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Can a specific diet and vitamin/mineral supplements improve your patients' chances of getting pregnant? That investigation has just begun, but we do know that by losing weight, overweight patients with fertility problems might just save themselves a trip to an infertility specialist. [ABSTRACT FROM AUTHOR]

Study Question: Does BMI of gestational carriers (GCs) affect perinatal outcomes after embryo transfer?, Summary Answer: Overweight and class I obesity in GCs does not affect the rate of good perinatal outcomes., What Is Known Already: The use of GCs is increasing, but uniform guidance regarding optimal BMI for GCs is lacking. Women with obesity who conceive without fertility treatment or through autologous or donor in vitro fertilization are at higher risk of adverse maternal and fetal outcomes, but data on obesity in GCs are very limited., Study Design, Size, Duration: We performed a retrospective cohort study of 1121 GC cycles from January 2015 to December 2020 at US Fertility, the largest national partnership of fertility practices in the USA., Participants/materials, Setting, and Methods: All GC cycles performed at a large network of fertility practices were reviewed. Same-sex partners undergoing co-IVF were excluded. The primary outcome was good perinatal outcome from the first embryo transfer, defined as a singleton live birth at ≥37 weeks of gestation with birth weight between 2500 and 4000 g. Secondary outcome measures included frequencies of live birth, clinical pregnancy, miscarriage, full-term birth, low birth weight, large for gestational age, and cesarean delivery. A generalized linear model (log-binomial) was used for each to compare outcomes across BMI groups using normal BMI (20-24.9 kg/m2) as the reference group. Risk ratios and 95% CIs were estimated for each category group relative to normal BMI., Main Results and the Role of Chance: We identified 1121 cycles in which GCs underwent first embryo transfer, of which 263 (23.5%) were in GCs with BMI >30. Demographics and reproductive history for GCs did not differ by BMI groups. The age of intended parents, use of frozen eggs, and fresh embryo transfers were higher with increasing BMI group. There were no statistically significant associations between BMI and good perinatal outcomes, live birth, clinical pregnancy, biochemical, spontaneous abortion, or low birth weight. However, among live births, higher BMI was significantly associated with birth by cesarean (P = 0.015) and large for gestational age infants (P = 0.023)., Limitations, Reasons for Caution: This was a retrospective study, and there may be unmeasured confounders. The number of patients with BMI <20 or ≥35 was small, limiting the power for these groups. We were not able to assess all maternal and fetal outcomes., Wider Implications of the Findings: In this study, we did not identify any significant impact of BMI on the chances of having a good perinatal outcome. Prior research studies have been inconsistent and this is the largest study to date., Study Funding/competing Interest(s): No external funding was received for this work. The authors do not have any conflicts of interest to declare., Trial Registration Number: N/A., (© The Author(s) 2024. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Study Objective: We aimed to evaluate herbal medicine and supplement use patterns among adolescent and young adult women at a clinic focused on family planning., Methods: We conducted a cross-sectional survey of patients (age 14-25) at an adolescent Title X clinic. Participants completed an electronic survey that assessed herbal medicine and supplement use, baseline demographic characteristics, and current contraceptive method. We evaluated supplement-drug interactions using the Natural Medicines database Interaction Checker. Quantitative analyses were performed using χ 2 and independent medians tests., Results: We enrolled 99 participants with a median age of 20 (15-24) years. Overall, 42.4% of patients reported ever having used supplements or herbal medicines, with 29.9% of patients reporting current supplement or herbal medicine use. Patients with higher education and private insurance were more likely to report a history of and current supplement use (P < .05). The most common herbal supplements reported were green tea (n = 26), cannabidiol (n = 17), and cranberry (n = 16), with 29.6% of participants reporting use to their general health care provider. The most common reasons for use were general health and wellness (29.1%), immune support (23.2%), stress (16.8%), and menstrual irregularities (6.0%). We found 62 moderate risk supplement-drug interactions, with 50 interactions attributed to hormonal contraceptive therapies. The most common interactions were via cytochrome P450 enzyme (CYP3A4 or CYP1A2) inhibition, decreased caffeine clearance, and potential hepatotoxicity., Conclusion: Adolescent and young adult women frequently reported past and current herbal medicine and supplement use, with high rates of moderate-risk supplement-drug interactions. Further research is needed to better elucidate these clinically relevant supplement-contraception interactions., Competing Interests: Conflicts of Interest AJP reports consultant work with Prima Temp. AL reports that the University Division of Family Planning has received research funding from Bayer, Agile Therapeutics, Organon and Co, Sebela, and Medicines360. All other authors disclose no conflicts., (Copyright © 2023. Published by Elsevier Inc.)

Purpose: There is an unclear relationship between estradiol levels and fresh embryo transfer (ET) outcomes. We determined the relationship between estradiol on the day of trigger, in fresh ET cycles without premature progesterone elevation, and good birth outcomes (GBO)., Methods: We identified autologous fresh ET cycles from 2015 to 2021 at multiple clinics in the USA. Patients with recurrent pregnancy loss, uterine factor, and elevated progesterone on the day of trigger (progesterone > 2 ng/mL or 3-day area under the curve > 4.5 ng/mL) were excluded. The primary outcome was GBO (singleton, term, live birth with appropriate weight). Log-binomial generalized estimating equations determined the likelihood of outcomes., Results: Of 17,608 fresh ET cycles, 5025 (29%) yielded GBO. Cycles with estradiol ≥ 4000 pg/mL had a greater likelihood of GBO compared to cycles < 1000 pg/mL (aRR = 1.32, 95% CI 1.13-1.54). Pairwise comparisons of estradiol between < 1000 pg/mL versus 1000-1999 pg/mL and 1000-1999 pg/mL versus 2000-2999 pg/mL revealed a higher likelihood of GBO with higher estradiol (aRR 0.83, 95% CI 0.73-0.95; aRR 0.91, 95% CI 0.85-0.97, respectively). Comparisons amongst more elevated estradiol levels revealed that the likelihood of GBO remained similar between groups (2000-2999 pg/mL versus 3000-3999 pg/mL, aRR 1.04, 95% CI 0.97-1.11; 3000-3999 pg/mL versus ≥ 4000 pg/mL, aRR 0.96, 95% CI 0.9-1.04)., Conclusion: In fresh ET cycles, higher estradiol levels were associated with an increased prevalence of GBO until estradiol 2000-2999 pg/mL, thereafter plateauing. In fresh ET candidates, elevated estradiol levels should not preclude eligibility though premature progesterone rise, and risk of ovarian hyperstimulation syndrome must still be considered., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To establish conditions for effective hypothalamic suppression in women with normal and high body mass index (BMI) and test the hypothesis that intravenous (IV) administration of pulsatile recombinant follicle-stimulating hormone (rFSH) can overcome the clinically evident dysfunctional pituitary-ovarian axis in women with obesity., Design: Prospective interventional study., Setting: Academic medical center., Patient(s): Twenty-seven normal-weight women and 27 women with obesity, who were eumenorrheic and aged 21-39 years., Intervention(s): Two-day frequent blood sampling study, in early follicular phase, before and after cetrorelix suppression of gonadotropins and exogenous pulsatile IV rFSH administration., Main Outcome Measure(s): Serum inhibin B and estradiol (E2) levels (basal and rFSH stimulated)., Result(s): A modified gonadotropin-releasing hormone antagonism protocol effectively suppressed production of endogenous gonadotropins in women with normal and high BMIs, providing a model to address the functional role of FSH in the hypothalamic-pituitary-ovarian axis. The IV rFSH treatment resulted in equivalent serum levels and pharmacodynamics in normal-weight women and those with obesity. However, women with obesity exhibited reduced basal levels of inhibin B and E2 and a significantly decreased response to FSH stimulation. The BMI was inversely correlated with serum inhibin B and E2. In spite of this observed deficit in ovarian function, pulsatile IV rFSH treatment in women with obesity resulted in E2 and inhibin B levels comparable with those in normal-weight women, in the absence of exogenous FSH stimulation., Conclusion(s): Despite normalization of FSH levels and pulsatility by exogenous IV administration, women with obesity demonstrate ovarian dysfunction with respect to E2 and inhibin B secretion. Pulsatile FSH can partially correct the relative hypogonadotropic hypogonadism of obesity, thereby providing a potential treatment strategy to mitigate some of the adverse effects of high BMI on fertility, assisted reproduction, and pregnancy outcomes., Clinical Trial Registration Number: ClinicalTrials.gov #NCT02478775., (Copyright © 2023 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

