patients (13.5%) with stage 1 lymphoma, 43 patients (48.3%) with stage 2, 13 patients (14.6%) with stage 3, 13 patients (14.6%) with stage 4, and 8 patients (9.0%) where staging information was not available. Forty-five of the patients proceeded with ovarian stimulation before initiating cancer treatment. Patients who underwent ovarian stimulation had a mean AMH level of 2.62 and median peak estradiol levels of 1772.0 pg/mL. Median oocytes retrieved was 16.77, mature oocytes were 11.00 and median oocytes frozen after completing FP was 8.00. These measures were also stratified by stage of lymphoma. Conclusion: We found no significant difference in number of retrieved, mature or vitrified oocytes between different cancer stages. There was also no difference in AMH levels in the different cancer stage groups. This suggests that even in higher stages of lymphoma, many patients respond to ovarian stimulation techniques and have a successful stimulation cycle.

Human follicular fluid elicits select dose- and age-dependent effects on mouse oocytes and cumulus-oocyte complexes in a heterologous in vitro maturation assay.

Follicular fluid (FF) is a primary microenvironment of the oocyte within an antral follicle. Although several studies have defined the composition of human FF in normal physiology and determined how it is altered in disease states, the direct impacts of human FF on the oocyte are not well understood. The difficulty of obtaining suitable numbers of human oocytes for research makes addressing such a question challenging. Therefore, we used a heterologous model in which we cultured mouse oocytes in human FF. To determine whether FF has dose-dependent effects on gamete quality, we performed in vitro maturation of denuded oocytes from reproductively young mice (6-12 weeks) in 10%, 50%, or 100% FF from participants of mid-reproductive age (32-36 years). FF impacted meiotic competence in a dose-dependent manner, with concentrations >10% inhibiting meiotic progression and resulting in spindle and chromosome alignment defects. We previously demonstrated that human FF acquires a fibro-inflammatory cytokine signature with age. Thus, to determine whether exposure to an aging FF microenvironment contributes to the age-dependent decrease in gamete quality, we matured denuded oocytes and cumulus-oocyte complexes (COCs) in FF from reproductively young (28-30 years) and old (40-42 years) participants. FF decreased meiotic progression of COCs, but not oocytes, from reproductively young and old (9-12 months) mice in an age-dependent manner. Moreover, FF had modest age-dependent impacts on mitochondrial aggregation in denuded oocytes and cumulus layer expansion dynamics in COCs, which may influence fertilization or early embryo development. Overall, these findings demonstrate that acute human FF exposure can impact select markers of mouse oocyte quality in both dose- and age-dependent manners.

A new tissue-agnostic microfluidic device to model physiology and disease: the lattice platform.

To accurately phenocopy human biology in vitro, researchers have been reducing their dependence on standard, static two-dimensional (2D) cultures and instead are moving towards three-dimensional (3D) and/or multicellular culture techniques. While these culture innovations are becoming more commonplace, there is a growing body of research that illustrates the benefits and even necessity of recapitulating the dynamic flow of nutrients, gas, waste exchange and tissue interactions that occur in vivo. However, cost and engineering complexity are two main factors that hinder the adoption of these technologies and incorporation into standard laboratory workflows. We developed LATTICE, a plug-and-play microfluidic platform able to house up to eight large tissue or organ models that can be cultured individually or in an interconnected fashion. The functionality of the platform to model both healthy and diseased tissue states was demonstrated using 3D cultures of reproductive tissues including murine ovarian tissues and human fallopian tube explants (hFTE). When exogenously exposed to pathological doses of gonadotropins and androgens to mimic the endocrinology of polycystic ovarian syndrome (PCOS), subsequent ovarian follicle development, hormone production and ovulation copied key features of this endocrinopathy. Further, hFTE cilia beating decreased significantly only when experiencing continuous media exchanges. We were then able to endogenously recreate this phenotype on the platform by dynamically co-culturing the PCOS ovary and hFTE. LATTICE was designed to be customizable with flexibility in 3D culture formats and can serve as a powerful automated tool to enable the study of tissue and cellular dynamics in health and disease in all fields of research.

Cumulus expansion is impaired with advanced reproductive age due to loss of matrix integrity and reduced hyaluronan.

