A Case-Control Study of Follicular Fluid Cytokine Profiles in Women with Diminished Ovarian Reserve.

Ovarian reserve is an important determinant of a woman's reproductive potential, and women with diminished ovarian reserve (DOR) often seek in vitro fertilization (IVF). The underlying etiology of DOR is unknown, but follicular fluid cytokine concentrations likely play a role in follicular development and maturation. The present study seeks to investigate the expression of cytokines in follicular fluid (FF) of women with DOR undergoing IVF and explore correlated functional pathways. One hundred ninety-four women undergoing ovarian stimulation were recruited at the time of oocyte retrieval. Women were classified as having DOR if they met one or more of the following criteria: AMH < 1 ng/ml, FSH > 10 mIU/ml, and/or AFC < 10. Controls included women undergoing IVF for male factor, tubal factor due to tubal ligation, or planned oocyte cryopreservation (non-oncologic). The concentrations of 480 cytokines and related growth factors in follicular fluid were determined using a multiplex immunoassay. Fifty-nine cytokines had significantly different concentrations (53 higher and 6 lower) in the DOR relative to the control group after adjusting for age and body mass index (BMI) (false discovery rate; FDR < 0.1). Using the most informative 44 biomarkers as indicated by a random forest (RF) model, an area under the curve (AUC) of 0.78 was obtained. Thus, follicular microenvironment differs between women with DOR and normal ovarian reserve. The differentially expressed cytokines belong to diverse processes that are primarily involved in follicular maturation and ovulation. These changes may play an important role in treatment outcomes in women with DOR.

A View from the past into our collective future: the oncofertility consortium vision statement.

PURPOSE: Today, male and female adult and pediatric cancer patients, individuals transitioning between gender identities, and other individuals facing health extending but fertility limiting treatments can look forward to a fertile future. This is, in part, due to the work of members associated with the Oncofertility Consortium. METHODS: The Oncofertility Consortium is an international, interdisciplinary initiative originally designed to explore the urgent unmet need associated with the reproductive future of cancer survivors. As the strategies for fertility management were invented, developed or applied, the individuals for who the program offered hope, similarly expanded. As a community of practice, Consortium participants share information in an open and rapid manner to addresses the complex health care and quality-of-life issues of cancer, transgender and other patients. To ensure that the organization remains contemporary to the needs of the community, the field designed a fully inclusive mechanism for strategic planning and here present the findings of this process. RESULTS: This interprofessional network of medical specialists, scientists, and scholars in the law, medical ethics, religious studies and other disciplines associated with human interventions, explore the relationships between health, disease, survivorship, treatment, gender and reproductive longevity. CONCLUSION: The goals are to continually integrate the best science in the service of the needs of patients and build a community of care that is ready for the challenges of the field in the future.

Examining Reproductive Health Outcomes in Females Exposed to Polychlorinated Biphenyl and Polybrominated Biphenyl.

In 1973, accidental contamination of Michigan livestock with polybrominated biphenyls (PBBs) led to the establishment of a registry of exposed individuals that have been followed for > 40 years. Besides being exposed to PBBs, this cohort has also been exposed to polychlorinated biphenyls (PCBs), a structurally similar class of environmental pollutants, at levels similar to average US exposure. In this study, we examined the association between current serum PCB and PBB levels and various female reproductive health outcomes to build upon previous work and inconsistencies. Participation in this cross-sectional study required a blood draw and completion of a detailed health questionnaire. Analysis included only female participants who had participated between 2012 and 2015 (N = 254). Multivariate linear and logistic regression models were used to identify associations between serum PCB and PBB levels with each gynecological and infertility outcome. Additionally, a generalized estimating equation (GEE) model was used to evaluate each pregnancy and birth outcome in order to account for multiple pregnancies per woman. We controlled for age, body mass index, and total lipid levels in all analyses. A p-value of <0.05 was used for statistical significance. Among the women who reported ever being pregnant, there was a significant negative association with higher total PCB levels associating with fewer lifetime pregnancies (â€Šß = -0.11, 95% CI = -0.21 to -0.005, p = 0.04). There were no correlations between serum PCB levels and the self-reported gynecological outcomes (pelvic inflammatory disease, endometriosis, polycystic ovarian syndrome, or uterine fibroids). No associations were identified between serum PCB levels and the prevalence of female infertility in women reporting ever having sexual intercourse with a male partner. There were no associations identified between serum PCB levels and pregnancy outcomes (singleton live births or miscarriages) or birth outcomes (preterm birth, birth weight, birth defects, hypertensive disorders of pregnancy, or gestational diabetes). PBB was not associated with any outcome. Further research is needed to determine if and how PCB may reduce pregnancy number.