To query if anti-Müllerian hormone (AMH) and/or follicle-stimulating hormone (FSH) predict live birth at the University of Colorado Advanced Reproductive Medicine (CU ARM). This was a retrospective analysis using the Society for Assisted Reproductive Technology (SART) Clinic Outcome Reporting System database at CU ARM from 2017 to 2019 to identify the pregnancy outcomes of the initial fresh or frozen embryo transfer (FET) and their corresponding AMH and FSH. Fisher's exact tests were used to identify differences in pregnancy outcome by age group, and area under the receiver operator characteristic curves was used to quantify live birth prediction. A total of 1083 records from 557 patients were reviewed. After only including the first autologous transfer, 270 cycles were analyzed. Overall live birth (L/B) rate was 58.15% (157/270), which declined with increasing age group (p ≤ 0.01). Although AMH significantly decreased with increasing age (p < 0.001), it was not associated with pregnancy outcome (3.54 ng/mL vs. 3.41 ng/mL, p = 0.56); this relationship was unchanged after controlling for age in logistic regression models (p = 0.52). FSH was also not significantly related to pregnancy outcome (7.00 IU/L vs 6.00 IU/L, p = 0.15), and this relationship did not change after controlling for age (p = 0.61). Using AUC, the only variable predictive of live birth was age (p = 0.002). AMH and FSH are not associated with the probability of live birth. Only age was significantly associated with live birth in this series. AMH and FSH should therefore be used cautiously when counseling patients about ART outcomes., (© 2022. The Author(s), under exclusive licence to Society for Reproductive Investigation.)

Problem: Immune cell trafficking and surveillance within the ovary and fallopian tube are thought to impact fertility and also tumorigenesis in those organs. However, little is known of how native cells of the ovary and fallopian tube interact with resident immune cells. Interaction of the Programmed Cell Death Protein-1 (PD-1/PDCD-1/CD279) checkpoint with PD-L1 is associated with downregulated immune response. We have begun to address the question of whether PD-1 ligand or its receptors (PD-L1/-L2) can regulate immune cell function in these tissues of the female reproductive tract., Method of Study: PD-1 and ligand protein expression was evaluated in human ovary and fallopian tube specimens, the latter of which included stages of tubal cell transformation and early tumorigenesis. Ovarian expression analysis included the determination of the proteins in human follicular fluid (HFF) specimens collected during in vitro fertilization procedures. Finally, checkpoint bioactivity of HFF was determined by treatment of separately-isolated human T cells and the measurement of interferon gamma (IFNγ)., Results: We show that membrane bound and soluble variants of PD-1 and ligands are expressed by permanent constituent cell types of the human ovary and fallopian tube, including granulosa cells and oocytes. PD-1 and soluble ligands were present in HFF at bioactive levels that control T cell PD-1 activation and IFNγ production; full-length checkpoint proteins were found to be highly enriched in HFF exosome fractions., Conclusion: The detection of PD-1 checkpoint proteins in the human ovary and fallopian tube suggests that the pathway is involved in immunomodulation during folliculogenesis, the window of ovulation, and subsequent egg and embryo immune-privilege. Immunomodulatory action of receptor and ligands in HFF exosomes is suggestive of an acute checkpoint role during ovulation. This is the first study in the role of PD-1 checkpoint proteins in human tubo-ovarian specimens and the first examination of its potential regulatory action in the contexts of normal and assisted reproduction., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To address the knowledge gap surrounding herbal medicine and supplement usage patterns and supplement-prescription medication interactions among patients seeking treatment for infertility., Design: Cross-sectional survey study., Setting: Academic infertility practice., Patients: Ninety-five reproductive-aged patients., Interventions: Not applicable., Main Outcome Measures: Use of herbal medications and supplements, baseline demographics, history of infertility treatments, and potential supplement-medication interactions., Results: We surveyed 95 participants with a median age of 35 years. Overall, 68.4% of patients reported ever having used supplements or herbal medicines in the past. Current use of herbal supplements and vitamins was reported by 53.7% and 93.7% of participants, respectively, with a median of 2 (range 19) supplements used per person. There were no significant associations between patient demographics, comorbidities, or infertility treatments with increased rates of supplement use. The most commonly used herbal supplements were: green tea (n = 14), chamomile (n = 12), peppermint (n = 9), turmeric (n = 8), elderberry (n = 7), ginger (n = 7), maca (6) with the most common modalities being pills/capsules (23.8%) and tea (42.3%). The most common reasons for use were: general health and wellness (24.5%), immune support (16.2%), stress (14.0%), and fertility (15.0%). Patients used maca (n = 5), chasteberry (n = 3), goji berry (n = 2), ginger (n = 2), yam-based progesterone (n = 2), and combination product (n = 2) for fertility purposes. A total of 7.9% of patients learned about these products from their general health care provider, and 33.3% of supplements were disclosed by patients to their provider. We identified 41 moderate-risk supplement-drug interactions, with 12 of these interactions attributed to infertility therapies. Based on the interaction checker, the most commonly proposed mechanisms of interaction were CYP3A4 and CYP2C19 inhibition. In terms of safety in pregnancy, cannabidiol and chasteberry were suggested to be "possibly unsafe in pregnancy," and red raspberry leaf "likely unsafe in pregnancy" without direct medical supervision., Conclusions: We found over two thirds of women seeking treatment for infertility reported past and over half reported current herbal medicine and supplement use. Notably, the Natural Medicines Interaction Checker suggested high rates of moderate-risk supplement-drug interactions and possible harmful effects in early pregnancy. Our results call for further investigation of clinically relevant supplement interactions with infertility therapies., (© 2022 Published by Elsevier Inc. on behalf of American Society for Reproductive Medicine.)

Background: The optimal protocol for minimal stimulation in vitro fertilization (IVF) has yet to be established. This study aims to determine if the use of gonadotropin-releasing hormone (GnRH) antagonist during minimal stimulation improves outcomes., Materials and Methods: All cycles designated as minimal stimulation from 2014 to 2016 from the Society for Assisted Reproductive Technology Clinic Online Reporting System were identified. Cycles in which GnRH antagonist was administered ( n  = 5984) were compared to those that did not receive it ( n  = 7066). Wilcoxon's rank-sum test and chi-square test were used to analyze continuous and categorical variables., Results: A total of 6750 patients undergoing 13,050 cycles were included. GnRH antagonist use was associated with a significantly higher total gonadotropin dosage (median 975.0 [interquartile range, IQR, 600.0, 1575.0] vs. median 660.0 [IQR 375.0, 975.0], p  < 0.001), lower cycle cancelation rate (11.3% vs. 13.6%, p  < 0.001; OR 1.24, 95% CI 1.12-1.38, p  < 0.001), and higher live birth rate (4.3% vs. 2.1%, p  < 0.001; OR 0.47, 95% CI 0.39-0.58, p  < 0.001). GnRH antagonist use was associated with a significantly higher live birth rate in women ≥35 years of age (2.7% vs. 0.9%, p  < 0.001; OR 0.34, 95% CI 0.25-0.47, p  < 0.001) and antimullerian hormone <1 (4.9% vs. 2.6%, p  = 0.004; OR 0.52, 95% CI 0.33-0.81, p  = 0.004)., Conclusion: The use of GnRH antagonist suppression during minimal stimulation IVF is associated with an improved live birth rate, especially in older women and in women with diminished ovarian reserve. Although GnRH antagonist use may increase costs, it significantly decreases cancelation rate, increases number of embryos cryopreserved, and should be encouraged for minimal stimulation IVF., Competing Interests: No competing financial interests exist., (© Emily G. Hurley et al., 2022; Published by Mary Ann Liebert, Inc.)