Reproductive aging is associated with ovulatory defects. Age-related ovarian fibrosis partially contributes to this phenotype as short-term treatment with anti-fibrotic compounds improves ovulation in reproductively old mice. However, age-dependent changes that are intrinsic to the follicle may also be relevant. In this study, we used a mouse model to demonstrate that reproductive aging is associated with impaired cumulus expansion which is accompanied by altered morphokinetic behavior of cumulus cells as assessed by time-lapse microscopy. The extracellular matrix integrity of expanded cumulus-oocyte complexes is compromised with advanced age as evidenced by increased penetration of fluorescent nanoparticles in a particle exclusion assay and larger open spaces on scanning electron microscopy. Reduced hyaluronan (HA) levels, decreased expression of genes encoding HA-associated proteins (e.g., Ptx3 and Tnfaip6), and increased expression of inflammatory genes and matrix metalloproteinases underlie this loss of matrix integrity. Importantly, HA levels are decreased with age in follicular fluid of women, indicative of conserved reproductive aging mechanisms. These findings provide novel mechanistic insights into how defects in cumulus expansion contribute to age-related infertility and may serve as a target to extend reproductive longevity.

Chronic endometritis: screening, treatment, and pregnancy outcomes in an academic fertility center.

PURPOSE: To identify the prevalence of chronic endometritis (CE), compare the efficacy of antibiotic regimens for CE, and examine pregnancy outcomes after treatment for CE among patients in an academic fertility clinic. METHODS: In this retrospective cohort study, data from patients who underwent endometrial sampling (ES) for CE evaluation at a single academic institution from 2014 to 2020 were collected and analyzed. Rates of CE were compared by indication for ES including recurrent pregnancy loss (RPL), implantation failure (IF), and recent first-trimester pregnancy loss. Treatment and pregnancy outcomes were also evaluated. RESULTS: Six hundred fifty-three individuals underwent ES to evaluate for CE. The overall prevalence of CE was 28.5%; when stratified by indication, the prevalence of CE was 66.2% for recent first-trimester loss, 27.9% for RPL, and 13.1% for IF (p < .001). Of those with CE, 91.9% received antibiotics, most commonly doxycycline (76.0%). CE clearance was not significantly different when doxycycline was compared to all other regimens (71.3% vs. 58.8%, p = .17), and 68.5% of patients cleared CE after one course of antibiotics. Following two antibiotic courses, CE was cleared in 88.3% of patients. Live birth rates (LBRs) were higher for those with cleared CE compared to patients with untreated CE (34.1% vs. 5.6%, p = .014) and similar for those with cleared CE versus those without CE (34.1% vs. 29.3%, p = .297). CONCLUSION: CE is common among patients with infertility, particularly those with a recent first-trimester loss. Treatment and clearance of CE were associated with higher LBRs; however, persistent CE was common despite treatment with antibiotics.

Fertility assessment and treatment in adolescent and young adult cancer survivors.

In the survivorship setting, adolescent and young adult (AYA) cancer survivors frequently demonstrate little knowledge of infertility risk, are unclear regarding their fertility status, and may under- or overestimate their treatment-related risk for infertility. In female AYA survivors, ovarian function usually parallels fertility, and can be assessed with serum hormone levels and ultrasonography. Posttreatment fertility preservation may be appropriate for survivors at risk for primary ovarian insufficiency. In male AYA survivors, fertility and gonadal function are not always equally affected, and can be assessed with a semen analysis and serum hormones, respectively. As reproductive health issues are commonly cited as an important concern by survivors of AYA cancer, multidisciplinary care teams including oncology, endocrinology, psychology, and reproductive medicine are advocated, with the aim of optimal provision of fertility advice and care for AYA cancer survivors.

Associations of childhood allergies with parental reproductive and allergy history.

PURPOSE: There has been a noted parallel rise in both the use of Assisted Reproductive Technology (ART) to conceive and childhood allergies in the last few decades. The purpose of this study was to investigate the possible association between reproductive and allergy history in parents and allergies in their children. METHODS: This exploratory study used a cross-sectional study design and web-based survey to collect anonymous data on demographics, allergy, and health history from parents and about each of their children under 18 years of age. Children were stratified into two groups by allergy status (yes/no), and associations between each variable and the odds of allergies were tested using univariable and multivariable mixed logistic regression models. RESULTS: Of the 563 children in the study, 237 were reported to have allergies whereas 326 did not. Age, residential community, household income, mode of conception, paternal age at conception, biological parental allergy status, and history of asthma and eczema were significantly associated with allergies in univariable analysis. Multivariable analysis revealed household income ($50 k to $99 k vs ≥ $200 k adj OR = 2.72, 95% CI 1.11, 6.65), biological parental allergies (mother-adj OR 2.74, 95% CI 1.59, 4.72, father-adj OR 2.06, 95% CI 1.24, 3.41) and each additional year of age of children (adj OR 1.17, CI 1.10, 1.24) were significantly associated with odds of allergies in children. CONCLUSION: Although the exploratory nature of this convenience, snowballing sample limited the generalizability of the findings, initial observations warrant further investigation and validation in a larger more diverse population.