Endometriosis, endocrine disrupters, and epigenetics: an investigation into the complex interplay in women with polybrominated biphenyl exposure and endometriosis.

PURPOSE: Endocrine disrupting compounds (EDCs) have been shown to affect multiple biologic processes especially steroid-hormone processes. We sought to determine differences in DNA methylation exists between women with and without endometriosis following exposure to polybrominated biphenyl (PBB). METHODS: Cross-sectional study of 305 females in the Michigan PBB Registry. DNA was extracted, and DNA methylation was interrogated using the MethylationEPIC BeadChip (Illumina, San Diego, California). Demographic data was analyzed using Chi-squared and T tests. Linear regressions were performed for each cytosine-guanine dinucleotide (CpG) site, modeling the logit transformation of the ß value as a linear function of the presence of endometriosis. Sensitivity analyses were conducted controlling for estradiol levels and menopausal status. Replication study performed evaluating for any association between CpGs reported in the literature and our findings. RESULTS: In total, 39,877 CpGs nominally associated with endometriosis (p < 0.05) after adjusting for age and cellular heterogeneity, although none remained significant after correction for multiple comparisons (FDR < 0.05). Pathway analysis of these CpGs showed enrichment in 68 biologic pathways involved in various endocrine, immunologic, oncologic, and cell regulation processes as well as embryologic reproductive tract development and function (FoxO, Wnt, and Hedgehog signaling). We identified 42,261 CpG sites in the literature reported to be associated with endometriosis; 2012 of these CpG sites were also significant in our cohort. CONCLUSION: We found 39,877 CpG sites that nominally associated with endometriosis (p < 0.05) after adjusting for age and cellular heterogeneity; however, none remained significant after correction for multiple comparisons (FDR < 0.05).

Uterine structural abnormality and intrauterine device malposition: analysis of ultrasonographic and demographic variables of 517 patients.

BACKGROUND: Intrauterine devices are currently one of the leading forms of reversible contraception in the world. However, in approximately 10-25% of women, intrauterine devices can become malpositioned, leading to consequences including pain, bleeding, as well as possible decreased contraceptive efficacy. OBJECTIVE: We sought to determine whether certain reproductive and uterine characteristics are associated with an increased risk of intrauterine device malposition. We hypothesized that anatomical characteristics such as the presence of any uterine anomalies, particularly congenital anomalies and fibroids that may lead to cavitary distortion, would be associated with a higher incidence of intrauterine device malposition. MATERIALS AND METHODS: We conducted a retrospective case-control study in an academic medical center. All patients presenting for scheduled ultrasound appointments for gynecologic indication between June 2004 and February 2016 were included (1,253 ultrasound reports identified). Of these, 236 demonstrated malpositioned intrauterine devices. With a control group of 281 patients with normal intrauterine device location, a total of 517 patients were included in the study. Transabdominal and transvaginal ultrasounds were performed followed by 3-dimensional rendering (as per our institution's protocol for patients with intrauterine devices) using Voluson 730 and Voluson E8 ultrasound machines. Demographic and reproductive characteristics, indication for ultrasound, intrauterine device, and uterine characteristics were all extrapolated from the electronic medical record. χ2 Tests were performed for categorical variables. Generalized linear models for Poisson distributed variables, and multiple logistic regression were used to ascertain significant independent predictors of IUD malposition. Ninety-five percent confidence intervals and effect sizes were calculated, and P < .05 was considered statistically significant. RESULTS: In this study, we found a cumulative IUD malposition rate of 19%. In patients with malpositioned intrauterine devices, there was increased incidence of retroflexed uterine positions (7.6% vs 1.8%, P = .001), and all uterine anomalies (this includes septate and bicornuate uteri and fibroids, 31.9% vs 23.5%, P = .02) compared with controls. The anterior midline uterine position was more commonly noted in controls (28.5% vs 11%, P < .001). A higher total number of fibroids was noted in the malpositioned group (3.7 vs 1.8, P = .01); however, fibroid size was not statistically significant. In particular, there was an increased incidence of submucosal fibroids in women with malpositioned intrauterine devices (P = .01). Multivariable logistic regression revealed that anterior midline position (odds ratio [OR], 0.33; 95% confidence interval [CI], 0.20-0.57) and absence of uterine anomalies (OR, 0.59; 95% CI, 0.38-0.93) were factors associated with a lower risk of IUD malposition; whereas vaginal bleeding (OR, 2.25; 95% CI, 1.38-3.67), pain (OR, 2.85; 95% CI, 1.84-4.44), or missing IUD strings at time of presentation (OR, 3.58; 95% CI, 1.88-6.82) were associated with an increased risk of malposition. CONCLUSION: Retroflexed uterine positions and all uterine malformations are associated with higher incidence of malpositioned intrauterine devices. Presence of increased number of fibroids and specifically submucosal fibroids showed a positive association with intrauterine device malposition, as did symptoms of bleeding, pain, and missing IUD strings at time of presentation. These findings pertain to women presenting for gynecologic ultrasound evaluation and may not be generalizable to all women with IUDs.