Research Question: Are preconception ovarian reserve markers, such as Anti-Mullerian hormone and antral follicle count, associated with preeclampsia and placenta mediated pregnancy complications among women with unexplained infertility who conceive with superovulation?, Design: This is a secondary analysis of women with unexplained infertility who had a singleton live birth after enrollment in the Analysis of Multiple Intrauterine Gestations after Ovarian Stimulation (AMIGOS) trial that randomized couples to superovulation with letrozole, clomiphene, or gonadotropins with insemination for up to 4 cycles., Results: Compared to controls (N = 156), women who developed preeclampsia (N = 17) had lower Anti-Mullerian hormone levels (2.24 ± 1.20 vs. 2.89 ± 2.32, p = 0.07) and lower antral follicle count (18 ± 7.67 vs. 21 ± 11.43, p = 0.16); though these differences were not statistically significant. There was no relationship between Anti-Mullerian hormone (OR: 1.00, 95% CI: 0.76-1.25) or antral follicle count (OR: 0.98, 95% CI 0.93-1.04) with preeclampsia and between Anti-Mullerian hormone (OR: 1.00, 95% CI: 0.83-1.17) and antral follicle count (OR: 1.00, 95% CI: 0.97-1.04) with placenta medicated pregnancy complications after adjusting for age, BMI and race., Conclusions: Preconception ovarian reserve markers are not associated with preeclampsia and placenta mediated pregnancy complications among women with unexplained infertility who conceive with superovulation with insemination., (Copyright © 2022 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Background: Despite the rising prevalence of infertility, studies have indicated that in the United States fertility awareness remains low. No published study to date, however, has investigated the impact of any racial or ethnic disparities in fertility awareness. Materials and Methods: We conducted a cross-sectional survey of people self-identifying as female, aged 18-45 years, via Amazon Mechanical Turk in August 2020. The study was approved by the institutional review board at the University of Colorado. The survey consisted of demographic questions and a validated questionnaire, the Fertility and Infertility Treatment Knowledge Score (FIT-KS). Participants were classified as non-Hispanic White (NHW) or "Minority" race/ethnicity. Results: A total of 476 women completed the survey, 405 of which were included in analysis. Of those, 54.6% self-identified as NHW and 45.4% were in the Minority group. The median FIT-KS was 51.7% (16 items answered correctly). The Minority group scored significantly lower than the NHW participants overall (58.6% vs. 48.3%, p  < 0.001) and in all three subscales ( p  < 0.05). The Minority group was significantly more likely to underestimate the rate of miscarriage (47.3% vs. 32.6%, p  = 0.003) and had a lower awareness of risk factors that can impact fertility including smoking (88.7% vs. 71.6%, p  < 0.001), obesity (90.5% vs. 70.5%, p  < 0.001), and/or a history of gonorrhea/chlamydia infection (83.7% vs. 64.7%, p  < 0.001). Conclusions: Minority women appear to have a lower fertility awareness than their NHW counterparts. Addressing these disparities and improving fertility education in diverse communities may lead to a reduction in clinically significant infertility disparities., Competing Interests: No competing financial interests exist., (© Dana R. Siegel et al., 2021; Published by Mary Ann Liebert, Inc.)

Mechanisms that directly control mammalian ovarian primordial follicle (PF) growth activation and the selection of individual follicles for survival are largely unknown. Follicle cells produce factors that can act as potent inducers of cellular stress during normal function. Consistent with this, we show here that normal, untreated ovarian cells, including pre-granulosa cells of dormant PFs, express phenotype and protein markers of the activated integrated stress response (ISR), including stress-specific protein translation (phospho-Serine 51 eukaryotic initiation factor 2α; P-EIF2α), active DNA damage checkpoints, and cell-cycle arrest. We further demonstrate that mRNAs upregulated in primary (growing) follicles versus arrested PFs mostly include stress-responsive upstream open reading frames (uORFs). Treatment of a granulosa cell (GC) line with the PF growth trigger tumor necrosis factor alpha results in the upregulation of a 'stress-dependent' translation profile. This includes further elevated P-eIF2α and a shift of uORF-containing mRNAs to polysomes. Because the active ISR corresponds to slow follicle growth and PF arrest, we propose that repair and abrogation of ISR checkpoints (e.g. checkpoint recovery) drives the GC cell cycle and PF growth activation (PFGA). If cellular stress is elevated beyond a threshold(s) or, if damage occurs that cannot be repaired, cell and follicle death ensue, consistent with physiological atresia. These data suggest an intrinsic quality control mechanism for immature and growing follicles, where PFGA and subsequent follicle growth and survival depend causally upon ISR resolution, including DNA repair and thus the proof of genomic integrity., (© The Author(s) 2021. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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

Study Question: For donor oocyte recipients, are birth outcomes superior for fresh versus frozen embryos?, Summary Answer: Among fresh donor oocyte recipients, fresh embryos are associated with better birth outcomes when compared with frozen embryos., What Is Known Already: Frozen embryo transfer (ET) with vitrification has been associated with improved pregnancy rates, but also increased rates of large for gestational age infants. Donor oocyte recipients represent an attractive biological model to attempt to isolate the impact of embryo cryopreservation on IVF outcomes, yet there is a paucity of studies in this population., Study Design, Size, Duration: A retrospective cohort of the US national registry, the Society for Assisted Reproductive Technology Clinic Outcome Reporting System, of IVF cycles of women using fresh donor oocytes resulting in ET between 2013 and 2015. Thawed oocytes were excluded., Participants/materials, Settings, Methods: Good obstetric outcome (GBO), defined as a singleton, term, live birth with appropriate for gestational age birth weight, was the primary outcome measure. Secondary outcomes included live birth, clinical pregnancy, spontaneous abortion, preterm birth, multiple births and gestational age-adjusted weight. Outcomes were modeled using the generalized estimating equation approach., Main Results and the Role of Chance: Data are from 25 387 donor oocyte cycles, in which 14 289 were fresh and 11 098 were frozen ETs. A GBO was 27% more likely in fresh ETs (26.3%) compared to frozen (20.9%) (adjusted risk ratio 1.27; 95% confidence interval (CI) 1.21-1.35; P < 0.001). Overall, fresh transfer was more likely to result in a live birth (55.7% versus 39.5%; adjusted risk ratio 1.21; 95% CI 1.18-1.26; P < 0.001). Among singleton births, there was no difference in gestational age-adjusted birth weight between groups., Limitation, Reasons for Caution: Our cohort findings contrast with data from autologous oocytes. Prospective studies with this population are warranted., Wider Implications of the Findings: Among donor oocyte recipients, fresh ETs may be associated with better birth outcomes. Reassuringly, given its prevalent use, modern embryo cryopreservation does not appear to result in phenotypically larger infants., Study Funding/competing Interest(s): None., Trial Registration Number: N/A., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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

