Gene Regulation and Mitochondrial Activity During White and Brown Adipogenesis Are Modulated by KDM5 Histone Demethylase.

Body fat accumulation differs between males and females and is influenced by both gonadal sex (ovaries vs testes) and chromosomal sex (XX vs XY). We previously showed that an X chromosome gene, Kdm5c, is expressed at higher levels in females compared to males and correlates with adiposity in mice and humans. Kdm5c encodes a KDM5 histone demethylase that regulates gene expression by modulating histone methylation at gene promoters and enhancers. Here, we use chemical inhibition and genetic knockdown to identify a role for KDM5 activity during early stages of white and brown preadipocyte differentiation, with specific effects on white adipocyte clonal expansion, and white and brown adipocyte gene expression and mitochondrial activity. In white adipogenesis, KDM5 activity modulates H3K4 histone methylation at the Dlk1 gene promoter to repress gene expression and promote progression from preadipocytes to mature adipocytes. In brown adipogenesis, KDM5 activity modulates H3K4 methylation and gene expression of Ucp1, which is required for thermogenesis. Unbiased transcriptome analysis revealed that KDM5 activity regulates genes associated with cell cycle regulation and mitochondrial function, and this was confirmed by functional analyses of cell proliferation and cellular bioenergetics. Using genetic knockdown, we demonstrate that KDM5C is the likely KDM5 family member that is responsible for regulation of white and brown preadipocyte programming. Given that KDM5C levels are higher in females compared to males, our findings suggest that sex differences in white and brown preadipocyte gene regulation may contribute to sex differences in adipose tissue function.

Health Care-Related Economic Burden of Polycystic Ovary Syndrome in the United States: Pregnancy-Related and Long-Term Health Consequences.

CONTEXT: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder of reproductive-aged women, affecting approximately 5% to 20% of women of reproductive age. The economic burden of PCOS was previously estimated at approximately $3.7 billion annually in 2020 USD when considering only the costs of the initial diagnosis and of reproductive endocrine morbidities, without considering the costs of pregnancy-related and long-term morbidities. OBJECTIVE: This study aimed to estimate the excess prevalence and economic burden of pregnancy-related and long-term health morbidities attributable to PCOS. METHODS: PubMed, EmBase, and Cochrane Library were searched, and studies were selected in which the diagnosis of PCOS was consistent with the Rotterdam, National Institutes of Health, or Androgen Excess and PCOS Society criteria, or that used electronic medical record diagnosis codes, or diagnosis based on histopathologic sampling. Studies that included an outcome of interest and a control group of non-PCOS patients who were matched or controlled for body mass index were included. Two investigators working independently extracted data on study characteristics and outcomes. Data were pooled using random effects meta-analysis. The I2 statistic was used to assess inter-study heterogeneity. The quality of selected studies was assessed using the Newcastle-Ottawa Scale. RESULTS: The additional total healthcare-related economic burden of PCOS due to pregnancy-related and long-term morbidities in the United States is estimated to be $4.3 billion annually in 2020 USD. CONCLUSION: Together with our prior analysis, the economic burden of PCOS is estimated at $8 billion annually in 2020 USD.

Sonographic abnormalities in pregnancies conceived following IVF with and without preimplantation genetic testing for aneuploidy (PGT-A).

PURPOSE: To report the rate of fetal anomalies detected on anatomy ultrasound in pregnant patients who underwent IVF with preimplantation genetic testing for aneuploidy (PGT-A) compared to patients who conceived following IVF with unscreened embryos and age-matched patients with natural conceptions. METHODS: Retrospective cohort study at a single maternal-fetal medicine practice. Patients with singleton pregnancies who had a mid-trimester anatomy ultrasound between January 2017 and December 2018 were screened for inclusion. A total of 712 patients who conceived after IVF with or without PGT-A were age-matched with natural conception controls. The primary outcome was the rate of fetal and placental anomalies detected on mid-trimester anatomical survey. Secondary outcomes included the rates of abnormal nuchal translucency (NT), second trimester serum analytes, non-invasive prenatal testing (NIPT), and invasive diagnostic testing. RESULT(S): There were no differences in the rate of fetal anomalies in patients who underwent IVF with PGT-A compared to patients who conceived following IVF with unscreened embryos and age-matched patients with natural conceptions. Rate of abnormal NT, high-risk NIPT, and abnormal invasive diagnostic testing were also similar. Patients who conceived after IVF with or without PGT-A had higher rates of abnormal placental ultrasound findings and abnormal second trimester serum analytes compared to natural conception controls. CONCLUSION: The use of PGT-A was not associated with a difference in risk of fetal anomaly detection on a mid-trimester anatomical survey. The results of this study highlight the importance of improved patient counseling regarding the limitations of PGT-A, and of providing standard prenatal care for pregnancies conceived through ART, regardless of whether PGT-A was performed.