Safe and cost-effective ultrasound guided removal of retained intrauterine device: our experience.

OBJECTIVES: To evaluate the efficacy and difference in cost of ultrasound guided removal of retained intrauterine device (IUD). STUDY DESIGN: A total of 23 women underwent ultrasound-guided retrieval of retained IUDs between January 2013 and March 2014. Transvaginal ultrasound was performed in all cases to assess the localization of the IUD. Under transabdominal ultrasound guidance, either the crochet type IUD hook (Gyneas, Goussainville, France) or Alligator forceps were used to grasp the IUD and remove it from the uterine cavity. The costs of the ultrasound guided procedure and the hysteroscopic removal of the IUD were compared. RESULTS: Twenty-three patients who failed IUD removal in the clinic were referred to our department for ultrasound-guided removal. All patients had an IUD present in the uterine cavity. Eleven patients had Paragard IUDs (48%), eight had Mirena IUDs (35%), three had Lippes loop (13%), and one had a ring IUD (4%). The patients' ages ranged from 20-56 years. The IUDs were in place for 8 months to 23 years. Of the 23 patients with retained IUDs, 19 were successfully removed (83%), and 4 underwent hysteroscopic removal of IUD. The IUD removal cost in the operating room on average was $3562 US dollars and the cost of ultrasound-guided removal was $465 US dollars. CONCLUSIONS: Retained intrauterine devices with or without strings can often be safely removed in an office-based setting under ultrasound guidance at less cost than in the operating room, even in cases with embedded IUDs. IMPLICATIONS: Our experience leads us to propose in-office IUD removal under ultrasound guidance as the first line in management of retained IUDs after failed removal by conventional practices. Ultrasound provides numerous advantages including direct visualization in a less invasive manner than hysteroscopy. Three-dimensional imaging can also be used for enhanced perspective.

GnRH agonist reduces estrogen receptor dimerization in GT1-7 cells: evidence for cross-talk between membrane-initiated estrogen and GnRH signaling.

17ß-estradiol (E2), a key participant on the initiation of the LH surge, exerts both positive and negative feedback on GnRH neurons. We sought to investigate potential interactions between estrogen receptors alpha (ERα) and beta (ERß) and gonadotropin releasing hormone receptor (GnRH-R) in GT1-7 cells. Radioligand binding studies demonstrated a significant decrease in saturation E2 binding in cells treated with GnRH agonist. Conversely, there was a significant reduction in GnRH binding in GT1-7 cells treated with E2. In BRET(1) experiments, ERα-ERα dimerization was suppressed in GT1-7 cells treated with GnRH agonist (p < 0.05). There was no evidence of direct interaction between ERs and GnRH-R. This study provides the first evidence of reduced ERα homodimerization by GnRH agonist. Collectively, these findings demonstrate significant cross-talk between membrane-initiated GnRH and E2 signaling in GT1-7 cells.