Objective: To evaluate the quantity and use of embryos cryopreserved at assisted reproductive technology (ART) clinics in the United States from 2004 through 2013 and to characterize trends in ART cycles in which all embryos were cryopreserved., Design: Retrospective analysis., Setting: Not applicable., Patients: Registry data from the Society for Assisted Reproductive Technology., Interventions: Historical cohort of U.S. ART cycles reported to the Society for Assisted Reproductive Technology Clinical Outcomes Reporting System between 2004 and 2013., Main Outcome Measures: Number of embryos cryopreserved and factors associated with having cryopreserved embryos., Results: The percentage of fresh cycles in which all embryos were frozen increased dramatically each year after 2010: 15.6% (2010), 19.9% (2011), 30.7% (2012), and 40.7% (2013). During 10 years, 1,954,548 embryos were cryopreserved and 717,345 embryos were transferred. In freeze-only cycles from 2004 to 2013, there was a significant increase in the percentage of women with diminished ovarian reserve (19.9% to 34.1%) and in those who used preimplantation genetic testing (3.2% to 6.9%). During the 10-year period, there were 294,575 fresh cycles with embryo transfer and at least one embryo cryopreserved. Overall, 52.5% (n = 154,543) did not undergo a subsequent frozen embryo transfer, 29.5% (n = 40,462) were left with no frozen embryos, 50.4% (n = 68,875) had one-five embryos, and 20.0% (n = 27,396) had ≥six. Factors associated with having excess embryos included donor oocyte cycles and increased antimüllerian hormone levels., Conclusions: There has been a sharp increase in U.S. ART cycles in which all embryos are frozen and this may result in more embryos in storage., (© 2020 The Authors.)

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

Background: Antimüllerian hormone is produced by small antral follicles and reflects ovarian reserve. Obesity is associated with lower serum antimüllerian hormone, but it is unclear whether lower levels of antimüllerian hormone in women with obesity reflect lower ovarian reserve., Objective: To determine whether lower antimüllerian hormone in women with obesity undergoing in vitro fertilization is associated with oocyte yield and live-birth rate., Materials and Methods: Retrospective cohort from the Society for Assisted Reproductive Technology Clinic Outcome Reporting System database of 13,316 women with obesity and 16,579 women with normal body mass index undergoing their first autologous in vitro fertilization with fresh transfers between 2012 and 2014. Normal body mass index was defined as body mass index 18.5-24.9 kg/m 2 , and obesity was defined as body mass index ≥30 kg/m 2 . Subjects with obesity were stratified as those with class 1 obesity (body mass index, 30.0-34.9 kg/m 2 ), class 2 obesity (body mass index, 35.0-39.9 kg/m 2 ), and class 3 obesity (body mass index, ≥40 kg/m 2 ) based on the World Health Organization body mass index guidelines. Antimüllerian hormone levels were stratified as normal (>1.1 ng/mL), low (0.16-1-1 ng/mL), and undetectable (≤0.16 ng/mL). Multivariable modeling was used to assess oocyte yield using linear regression with a logarithmic transformation and odds of live birth using logistic regression., Results: Women with obesity were older (36.0 ± 4.8 vs 35.5 ± 4.8, P < .001), had lower antimüllerian hormone (1.8 ± 2.0 ng/mL vs 2.1 ± 2.0 ng/mL, P < .001), and had fewer oocytes retrieved (11.9 ± 7.3 vs 12.8 ± 7.7, P < .001) than women with normal body mass index. Lower oocyte yield was observed among women with obesity and normal antimüllerian hormone levels compared to women with normal body mass index and normal antimüllerian hormone levels (13.6 ± 7.3 vs 15.8 ± 8.1, P < .001). No difference in oocyte yield was observed among women with obesity and low antimüllerian hormone levels (P = .58) and undetectabl antimüllerian hormone (P = .11) compared to women with normal BMI and similar antimüllerian hormone levels. Among women with a body mass index ≥30 kg/m 2 , antimüllerian hormone levels were associated with the number of oocytes retrieved (β = 0.069; standard error, 0.005; P < .001) but not live-birth rate (odds ratio, 0.98; 95% confidence interval, 0.93-1.04, P = .57)., Conclusion: Lower antimüllerian hormone in infertile women with obesity appears to reflect lower ovarian reserve, as antimüllerian hormone is associated with lower oocyte yield. Despite lower oocyte yield, lower antimüllerian hormone was not associated with lower live-birth rate among women with obesity., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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

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

Study Objective: To evaluate the efficacy of nontubal ectopic pregnancy (NTEP) management with direct methotrexate (MTX) injection into the gestational sac., Design: A retrospective chart review., Setting: A tertiary academic and teaching hospital., Patients: All cases of confirmed NTEP were retrospectively identified from 2012 to 2017., Interventions: Ultrasound-guided direct injection of MTX into the fetal pole and surrounding gestational sac and a single dose of systemic MTX with or without fetal intracardiac injection of potassium chloride., Measurements and Main Results: Treatment failure, complications from treatment, operating time, and days to negative serum human chorionic gonadotropin (hCG) after treatment were measured. Fourteen women (age 34 ± 5.2 years) with NTEP underwent direct MTX injection (cesarean scar, n = 4; interstitial, n = 6; cervical, n = 4). The mean estimated gestational age was 49 ± 11, CI (43, 56 days). One patient required laparoscopic intervention with a failure rate of 1 of 14 (a double interstitial, heterotopic pregnancy). There were no other major complications. The time in the operating room was similar for all NTEP types. The average time to negative serum hCG was not different for cesarean scar (84.5 ± 36 days), cervical pregnancies (70.5 ± 19 days), or interstitial pregnancies (45.3 ± 38 days, p = .15)., Conclusion: Direct MTX injection into the gestational sac for NTEP treatment is safe and effective. The failure rate of 7% is considerably lower than what was previously reported for a failure of systemic MTX in similar cases (25%). Resolution of serum hCG after treatment can be quite prolonged even in uncomplicated cases., (Copyright © 2019 AAGL. Published by Elsevier Inc. All rights reserved.)

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

Most children diagnosed with cancer survive for many years after treatment. However, the fertility potential of these patients may suffer due to their oncologic therapies. Certain chemotherapies and radiation are more likely to be detrimental to gonadal function, and put patients at risk of acute or premature ovarian failure. Prepubertal cancer patients will need different follow-up and testing from their post-pubertal counterparts. This review will present evidence to help patients, family members and physicians determine who is most at risk of ovarian insufficiency and how to monitor childhood cancer survivors. It will discuss the impact of age at diagnosis and cancer therapies on reproductive outcomes, and guide caregivers and patients on monitoring gonadal function after therapy., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Purpose: To compare saline infusion sonohysterography (SIS) versus hysterosalpingogram (HSG) for confirmation of tubal patency., Methods: Secondary analysis of a randomized controlled trial, Pregnancy in Polycystic Ovary Syndrome II (PPCOS II). Seven hundred fifty infertile women (18-40 years old) with polycystic ovary syndrome (PCOS) were randomized to up to 5 cycles of letrozole or clomiphene citrate. Prior to enrollment, tubal patency was determined by HSG, the presence of free fluid in the pelvis on SIS, laparoscopy, or recent intrauterine pregnancy. Logistic regression was conducted in patients who ovulated with clinical pregnancy as the outcome and HSG or SIS as the key independent variable., Results: Among women who ovulated, 414 (66.9%) had tubal patency confirmed by SIS and 187 (30.2%) had at least one tube patent on HSG. Multivariable analysis indicated that choice of HSG versus SIS did not have a significant relationship on likelihood of clinical pregnancy, after adjustment for treatment arm, BMI, duration of infertility, smoking, and education (OR 1.14, 95% CI 0.77, 1.67, P = 0.52). Ectopic pregnancy occurred more often in women who had tubal patency confirmed by HSG compared to SIS (2.8% versus 0.6%, P = 0.02)., Conclusions: In this large cohort of women with PCOS, there was no significant difference in clinical pregnancy rate between women who had tubal patency confirmed by HSG versus SIS. SIS is an acceptable imaging modality for assessment of tubal patency in this population.