Natural Cycle Frozen Embryo Transfer: Evaluating Optimal Protocols for Preparation and Timing.

Background: While natural cycle frozen embryo transfer (NC-FET) is becoming increasingly common, significant practice variation exists in the use of ovulation induction medications, administration of ovulation trigger, and timing of embryo transfer without consensus as to the optimal protocol. Aims: The objective of this study is to evaluate the association of key aspects of the NC-FET protocol with implantation, pregnancy and live birth. Settings and Design: This was a retrospective cohort study of blastocyst stage NC-FET cycles from October 2019 to July 2021 at a single academic fertility centre. Materials and Methods: Protocols varied between cycles across three key parameters which were evaluated as primary predictors of cycle outcomes: (1) use of letrozole for mild ovarian stimulation/ovulation induction, (2) administration of exogenous ovulation trigger versus spontaneous luteinising hormone surge and (3) transfer timing based on ovulation trigger versus sequential progesterone monitoring. Primary outcomes included implantation rate, clinical pregnancy and ongoing pregnancy. Statistical Analysis Used: Generalised estimating equations were fitted to obtain adjusted odds ratios or rate ratios as appropriate with 95% confidence intervals for each outcome across the three primary predictors. Results: A total of 183 cycles from 170 unique patients were eligible for inclusion. The average implantation rate was 0.58, resulting in an overall clinical pregnancy and ongoing pregnancy rate of 59.0% and 51.4%, respectively. After adjusting for age at embryo freeze and history of a failed embryo transfer, there were no significant associations between any predictor and implantation rate, clinical pregnancy, ongoing pregnancy, or live birth. Conclusion: In NC-FET, a variety of preparation and timing protocols may lead to comparable cycle outcomes, potentially allowing for flexibility on the basis of patient and physician preference. These findings warrant validation in a larger, randomised trial.

Early ß-hCG levels predict live birth after single embryo transfer.

PURPOSE: Specific serum beta human chorionic gonadotropin (ß-hCG) parameters that can predict live birth after an embryo transfer have yet to be defined. METHODS: We performed a retrospective cohort study of 1,028 patients with a detectable ß-hCG who underwent a single embryo transfer between 2002 and 2019 at a large academic center. Two ß-hCG parameters were examined in relation to live birth: 1) "doubling" defined as ß-hCG doubling over 48 h and 2) "reaching 100" defined as a ß-hCG ≥ 100 mIU/mL by 15 days after oocyte retrieval (AOR). RESULTS: One thousand three hundred forty cycles involving a single embryo were analyzed. Two thirds were frozen embryos and 86% were blastocyst transfers. Preimplantation genetic testing was performed in almost 30% of cycles. When ß-hCG levels "doubled," a live birth occurred in 80.7% of cycles and when ß-hCG levels "reached 100" by 15 days AOR, live birth occurred in 81.6% of cycles. When ß-hCG levels both doubled and reached 100 by 15 days, AOR 85.4% cycles resulted in live birth. A multiple logistic regression model to control for patient and cycle level factors revealed a live birth odds ratio (OR) of 8.0 (95% CI 5.7-11.1) when ß-hCG "doubled" and an OR of 21.2 (95% CI 14.3-31.5) when ß-hCG "reached 100." When both these latter parameters were met, the OR was 12.5 (95% CI 8.9-17.8). CONCLUSION: ß-hCG parameters of "doubling" and "reaching 100" by 15 days AOR are robust predictors of live birth and can aid in patient counseling regarding pregnancy outcomes soon after single embryo transfer.

Retained pregnancy tissue after miscarriage is associated with high rate of chronic endometritis.