Routine endometrial receptivity array in first embryo transfer cycles does not improve live birth rate.

OBJECTIVE: To compare the live birth rate between patients who undergo personalized embryo transfer (pET) after endometrial receptivity array (ERA) versus frozen embryo transfer (FET) with standard timing in first single euploid FET cycles. To report the rate of displacement of the window of implantation (WOI) in an infertile population without a history of implantation failure. DESIGN: Prospective cohort study of patients who underwent their first single euploid programmed FET. SETTING: Private fertility clinic. PATIENT(S): Patients who underwent first autologous single euploid programmed FET between January 2018 and April 2019. INTERVENTION(S): Endometrial biopsy with ERA followed by pET as indicated. MAIN OUTCOME MEASURE(S): Live birth rate and rate of receptive and nonreceptive ERA. RESULT(S): A total of 228 single euploid FET cycles were included in our analysis. Of those, 147 (64.5%) were ERA/pET cycles, and 81 (35.5%) were standard timing FET cycles. Endometrial receptivity array was receptive in 60/147 (40.8%) and nonreceptive in 87/147 (59.2%) patients. Nonreceptive ERAs were prereceptive in 93.1% of cases. The live birth rate did not differ between patients who underwent FET with standard timing and patients who underwent ERA/pET, 45/81 (56.6%) and 83/147 (56.5%), respectively. CONCLUSION(S): Our data do not support the routine use of ERA in an unselected patient population undergoing first autologous single euploid programmed embryo transfer.

Endometrial compaction does not predict live birth rate in single euploid frozen embryo transfer cycles.

PURPOSE: To evaluate whether endometrial compaction using sequential transvaginal ultrasound is associated with improved live birth rates in medicated single euploid frozen embryo transfer (FET) cycles. METHODS: Prospective observational cohort study at a private fertility clinic. Patients who underwent FETs between January and December 2018 were assessed for inclusion. The change in endometrial thickness between the end of the estrogen phase and the day before embryo transfer, measured by sequential transvaginal ultrasound, was used to categorize cycles with compaction (≥ 5%), no change, or expansion (≥ 5%). FET cycle outcomes were then compared between groups. The primary outcome was live birth. Secondary outcomes include clinical pregnancy rate and rate of spontaneous abortion. RESULTS: Of the 259 single euploid medicated FETs performed during the study period, only 43/259 (16.6%) of the cycles demonstrated ≥ 5% compaction, whereas 152/259 (58.7%) expanded and 64/259 (24.7%) were unchanged. Live birth rates did not differ between cycles with compaction (58.1%), no change (54.7%), or expansion (58.6%), p = 0.96. Clinical pregnancy and spontaneous abortion rates were also similar between groups. CONCLUSION: The vast majority of cycles did not demonstrate endometrial compaction. Endometrial compaction is not associated with live birth rate or spontaneous abortion rate in medicated single euploid FETs in this cohort.

Measures of Patient Dissatisfaction With Health Care in Polycystic Ovary Syndrome: Retrospective Analysis.