This work is motivated by a desire to quantify relationships between two time series of pulsing hormone concentrations. The locations of pulses are not directly observed and may be considered latent event processes. The latent event processes of pulsing hormones are often associated. It is this joint relationship we model. Current approaches to jointly modeling pulsing hormone data generally assume that a pulse in one hormone is coupled with a pulse in another hormone (one-to-one association). However, pulse coupling is often imperfect. Existing joint models are not flexible enough for imperfect systems. In this article, we develop a more flexible class of pulse association models that incorporate parameters quantifying imperfect pulse associations. We propose a novel use of the Cox process model as a model of how pulse events co-occur in time. We embed the Cox process model into a hormone concentration model. Hormone concentration is the observed data. Spatial birth and death Markov chain Monte Carlo is used for estimation. Simulations show the joint model works well for quantifying both perfect and imperfect associations and offers estimation improvements over single hormone analyses. We apply this model to luteinizing hormone (LH) and follicle stimulating hormone (FSH), two reproductive hormones. Use of our joint model results in an ability to investigate novel hypotheses regarding associations between LH and FSH secretion in obese and non-obese women., (© 2017, The International Biometric Society.)

Initial stages of implantation involve bi-directional molecular crosstalk between the blastocyst and endometrium. This study investigated an association between infertility etiologies, specifically advanced maternal age (AMA) and endometriosis, on the embryo-endometrial molecular dialogue prior to implantation. Co-culture experiments were performed with endometrial epithelial cells (EEC) and cryopreserved day 5 blastocysts ( n  = 41 ≥ Grade 3BB) donated from patients presenting with AMA or endometriosis, compared to fertile donor oocyte controls. Extracellular vesicles isolated from co-culture supernatant were analyzed for miRNA expression and revealed significant alterations correlating to AMA or endometriosis. Specifically, AMA resulted in 16 miRNAs with increased expression ( P  ≤ 0.05) and strong evidence for negative regulation toward 206 target genes. VEGFA , a known activator of cell adhesion, displayed decreased expression ( P  ≤ 0.05), validating negative regulation by 4 of these increased miRNAs: miR-126; 150; 29a; 29b ( P  ≤ 0.05). In endometriosis patients, a total of 10 significantly altered miRNAs displayed increased expression compared to controls (miR-7b; 9; 24; 34b; 106a; 191; 200b; 200c; 342-3p; 484) ( P  ≤ 0.05), targeting 1014 strong evidence-based genes. Three target genes of miR-106a ( CDKN1A , E2F1 and RUNX1 ) were independently validated. Functional annotation analysis of miRNA-target genes revealed enriched pathways for both infertility etiologies, including disrupted cell cycle regulation and proliferation ( P  ≤ 0.05). These extracellular vesicle-bound secreted miRNAs are key transcriptional regulators in embryo-endometrial dialogue and may be prospective biomarkers of implantation success. One of the limitations of this study is that it was a stimulated, in vitro model and therefore may not accurately reflect the in-vivo environment., (© 2018 Society for Reproduction and Fertility.)

Background: Prenatal exposures have known adverse effects on maternal and neonatal outcomes. Professional societies recommend routine screening for environmental, occupational, and dietary exposures to reduce exposures and their associated sequelae., Objective: Our objective was to determine the frequency of environmental exposure screening by obstetricians and gynecologists (OBGYNs) at initial patient visits., Study Design: Practicing OBGYNs were approached at the University of Colorado and by social media. The survey instrument queried demographics, environmental literacy, and screening practices. Statistical analysis was performed using Chi-square and two-sample t-test., Results: We received 312 online survey responses (response rate of 12%). Responding OBGYNs were predominantly female (96%), board-certified (78%), generalists (65%) with a mean age of 37.1 years. Fewer than half of physicians screened for the following factors: occupational exposures, environmental chemicals, air pollution, pesticide use, personal care products, household cleaners, water source, use of plastics for food storage, and lead and mercury exposure. Eighty five percent of respondents reported that they did not feel comfortable obtaining an environmental history and 58% respondents reported that they performed no regular screening of environmental exposures. A higher frequency of screening was associated with > 4 years of practice (p = 0.001), and having read the environmental committee opinion (p = <0.001)., Conclusion: The majority of OBGYNs did not incorporate screening for known environmental exposures into routine practice. Reading the environmental committee opinions was strongly and significantly associated with a higher rate of screening. Improving physician comfort in counseling patients may enhance screening for exposures that affect reproductive health.

Phthalates are known endocrine disruptors and associated with decreased fecundity, pregnancy loss, and adverse obstetrical outcomes, however the underlying mechanisms remain to be established. Environmental factors can influence gene expression and cell function by modifying epigenetic marks, impacting the developing embryo as well as future generations of offspring. The impact of phthalates on placental gene methylation and expression is largely unknown. We studied the effect of maternal phthalate exposure on the human placental DNA methylome and transcriptome. We determined epigenome-wide DNA methylation marks (Illumina Infinium Human Methylation 850k BeadChip) and gene expression (Agilent whole human genome array) associated with phthalate exposure in first trimester placenta. Integrative genomic analysis of candidate genes was performed to define gene methylation-expression relationships. We identified 39 genes with significantly altered methylation and gene expression in the high phthalate exposure group. Most of these relationships were inversely correlated. This analysis identified epidermal growth factor receptor (EGFR) as a critical candidate gene mediating the effects of phthalates on early placental function. Although additional studies are needed to determine the functional consequences of these changes, our findings are consistent with the model that phthalates impact placental function by modulating the expression of critical placental genes through epigenetic regulation.