The objective of this study was to evaluate prevalence of chronic endometritis in a cohort of patients with retained pregnancy tissue (RPT) following miscarriage, with and without a history of recurrent pregnancy loss (RPL). In a cohort of our single academic fertility centre, we evaluated women with unexplained RPL (two or more losses) without evidence of RPT and women undergoing hysteroscopic resection of RPT following miscarriage. Endometrial samples underwent staining with H and E and CD138. A pathologist blinded to patient history recorded the number of plasma cells per 10 high power fields (HPF) and the presence or absence of endometrial stromal changes. Our main outcome measure was to measure the prevalence of chronic endometritis. Endometrial samples from 50 women with RPT following miscarriage and 50 women with unexplained RPL without evidence of RPT were reviewed. The prevalence of chronic endometritis was significantly higher in the RPT cohort (62% versus 30%). A multivariable regression demonstrated significantly higher odds of chronic endometritis in the RPT cohort, aOR 7.3 (95% CI 2.1, 25.5). We conclude that women with RPT following pregnancy loss have a high rate of chronic endometritis, suggesting that RPT is a risk factor for this disorder. Impact StatementWhat is already known on this subject? Known risk factors for chronic endometritis include a history of pelvic inflammatory disease, intrauterine polyps and fibroids. The aetiology for increased chronic endometritis among women with RPL is unknown.What do the results of this study add? The prevalence of chronic endometritis is significantly higher among women with retained pregnancy tissue (RPT) following miscarriage compared to women with RPL. These data presented suggest that RPT is associated with chronic endometritis among women with a history of miscarriage.What are the implications of these findings for clinical practice and/or further research? We suggest a pathologic evaluation for chronic endometritis be performed on all patients who undergo hysteroscopic resection of RPT following miscarriage. Our findings also suggest that a uterine cavity evaluation with hysteroscopy to evaluate for RPT may be reasonable in women with a history of miscarriage who are found to have chronic endometritis on endometrial biopsy. Further research is needed to determine if resection of retained tissue is sufficient to treat RPOC associated chronic endometritis, or if additional antibiotic treatment is necessary.

The parent trap: desire for multifetal gestation among patients treated for infertility.

OBJECTIVE: To evaluate predictors for patient preference regarding multifetal or singleton gestation among women presenting for infertility care. DESIGN: Cross-sectional study. SETTING: Academic university hospital-based infertility clinic. PATIENT(S): Five hundred thirty-nine female patients with infertility who presented for their initial visit. MAIN OUTCOME MEASURE(S): Demographic characteristics, infertility history, insurance coverage, desired treatment outcome, acceptability of multifetal reduction, and knowledge of the risks of multifetal pregnancies were assessed using a previously published 41-question survey. Univariate analysis was performed to assess patient factors associated with the desire for multiple births. Independent factors associated with this desire were subsequently assessed by multivariate logistic regression analysis. RESULT(S): Nearly a third of women preferred multiples over a singleton gestation. Nulliparity, lower annual household income, older maternal age, marital status, larger ideal family size, openness to multifetal reduction, and lack of knowledge of the maternal/fetal risks of twin pregnancies were associated with pregnancy desire. Older age (OR (95% CI) 1.66 (1.20-2.29)), nulliparity (OR (95% CI) 0.34 (0.20-0.58)), larger ideal family size (OR (95% CI) 2.34 (1.73-3.14)), and lesser knowledge of multifetal pregnancy risk (OR (95% CI) 0.67 (0.55-0.83)) were independently associated with desire. CONCLUSION(S): A large number of patients undergoing fertility treatment desire multifetal gestation. Although a lack of understanding of the risks associated with higher order pregnancies contributes to this desire, additional individual specific variables also contribute to this trend. Efforts to reduce the incidence of multiples should focus not only on patient education on comparative risks of multiples vs singleton pregnancies but also account for individual specific reservations.

Disposition preferences in oocyte preservation patients.