BACKGROUND: Polycystic ovary syndrome (PCOS) is a common reproductive and metabolic disorder in women; however, many clinicians may not be well versed in scientific advances that aid understanding of the associated reproductive, metabolic, and psychological abnormalities. Women with PCOS are dissatisfied with health care providers, the diagnostic process, and the initial treatment of PCOS and seek information through alternative sources. This has affected the patient-physician relationship by allowing medical information acquired through the internet, whether correct or not, to become accessible to patients and reshape their health care perspective. Patient dissatisfaction with health care providers regarding PCOS raises questions about the responsibilities of academic institutions to adequately train and maintain the competence of clinicians and government agencies to sufficiently support scientific investigation in this field. OBJECTIVE: The primary aim was to examine internet searching behaviors of the public regarding PCOS vs another highly prevalent gynecologic disorder. The secondary aim was to explore satisfaction with health care among patients with PCOS and their internet use. The tertiary aim was to examine medical education in reproductive endocrinology and infertility (REI) during obstetrics and gynecology (Ob/Gyn) residency as a proxy for physician knowledge in this field. METHODS: Google search trends and StoryBase quantified monthly Google absolute search volumes for search terms related to PCOS and fibroids (January 2004 to December 2017; United States). The reproductive disorder, fibroids, was selected as a comparison group because of its high prevalence among women. Between female groups, monthly absolute search volumes and their trends were compared. A Web-based questionnaire (June 2015 to March 2018) explored health care experiences and the internet use of women with PCOS. REI rotation information during Ob/Gyn residency in the United States was obtained from the Association of Professors of Gynecology and Obstetrics website. RESULTS: For PCOS (R=0.89; P<.01), but not fibroids (R=0.09; P=.25), monthly absolute search volumes increased significantly. PCOS-related monthly absolute search volumes (mean 384,423 searches, SD 88,756) were significantly greater than fibroid-related monthly absolute search volumes (mean 348,502 searches, SD 37,317; P<.05). PCOS was diagnosed by an Ob/Gyn in 60.9% (462/759) of patients, and 57.3% (435/759) of patients were dissatisfied with overall care. Among patients with PCOS, 98.2% (716/729) searched for PCOS on the Web but only 18.8% (143/729) of patients joined an online PCOS support group or forum. On average, Ob/Gyn residencies dedicated only 4% (2/43) of total block time to REI, whereas 5.5% (11/200) of such residencies did not offer any REI rotations. CONCLUSIONS: Over time, PCOS has been increasingly searched on the Web compared with another highly prevalent gynecologic disorder. Patients with PCOS are dissatisfied with their health care providers, who would benefit from an improved understanding of PCOS during Ob/Gyn residency training.

Follicle-stimulating hormone receptor autoantibody associated primary ovarian insufficiency successfully treated with corticosteroids: a case report.

OBJECTIVE: To report a case of successful controlled ovarian stimulation (COH) for oocyte cryopreservation in a patient with autoimmune primary ovarian insufficiency (POI) and polyglandular autoimmune syndrome (PGAS) type 2. DESIGN: Case report. SETTING: Private in vitro fertilization clinic. PATIENTS: 25-Year-old woman, G0, with autoimmune POI and PGAS type 2. INTERVENTIONS: Diagnosis of autoimmune interference with FSH signaling, with subsequent high-dose corticosteroid immune suppression and successful oocyte cryopreservation. MAIN OUTCOMES MEASURES: Successful stimulation with exogenous gonadotropins, oocyte retrieval, and cryopreservation. RESULTS: Retrieval and cryopreservation of 36 metaphase-II (MII) oocytes. CONCLUSIONS: Scrutiny of POI cases will facilitate identification of a subset of patients in whom immune suppression with short-term, high-dose corticosteroids may enable successful COH.

Heterotopic Triplet Pregnancy in Gonadotropin Stimulation Cycle: A Case Report.

Background: Heterotopic pregnancy is defined as the simultaneous presence of 2 or more pregnancies at different implantation sites, most commonly one intrauterine and one ectopic. Triplet heterotopic pregnancy refers to the presence of specifically 3 concurrent gestations with at least 1 being abnormally implanted. Heterotopic pregnancy is a potentially life-threatening condition that requires thorough diagnostic workup and prompt intervention. Case: We report the fourth case of triplet heterotopic pregnancy after ovarian stimulation with gonadotropins. A 24-year-old woman, G0, presented at 6 weeks of gestation with bilateral tubal ectopic pregnancies and a nonviable intrauterine pregnancy (IUP) after gonadotropin stimulation cycle. Bilateral tubal pregnancies were removed laparoscopically and the nonviable IUP via dilation and curettage. Conclusion: Although rare, heterotopic pregnancy of 2 or more gestations must be kept in mind when managing patients undergoing treatment with ART. Careful examination of bilateral adnexa and consideration of uterine sampling at the time of surgery for ectopic pregnancy is advisable, even for patients with few or no risk factors.