Even with the benefit of assisted reproductive technologies (ART), many women are unable to conceive and deliver healthy offspring. One common cause of infertility is the inability to produce eggs capable of contributing to live birth. This can occur despite standard-of-care treatment to maximize the recovery of eggs from growing ovarian follicles. Dormant primordial follicles in the human ovary are a 'reserve ' that can be exploited clinically to overcome this problem. We discuss how controlling primordial follicle growth activation (PFGA) can produce increased numbers of high-quality eggs available for fertility treatment(s). We consider the state of the art in interventions used to control PFGA, and consider genetic and epigenetic strategies on the horizon that might improve compromised oocyte quality to increase live births., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Pulsatile secretion of hormones in the hypothalamic-pituitary-gonadal axis is critical for normal functioning of the reproductive system. Thus, appropriate characterization of pulsatile secretion is important for identifying the (patho)physiology of reproductive conditions. Existing analysis methods often fail to adequately characterize pulsatility, especially when the signal-to-noise ratio is low. Newer Bayesian analysis methods for pulsatile hormones may offer improved secretion quantification in noisier data. The objective of this study was to extensively validate a Bayesian analysis approach for analyzing pulsatile hormones in settings that occur in reproductive studies. An investigative approach was chosen so that clinical research teams will have the knowledge to adopt this newer analysis approach in practice. Three experimental conditions were investigated: luteinizing hormone (LH) profiles in ovariectomized ewes (N=6; high signal-to-noise setting), LH profiles in young ovulating women (N=12; lower signal-to-noise setting), and computer-simulated scenarios (N=200). For each experimental condition, differences in luteinizing hormone pulse outcomes (pulse number, average pulse size, hormone half-life, and non-pulse secretion) were obtained and compared between non-Bayesian and Bayesian analysis pulse analysis methods. For the ewe model, the estimated pulse number and mass were comparable between the Bayesian and non-Bayesian analyses. For the human model, only 4 of 12 subjects could be fitted with the non-Bayesian analysis compared to 10 of the 12 with Bayesian analysis. In general, the Bayesian analysis had lower false negative rates (<4.5%) compared to the non-Bayesian analysis while maintaining a high specificity (false positive rate <2.5%). The Bayesian analysis also had less biased estimates of all pulse features. In conclusion, Bayesian analysis provides a more reliable pulse characterization in low signal-to-noise experiments and should be used for the analysis of reproductive physiology studies of pulsatile hormones. Software is available at www.github.com/BayesPulse ., Abbreviations: LH: luteinizing hormone; FSH: follicle stimulating hormone; GnRH: gonadotropin-releasing hormone; FP: false positive; FN: false negative.

Studies of reproductive physiology involve rapid sampling protocols that result in time series of hormone concentrations. The signature pattern in these times series is pulses of hormone release. Various statistical models for quantifying the pulsatile release features exist. Currently these models are fitted separately to each individual and the resulting estimates averaged to arrive at post hoc population-level estimates. When the signal-to-noise ratio is small or the time of observation is short (e.g., 6 h), this two-stage estimation approach can fail. This work extends the single-subject modelling framework to a population framework similar to what exists for complex pharamacokinetics data. The goal is to leverage information across subjects to more clearly identify pulse locations and improve estimation of other model parameters. This modelling extension has proven difficult because the pulse number and locations are unknown. Here, we show that simultaneously modelling a group of subjects is computationally feasible in a Bayesian framework using a birth-death Markov chain Monte Carlo estimation algorithm. Via simulation, we show that this population-based approach reduces the false positive and negative pulse detection rates and results in less biased estimates of population-level parameters of frequency, pulse size, and hormone elimination. We then apply the approach to a reproductive study in healthy women where approximately one-third of the 21 subjects in the study did not have appropriate fits using the single-subject fitting approach. Using the population model produced more precise, biologically plausible estimates of all model parameters. Copyright © 2017 John Wiley & Sons, Ltd., (Copyright © 2017 John Wiley & Sons, Ltd.)

Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Background: Women with polycystic ovarian syndrome have a high prevalence of metabolic syndrome and type 2 diabetes mellitus. Blacks and Hispanics have a high morbidity and mortality due to cardiovascular disease and diabetes mellitus in the general population. Since metabolic syndrome is a risk factor for development of type 2 diabetes and cardiovascular disease, understanding any racial and ethnic differences in metabolic syndrome among women with polycystic ovarian syndrome is important for prevention strategies. However, data regarding racial/ethnic differences in metabolic phenotype among women with polycystic ovary syndrome are inconsistent., Objective: We sought to determine if there are racial/ethnic differences in insulin resistance, metabolic syndrome, and hyperandrogenemia in women with polycystic ovarian syndrome., Study Design: We conducted secondary data analysis of a prospective multicenter, double-blind controlled clinical trial, the Pregnancy in Polycystic Ovary Syndrome II study, conducted in 11 academic health centers. Data on 702 women with polycystic ovarian syndrome aged 18-40 years who met modified Rotterdam criteria for the syndrome and wished to conceive were included in the study. Women were grouped into racial/ethnic categories: non-Hispanic whites, non-Hispanic blacks, and Hispanic. The main outcomes were the prevalence of insulin resistance, metabolic syndrome, and hyperandrogenemia in the different racial/ethnic groups., Results: Body mass index (35.1 ± 9.8 vs 35.7 ± 7.9 vs 36.4 ± 7.9 kg/m 2 ) and waist circumference (106.5 ± 21.6 vs 104.9 ± 16.4 vs 108.7 ± 7.3 cm) did not differ significantly between non-Hispanic white, non-Hispanic black, and Hispanic women. Hispanic women with polycystic ovarian syndrome had a significantly higher prevalence of hirsutism (93.8% vs 86.8%), abnormal free androgen index (75.8% vs 56.5%), abnormal homeostasis model assessment (52.3% vs 38.4%), and hyperglycemia (14.8% vs 6.5%), as well as lower sex hormone binding globulin compared to non-Hispanic whites. Non-Hispanic black women had a significantly lower prevalence of metabolic syndrome (24.5% vs 42.2%) compared with Hispanic women, and lower serum triglyceride levels compared to both Hispanics and non-Hispanic whites (85.7 ± 37.3 vs 130.2 ± 57.0 vs 120.1 ± 60.5 mg/dL, P < .01), with a markedly lower prevalence of hypertriglyceridemia (5.1% vs 28.3% vs 30.5%, P < .01) compared to the other 2 groups., Conclusion: Hispanic women with polycystic ovarian syndrome have the most severe phenotype, both in terms of hyperandrogenism and metabolic criteria. Non-Hispanic black women have an overall milder polycystic ovarian syndrome phenotype than Hispanics and in some respects, than non-Hispanic white women., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To investigate the association of non-cavity-distorting uterine fibroids and pregnancy outcomes after ovarian stimulation-intrauterine insemination (OS-IUI) in couples with unexplained infertility., Design: Secondary analysis from a prospective, randomized, multicenter clinical trial investigating fertility outcomes after OS-IUI., Setting: Reproductive Medicine Network clinical sites., Patient(s): Nine hundred couples with unexplained infertility who participated in the Assessment of Multiple Intrauterine Gestations from Ovarian Stimulation (AMIGOS) clinical trial., Intervention(s): Participants were randomized to one of three arms (clomiphene citrate, letrozole, or gonadotropins), and treatment was continued for up to four cycles or until pregnancy was achieved., Main Outcomes Measure(s): Conception (serum hCG increase), clinical pregnancy (fetal cardiac activity), and live birth rates., Result(s): A total of 102/900 participants (11.3%) had at least one documented fibroid and a normal uterine cavity. Women with fibroids were older, more likely to be African American, had a greater uterine volume, lower serum antimüllerian hormone levels, and fewer antral follicles than women without fibroids. In conception cycles, clinical pregnancy rates were significantly lower in participants with fibroids than in those without uterine fibroids. Pregnancy loss before 12 weeks was more likely in African American women with fibroids compared with non-African American women with fibroids. There was no difference in conception and live birth rates in subjects with and without fibroids., Conclusion(s): No differences were observed in conception and live birth rates in women with non-cavity-distorting fibroids and those without fibroids. These findings provide reassurance that pregnancy success is not impacted in couples with non-cavity-distorting fibroids undergoing OS-IUI for unexplained infertility., Clinical Trial Registration Number: NCT01044862., (Copyright © 2016 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Obesity and malnutrition are associated with decreased fecundity in women. Impaired reproductive capacity in obese women is often attributed to anovulation. However, obese women with ovulatory cycles also have reduced fertility, but the etiology of their impaired reproduction is only partially understood. Accumulating evidence suggests that obesity directly impairs oocyte and embryo quality as well as endometrial receptivity. In obese women, urinary progesterone metabolite excretion is decreased, but in excess of what can be explained by suppressed gonadotropin secretion, suggesting that apart from its central effect obesity may directly affect progesterone (P4) production. These observations have led to the novel hypothesis that obesity directly affects corpus luteum (CL) function. Similarly, we hypothesize that weight loss may contribute to luteal dysfunction. Here, we propose a non-human primate model, the vervet monkey, to examine the effect of weight gain and loss on menstrual cycle parameters and CL gene expression. In this model, weight gain and loss did not significantly alter menstrual cyclicity; however, both induced alterations in the CL transcriptome. In the weight gain monkey, we observed that impaired mid-luteal P4 secretion was associated with downregulation of steroidogenic pathways in CL. Collectively, these preliminary findings support our hypothesis that weight gain and loss may contribute to CL dysfunction. The vervet model described and preliminary observations provide a basis for a larger study to address this important question. Understanding the mechanisms by which weight gain and loss contribute to reproductive dysfunction can assist in the development of targeted treatments to enhance women's reproductive capability when it is desired., Abbreviations: CL: corpus luteum; P4: progesterone; E2: estradiol; PDG: pregnanediol 3-glucoronide; LH: luteinizing hormone; FSH: follicle-stimulating hormone; GnRH: gonadotropin releasing hormone; BMI: body mass index; qrtPCR: quantitative real-time PCR; PGR: progesterone receptor; ART: assisted reproductive technology; IVF: in vitro fertilization; HPO: hypothalamic-pituitary-ovarian axis; MMPs: matrix metalloproteinases Gene symbols: LH receptor (LHGCR); cholesterol side-chain cleavage enzyme (CYP11A1); 3 beta-hydroxysteroid dehydrogenase type II (HSD3B2); steroidogenic acute regulatory protein (STAR); LDL receptor (LDLR); scavenger receptor B1 (SCARB1); ATP-binding cassette sub-family A member 1 (ABCA1); ATP-binding cassette sub-family G member 1 (ABCG1); apolipoprotein A (APOA1); 24 dehydrocholesterol reductase (DHCR24); 3-hydroxy-3-methylglytaryl-CoA reductase (HMGCR); vascular endothelial growth factor A (VEGFA); vascular endothelial growth factor C (VEGFC); vascular endothelial growth factor receptor 1 (VEGFR1); and TIMP metallopeptidase inhibitor 1 (TIMP1); amphiregulin (AREG); epiregulin (EREG); CCAAT/enhancer binding protein alpha (CEBPBA); cAMP responsive element binding protein 3-like 1 (CREB3L1); ADAM metallopeptidase with thrombospodin type 1 motif 1 (ADAMTS1); matrix metallopeptidase 9 (MMP9); cytochrome b-245 beta polypeptide (CYBB or NOX2); NADH oxidase (NCF2 or NOXA2); Fc fragment of IgG receptor IIb (FCGR2B); Fc fragment of IgG receptor IIb (FCGR2C); ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1); RAB27A member RAS oncofamily (RAB27A); hydroxyprostaglandin dehydrogenase (HPGD); prostaglandin-endoperoxidase synthase 1 (PTGS1); integrin B2 (ITGB2); leukotriene A4 hydrolase (LTA4H); radixin (RDX); ezrin (EZR); nuclear receptor subfamily 5 group A member 2 (NR5A2)., Competing Interests: Declaration of interest The authors report no declarations of interest.