PURPOSE: To characterize the frozen oocyte disposition preferences of patients undergoing medical and planned fertility preservation. METHODS: All oocyte cryopreservation (OC) patients were identified between 2015 and 2018. Demographic information and fertility preservation (FP) indication (medical or planned) were identified for each patient. Oocyte disposition options included disposal, donation to research, or donation to a specified third party, which was decided at the time of initial consent and made available in the electronic medical record. The primary outcome was the disposition selection. Secondary outcomes included differences in demographic variables and disposition selections between medical and planned FP patients using chi-squared analysis. RESULTS: A total of 336 OC patients with a documented oocyte disposition preference were identified in the study timeframe. Patients were on average 34.5 years old (SD = 5.1) and were predominantly White (70.2%), nulliparous (83.0%), with a BMI of 24.7 (SD = 5.4). A total of 101 patients underwent OC for medical FP and 235 for planned FP. In both groups, the most commonly selected disposition option was donation to research (50% planned, 52% medical), followed by donation to a specified third party (30% planned, 30% medical), and finally disposal of oocytes (20% planned, 18% medical). There were no significant differences in disposition selection between each group. When comparing patient variables between groups, medical FP patients were more likely to be under the age of 35 and were less likely to be nulliparous (p < .001). CONCLUSION: This study shows that oocyte disposition choices are similar in patients undergoing OC for medical and planned indications. As donation to research was the most commonly selected option in both groups, it is time to start thinking of streamlining ways to utilize this potential research material in the future.

Body mass index, not race, may be associated with an alteration in early embryo morphokinetics during in vitro fertilization.

OBJECTIVE: To assess the relationship between maternal body mass index (BMI) and embryo morphokinetics on time-lapse microscopy (TLM). DESIGN: Retrospective cohort study. METHODS: All IVF cycles between June 2015 and April 2017 were reviewed. Female BMI prior to egg retrieval was collected through chart review. BMI (kg/m2) classification included underweight (< 18.5), normal weight (18.5-25), overweight (25-30), and obese (≥ 30). Embryos' morphokinetic parameters were assessed with TLM and included time to syngamy, 2-cell, 3-cell, 4-cell, and 8-cell. A generalized linear mixed model was used to control for potential confounders and multiple embryos resulting from a single IVF cycle. RESULTS: A total of 2150 embryos from 589 IVF cycles were reviewed and included in the analysis. Classification based on BMI was as follows: underweight (N = 56), normal weight (N = 1252), overweight (N = 502), and obese (N = 340). After adjusting for race and use of intracytoplasmic sperm injection, the mean time to the 8-cell stage in the underweight group was 4.3 (95% CI: - 8.31, - 0.21) h less than in the normal weight group (P = 0.025) and 4.6 (95% CI: - 8.8, - 0.21) h less than in the obese group (p = 0.022). No significant difference was noted between race and TLM after controlling for possible confounders. CONCLUSIONS: Embryos from underweight women were demonstrated to have a faster time to the 8-cell stage than normal weight or obese women. No significant difference was noted for race. This study demonstrates that weight can be a factor contributing to embryo development as observed with TLM.

Reproductive endocrinologists' knowledge and attitudes in the identification of intimate partner violence.

OBJECTIVE: To assess reproductive endocrinologists' attitudes, beliefs, knowledge, and experiences with intimate partner violence (IPV). DESIGN: Cross-sectional survey of US reproductive endocrinologists. SETTING: The survey was disseminated via both direct mail and e-mail to a voluntary, semirandomized US national sample of reproductive endocrinologists. We randomly selected a maximum of six clinics per state using the Centers for Disease Control and Prevention Fertility Clinic Success Rates Report. PATIENT(S): None. INTERVENTION(S): None. MAIN OUTCOME MEASURES: Clinician perceptions and knowledge regarding IPV and its relevance to the infertility setting. RESULTS: A total of 95 reproductive endocrinology and infertility physicians practicing in either academic or private clinics in the United States completed the survey with an overall response rate of 46% (95/200). General knowledge of IPV was good among respondents. Intimate partner violence assessment was very relevant among 39% (37/95) of respondents and possibly relevant among 56% (53/95) of respondents. A history of IPV awareness training was associated with a decreased frequency of reported barriers, including fewer perceived time constraints, decreased knowledge regarding IPV community resources, and less discomfort asking about IPV. Most respondents estimated the prevalence of IPV in their practice to be rare (≤1%). However, 33% (31/95) reported identifying between one and five active victims of IPV over the prior year, and 63% (60/95) reported identifying a victim of IPV throughout their careers. Only 17% (16/95) of respondents were certain that their clinic had guidelines for detection or management of IPV. CONCLUSION: Reproductive endocrinology and infertility physicians would benefit from education and training in IPV to enable them to better identify and assist patients who are victims of IPV.

Fibroinflammatory Signatures Increase with Age in the Human Ovary and Follicular Fluid.

