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.

Sex-specific DNA methylation differences in people exposed to polybrominated biphenyl.

Aim: Michigan residents were exposed to polybrominated biphenyls (PBBs) when it was accidentally added to the food supply. Highly exposed individuals report sex-specific health problems, but the underlying biological mechanism behind these different health risks is not known. Materials and methods: DNA methylation in blood from 381 women and 277 men with PBB exposure was analyzed with the MethylationEPIC BeadChip. Results: 675 CpGs were associated with PBBs levels in males, while only 17 CpGs were associated in females (false discovery rate <0.05). No CpGs were associated in both sexes. These CpGs were enriched in different functional regions and transcription factor binding sites in each sex. Conclusion: Exposure to PBBs may have sex-specific effects on the epigenome that may underlie sex-specific adverse health outcomes.

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).

Reasons that should prompt a referral to a reproductive urologist: guidelines for the gynecologist and reproductive endocrinologist.

Obstetricians and gynecologists, and in particular reproductive endocrinologists (REIs), are typically the gatekeepers and first-line providers for couples initially seeking an infertility evaluation. A timely referral to a reproductive urologist may improve pregnancy outcomes in certain clinical scenarios. This review examines the evidence behind circumstances requiring referral and delivers practice-based recommendations on commonly encountered scenarios in the clinic. Scenarios that should prompt referral to a reproductive urologist include semen analysis (SA) abnormalities (e.g., asthenozoospermia, azoospermia, globozoospermia, leukocytospermia, necrozoospermia, oligospermia), recurrent intrauterine insemination (IUI)/in vitro fertilization (IVF) failure, and idiopathic recurrent pregnancy loss (RPL). Conversely, deferment is appropriate in the cases of isolated teratozoospermia and subclinical varicocele. Men with infertility are also at higher risk for other comorbid conditions and should have at least a baseline evaluation by a primary care physician. Coordination of care between a REI and reproductive urologist is critical in several clinical scenarios and expedient referral can improve reproductive outcomes.

Thyroid hormone levels associate with exposure to polychlorinated biphenyls and polybrominated biphenyls in adults exposed as children.

BACKGROUND: Michigan residents were directly exposed to endocrine-disrupting compounds, polybrominated biphenyl (PBB) and polychlorinated biphenyl (PCB). A growing body of evidence suggests that exposure to certain endocrine-disrupting compounds may affect thyroid function, especially in people exposed as children, but there are conflicting observations. In this study, we extend previous work by examining age of exposure's effect on the relationship between PBB exposure and thyroid function in a large group of individuals exposed to PBB. METHODS: Linear regression models were used to test the association between serum measures of thyroid function (total thyroxine (T4), total triiodothyronine (T3), free T4, free T3, thyroid stimulating hormone (TSH), and free T3: free T4 ratio) and serum PBB and PCB levels in a cross-sectional analysis of 715 participants in the Michigan PBB Registry. RESULTS: Higher PBB levels were associated with many thyroid hormones measures, including higher free T3 (p = 0.002), lower free T4 (p = 0.01), and higher free T3: free T4 ratio (p = 0.0001). Higher PCB levels were associated with higher free T4 (p = 0.0002), and higher free T3: free T4 ratio (p = 0.002). Importantly, the association between PBB and thyroid hormones was dependent on age at exposure. Among people exposed before age 16 (N = 446), higher PBB exposure was associated with higher total T3 (p = 0.01) and free T3 (p = 0.0003), lower free T4 (p = 0.04), and higher free T3: free T4 ratio (p = 0.0001). No significant associations were found among participants who were exposed after age 16. No significant associations were found between TSH and PBB or PCB in any of the analyses conducted. CONCLUSIONS: This suggests that both PBB and PCB are associated with thyroid function, particularly among those who were exposed as children or prenatally.

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.

Assisted reproductive technology with donor sperm: national trends and perinatal outcomes.

BACKGROUND: Information regarding the use of donor sperm in assisted reproductive technology, as well as subsequent treatment and perinatal outcomes, remains limited. Outcome data would aid patient counseling and clinical decision making. OBJECTIVES: The objectives of the study were to report national trends in donor sperm utilization and live birth rates of donor sperm-assisted reproductive technology cycles in the United States and to compare assisted reproductive technology treatment and perinatal outcomes between cycles using donor and nondonor sperm. We hypothesize these outcomes to be comparable between donor and nondonor sperm cycles. STUDY DESIGN: This was a retrospective cohort study using data from all US fertility centers reporting to the Centers for Disease Control and Prevention's National Assisted Reproductive Technology Surveillance System, accounting for ∼98% of assisted reproductive technology cycles (definition excludes intrauterine insemination). The number and percentage of assisted reproductive technology cycles using donor sperm and rates of pregnancy, live birth, preterm birth (<37 weeks), and low birthweight (<2500 g) were the primary outcomes measured. Treatments assessed include use of donor vs nondonor sperm. The trends analysis included all banking and fresh assisted reproductive technology cycles using donor and autologous oocytes performed between 1996 and 2014 (n = 1,710,034). The outcomes analysis was restricted to include only fresh autologous cycles performed between 2010 and 2014 (n = 437,569) to focus on cycles with a potential outcome and cycles reflective of current practice, thereby improving the clinical relevance. Cycles canceled prior to retrieval were excluded. Statistical analysis included linear regression to explore polynomial trends and log-binomial regression to estimate relative risk for outcomes among cycles using donor and nondonor sperm. RESULTS: Of all banking and fresh donor and autologous oocyte assisted reproductive technology cycles performed between 1996 and 2014, 74,892 (4.4%) used donor sperm. In 2014, 7351 assisted reproductive technology cycles using donor sperm were performed, as compared with 1763 in 1996 (6.2% vs 3.8% of all cycles). Among all autologous oocyte cycles performed between 2010 and 2014, the live birth rate was lower for donor sperm (27.9%) than nondonor sperm cycles (32.5%); however, after adjustment for maternal age, donor sperm use was associated with an increased likelihood of live birth (adjusted relative risk, 1.06, 95% confidence interval, 1.01-1.10). Per transfer, there was no significant difference in live birth rates for donor vs nondonor sperm (31.9% vs 36.8%; adjusted relative risk, 1.04, 95% confidence interval, 0.998-1.09). Per singleton live birth, there was no significant difference in preterm birth (11.5% vs 11.8%; adjusted relative risk, 0.98, 95% confidence interval, 0.90-1.06); however, low birthweight delivery was slightly lower in donor sperm cycles (8.8% vs 9.4%; adjusted relative risk, 0.91, 95% confidence interval, 0.83-0.99). CONCLUSION: Donor sperm use in assisted reproductive technology has increased in the United States, accounting for approximately 6% of all assisted reproductive technology cycles in 2014. Assisted reproductive technology treatment and perinatal outcomes were clinically similar in donor and nondonor sperm cycles.

Role of Abnormal Sperm Morphology in Predicting Pregnancy Outcomes.

The evaluation of strict morphology for predicting successful pregnancy has been controversial, nevertheless remains an essential component of semen analysis. Patients with teratozoospermia (abnormal strict morphology) have traditionally been counseled to undergo assisted reproduction. However, recent studies suggest that patients with abnormal sperm morphology alone should not be precluded from attempting natural conception before undergoing assisted reproduction. The goal of this review is to provide an update on the evaluation of sperm morphology for prognosis in assisted reproductive techniques such as intrauterine insemination and in vitro fertilization with or without intracytoplasmic sperm injection. Additionally, we propose a logical approach to the evaluation of a patient with teratozoospermia seeking fertility treatment.

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.