What is the impact of intentional weight loss and regain on serum androgens in women? We conducted an ancillary analysis of prospectively collected samples from a randomized controlled trial. The trial involved supervised 10% weight loss (8.5 kg on average) with diet and exercise over 4-6 months followed by supervised intentional regain of 50% of the lost weight (4.6 kg on average) over 4-6 months. Participants were randomized prior to the partial weight regain component to either continuation or cessation of endurance exercise. Analytic sample included 30 obese premenopausal women (mean age of 40 ± 5.9 years, mean baseline body mass index (BMI) of 32.9 ± 4.2 kg/m(2)) with metabolic syndrome. We evaluated sex hormone binding globulin (SHBG), total testosterone (T), free androgen index (FAI), and high molecular weight adiponectin (HMWAdp). Insulin, homeostasis model assessment (HOMA), and quantitative insulin sensitivity check index (QUICKI), and visceral adipose tissue (VAT) measured in the original trial were reanalyzed for the current analytic sample. Insulin, HOMA, and QUICKI improved with weight loss and were maintained despite weight regain. Log-transformed SHBG significantly increased from baseline to weight loss, and then significantly decreased with weight regain. LogFAI and logVAT decreased similarly and increased with weight loss followed by weight regain. No changes were found in logT and LogHMWAdp. There was no significant difference in any tested parameters by exercise between the groups. SHBG showed prominent sensitivity to body mass fluctuations, as reduction with controlled intentional weight regain showed an inverse relationship to VAT and occurred despite stable HMWAdp and sustained improvements with insulin resistance. FAI showed opposite changes to SHBG, while T did not change significantly with weight. Continued exercise during weight regain did not appear to impact these findings.

Objective: To evaluate factors associated with elective single-embryo transfer (eSET) utilization and its effect on assisted reproductive technology outcomes in the United States., Design: Historical cohort., Setting: Not applicable., Patient(s): Fresh IVF cycles of women aged 18-37 years using autologous oocytes with either one (SET) or two (double-embryo transfer [DET]) embryos transferred and reported to the Society for Assisted Reproductive Technology Clinic Outcome Reporting System between 2004 and 2012. Cycles were categorized into four groups with ([+]) or without ([-]) supernumerary embryos cryopreserved. The SET group with embryos cryopreserved was designated as eSET., Intervention(s): None., Main Outcomes Measure(s): The likelihood of eSET utilization, live birth, and singleton non-low birth weight term live birth, modeled using logistic regression. Presented as adjusted odds ratios (aORs) and 95% confidence intervals (CIs)., Result(s): The study included 263,375 cycles (21,917 SET[-]cryopreservation, 20,996 SET[+]cryopreservation, 103,371 DET[-]cryopreservation, and 117,091 DET[+]cryopreservation). The utilization of eSET (SET[+]cryopreservation) increased from 1.8% in 2004 to 14.9% in 2012 (aOR 7.66, 95% CI 6.87-8.53) and was more likely with assisted reproductive technology insurance coverage (aOR 1.60, 95% CI 1.54-1.66), Asian race (aOR 1.26, 95% CI 1.20-1.33), uterine factor diagnosis (aOR 1.48, 95% CI 1.37-1.59), retrieval of ≥16 oocytes (aOR 2.85, 95% CI 2.55-3.19), and the transfer of day 5-6 embryos (aOR 4.23, 95% CI 4.06-4.40); eSET was less likely in women aged 35-37 years (aOR 0.76, 95% CI 0.73-0.80). Compared with DET cycles, the likelihood of the ideal outcome, term non-low birth weight singleton live birth, was increased 45%-52% with eSET., Conclusion(s): Expanding insurance coverage for IVF would facilitate the broader use of eSET and may reduce the morbidity and healthcare costs associated with multiple pregnancies., (Copyright © 2016 American Society for Reproductive Medicine. All rights reserved.)