The female reproductive system ages before any other organ system in the body. This phenomenon can have tangible clinical implications leading to infertility, miscarriages, birth defects and systemic deterioration due to estrogen loss. "Fibroinflammation" is a hallmark of aging tissues; there is an increase in inflammatory cytokines and fibrotic tissue in the aging ovarian stroma. We systematically evaluated immunomodulatory factors in human follicular fluid, which, like the stroma, is a critical ovarian microenvironment directly influencing the oocyte. Using a cytokine antibody array, we identified a unique fibroinflammatory cytokine signature in follicular fluid across an aging series of women (27.7-44.8 years). This signature (IL-3, IL-7, IL-15, TGFß1, TGFß3 and MIP-1) increased with chronologic age, was inversely correlated to anti-Müllerian hormone (AMH) levels, and was independent of body mass index (BMI). We focused on one specific protein, TGFß3, for further validation. By investigating this cytokine in human cumulus cells and ovarian tissue, we found that the age-dependent increase in TGFß3 expression was unique to the ovarian stroma but not other ovarian sub-compartments. This study broadens our understanding of inflammaging in the female reproductive system and provides a defined fibroinflammatory aging signature in follicular fluid and molecular targets in the ovary with potential clinical utility.

Redefining chronic endometritis: the importance of endometrial stromal changes.

OBJECTIVE: To develop diagnostic criteria for chronic endometritis and compare the prevalence of chronic endometritis between women with recurrent pregnancy loss (RPL) and controls. DESIGN: Cohort study. SETTING: Single academic fertility center. PATIENTS: Women with unexplained RPL (two or more pregnancy losses) and prospectively recruited controls without a history of RPL or infertility. INTERVENTIONS: Endometrial samples were stained with hematoxylin and eosin and CD138. A pathologist blinded to patient history recorded the number of plasma cells per 10 high-power fields (HPFs). In addition, the presence or absence of endometrial stromal changes was documented. MAIN OUTCOME MEASURE: Prevalence of chronic endometritis. RESULTS: Endometrial samples from 50 women with unexplained RPL and 26 controls were evaluated. When chronic endometritis was defined as the presence of one or more plasma cells per 10 HPFs, 31% of controls and 56% of women with RPL met the criterion. When both endometrial stromal changes and plasma cells were required for a diagnosis of chronic endometritis, no controls and 30% of women with RPL met the criteria. CONCLUSIONS: Although rare plasma cells were found in biopsy samples from controls, the presence of both plasma cells and endometrial stromal changes was limited to the RPL cohort. We propose that chronic endometritis be defined as the presence of one or more plasma cells per 10 HPFs in the setting of endometrial stromal changes. With the use of these strict diagnostic criteria, women with RPL have a significantly higher rate of chronic endometritis, supporting an association between chronic endometritis and RPL.

Management and Recommendations for Future Pregnancy in Patients with Early-Stage Endometrial Cancer: A Survey of Gynecologic Oncologists and Reproductive Endocrinology and Infertility Specialists.

Purpose: To determine how young patients with early-stage endometrial cancer are counseled regarding fertility preserving therapy and pregnancy options by gynecologic oncology and reproductive endocrinology and infertility (REI) providers. Methods: Anonymous online survey of Society of Gynecology Oncology (SGO) and the Society for Reproductive Endocrinology and Infertility (SREI) members; data were analyzed using chi-square and t-tests. Results: Twelve percent (169/1433) of SGO and 6.5% (60/927) of SREI members responded to the survey request. Most providers manage fewer than 10 fertility preservation patients annually. All gynecologic oncologists offer conservative management to patients with grade 1 endometrial cancer without evidence of invasion, and 40% would offer it to patients with grade 2 or <50% invasion. Magnetic resonance imaging was the most common method of assessing invasion, and the progesterone intrauterine device was the preferred first-line treatment. Two-thirds of providers would recommend hysterectomy if no endometrial response was noted by 12 months, two-thirds would continue conservative management for more than a year if a partial response was noted, and 70% would recommend hysterectomy after a patient completes childbearing. Comparatively, 60% of REI providers would recommend hysterectomy after childbearing. More gynecologic oncologists than REI providers recommend attempting spontaneous conception and for longer durations before initiating fertility treatments. Conclusion: Heterogeneous management styles exist among and between gynecologic oncology and REI providers for patients with early-stage endometrial cancer desiring future pregnancy. Improved guidelines are needed regarding treatment and monitoring surrounding trials of conception and pregnancy.