Excess calorie consumption, particularly of a diet high in fat, is a risk factor for both obesity and reproductive disorders. Animal model studies indicate that elevated dietary fat can influence some reproductive functions independent of obesity. In the current study we sought to determine whether a high-fat diet (HFD) impacts ovarian function, long-term fertility, and local and systemic markers of inflammation independent of obesity. Five-week-old mice were fed either low-fat diet (control group-LF-Ln) or HFD for 10 wk and were divided based on body weight into high-fat obese (HF-Ob: >25 g) and high-fat lean (HF-Ln: <22 g). Ovaries were collected to assess ovarian follicles and to determine the degree of local inflammation. Serum proinflammatory cytokines were also measured. A group of animals was followed for breeding trials for 5 mo while being exposed to LFD or HFD. We found that both 10-wk and 32-wk exposure to HFD resulted in depleted primordial follicles regardless of obesity phenotype. Macrophage counts revealed increased tissue inflammation in the ovary independent of obesity. In addition, serum proinflammatory cytokines were increased in HF-Ln and HF-Ob in comparison to LF-Ln mice. Moreover, HFD had a sustained effect on litter production rate and number of pups per litter regardless of obese phenotype. This study describes for the first time that exposure to HFD causes significant reduction in primordial follicles, compromised fertility, produced higher proinflammatory cytokine levels, and increased ovarian macrophage infiltration, independent of obesity. The negative effects of HFD on primordial follicles may be mediated by increased tissue inflammation., (© 2016 by the Society for the Study of Reproduction, Inc.)

Context: Dietary omega-3 fatty acids delay ovarian aging and promote oocyte quality in mice., Objective: To test whether dietary supplementation with omega-3 polyunsaturated fatty acids (PUFA) modulates reproductive hormones in reproductive-age women., Design: Prospective interventional study., Setting: Academic center., Participants: Fifteen obese and 12 normal-weight (NW) eumenorrheic women, ages 28-34 years., Intervention: Two frequent blood-sampling studies were performed before and after 1 month of omega-3 PUFA supplementation with 4 g of eicosapentaenoic acid and docosahexaenoic acid daily., Main Outcome Measures: Serum LH and FSH (basal and after GnRH stimulation)., Results: The ratio of omega-6 to omega-3 PUFA was significantly reduced in plasma and red blood cell components for both groups after treatment (both P < .01). Omega-3 PUFA supplementation resulted in reduction of FSH and FSH response to GnRH by 17% on average (P = .06 and P = .03, respectively) in NW but not obese women. Serum levels of IL-1β and TNF-α were reduced after omega-3 PUFA supplementation (-72% for IL-1β; -56% for TNF-α; both, P < .05) in obese but not in NW women. This reduction, however, was not associated with a hormonal change in obese women., Conclusions: Dietary administration with omega-3 PUFA decreased serum FSH levels in NW but not in obese women with normal ovarian reserve. This effect is intriguing and is directionally consistent with murine data whereby higher dietary omega-3 PUFA extends reproductive lifespan. Our results imply that this nutritional intervention should be tested in women with diminished ovarian reserve in an attempt to delay ovarian aging.

Context: Obesity is associated with a pro-inflammatory state and relative hypogonadotropic hypogonadism. Estrogen (E2) is a potential link between these phenomena because it exhibits negative feedback on gonadotropin secretion and also inhibits production of pro-inflammatory cytokines., Objective: We sought to examine the effect of estrogen priming on the hypothalamic-pituitary-ovarian axis in obesity., Design, Setting, and Participants: This was an interventional study at an academic center of 11 obese and 10 normal-weight (NW) women., Intervention: A frequent blood-sampling study and one month of daily urinary collection were performed before and after administration of transdermal estradiol 0.1 mg/d for one entire menstrual cycle., Main Outcome Measures: Serum LH and FSH before and after GnRH stimulation, and urinary estrogen and progesterone metabolites were measured., Results: E2 increased LH pulse amplitude and FSH response to GnRH (P = .048, and P < .03, respectively) in obese but not NW women. After E2 priming, ovulatory obese but not NW women had a 25% increase in luteal progesterone (P = .01). Obese women had significantly higher baseline IL-6, IL-10, TGF-β, and IL-12 compared with NW (all P < .05); these levels were reduced after E2 (-6% for IL-1β, -21% for IL-8, -5% for TGF-β, -5% for IL-12; all P < .05) in obese but not in NW women., Conclusions: E2 priming seems to improve hypothalamic-pituitary-ovarian axis function and systemic inflammation in ovulatory, obese women. Reducing chronic inflammation at the pituitary level may decrease the burden of obesity on fertility.

Objective: To determine whether obesity alters genes important in cellular growth and inflammation in human cumulus granulosa cells (GCs)., Methods: Eight reproductive-aged women who underwent controlled ovarian hyperstimulation followed by oocyte retrieval for in vitro fertilization were enrolled. Cumulus GC RNA was extracted and processed for microarray analysis on Affymetrix Human Genome U133 Plus 2.0 chips. Gene expression data were validated on GCs from additional biologically similar samples using quantitative real-time polymerase chain reaction (RT-PCR). Comparison in gene expression was made between women with body mass index (BMI) <25 kg/m(2) (group 1; n = 4) and those with BMI ≥25 kg/m(2) (group 2; n = 4)., Results: Groups 1 and 2 had significantly different BMI (21.4 ± 1.4 vs 30.4 ± 2.7 kg/m(2), respectively; P = .02) but did not differ in age (30.5 ± 1.7 vs 32.7 ± 0.3 years, respectively; P = .3). Comparative analysis of gene expression profiles by supervised clustering between group 1 versus group 2 resulted in the selection of 7 differentially expressed genes: fibroblast growth factor 12 (FGF-12), protein phosphatase 1-like (PPM1L), zinc finger protein multitype 2 (ZFPM2), forkhead box M1 (FOXM1), cell division cycle 20 (CDC20), interleukin 1 receptor-like 1 (IL1RL1), and growth arrest-specific protein 7 (GAS7). FOXM1, CDC20, and GAS7 were downregulated while FGF-12 and PPM1L were upregulated in group 2 when compared to group 1. Validation with RT-PCR confirmed the microarray data except for ZFPM2 and IL1RL. As BMI increased, expression of FOXM1 significantly decreased (r = -.60, P = .048)., Conclusions: Adiposity is associated with changes in the expression of genes important in cellular growth, cell cycle progression, and inflammation. The upregulation of the metabolic regulator gene PPM1L suggests that adiposity induces an abnormal metabolic follicular environment, potentially altering folliculogenesis and oocyte quality., (© The Author(s) 2015.)

Obese women exhibit decreased fertility, high miscarriage rates and dysfunctional corpus luteum (CL), but molecular mechanisms are poorly defined. We hypothesized that weight gain induces alterations in CL gene expression. RNA sequencing was used to identify changes in the CL transcriptome in the vervet monkey (Chlorocebus aethiops) during weight gain. 10 months of high-fat, high-fructose diet (HFHF) resulted in a 20% weight gain for HFHF animals vs. 2% for controls (p = 0.03) and a 66% increase in percent fat mass for HFHF group. Ovulation was confirmed at baseline and after intervention in all animals. CL were collected on luteal day 7-9 based on follicular phase estradiol peak. 432 mRNAs and 9 miRNAs were differentially expressed in response to HFHF diet. Specifically, miR-28, miR-26, and let-7b previously shown to inhibit sex steroid production in human granulosa cells, were up-regulated. Using integrated miRNA and gene expression analysis, we demonstrated changes in 52 coordinately regulated mRNA targets corresponding to opposite changes in miRNA. Specifically, 2 targets of miR-28 and 10 targets of miR-26 were down-regulated, including genes linked to follicular development, steroidogenesis, granulosa cell proliferation and survival. To the best of our knowledge, this is the first report of dietary-induced responses of the ovulating ovary to developing adiposity. The observed HFHF diet-induced changes were consistent with development of a dysfunctional CL and provide new mechanistic insights for decreased sex steroid production characteristic of obese women. MiRNAs may represent novel biomarkers of obesity-related subfertility and potential new avenues for therapeutic intervention.