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.

The pervasive issue of racism and its impact on infertility patients: what can we do as reproductive endocrinologists?

Following the horrific events surrounding the death of George Floyd, we aim to shed some light on our perceptions of the pervasive issue of racism in America and how it impacts the work we do as reproductive endocrinologists. This issue is deeply rooted, and tackling it will involve a multifaceted approach. Ultimately, we are interested in starting this conversation and hope that our colleagues will not only acknowledge that there is a problem that requires immediate attention but will join us in providing sustainable solutions to it.

Multiple Myeloma 1 Transcription Factor Is Superior to CD138 as a Marker of Plasma Cells in Endometrium.

Chronic endometritis is characterized by plasma cell (PC) infiltration of endometrial stroma. Identification of PCs can be challenging by routine hematoxylin and eosin (H&E) stain due to the low numbers of PCs or to their being obscured by other cells in the stroma. CD138 is widely used as an ancillary immunohistochemistry stain to identify PCs; however, it has a high background reaction. In this study, multiple myeloma 1 (MUM1) transcription factor is introduced as an alternative PC marker in endometrial tissues. In this study, 311 endometrial biopsies, submitted to rule out chronic endometritis, were selected. They were divided into Group I (n = 87) and Group II (n = 224). Both had MUM1 and H&E while Group I also had accompanying CD138 stains. In both groups combined, MUM1 detected plasma cells in 48% of the cases, while CD138 and H&E identified the cells in 23% and 15% of the biopsies, respectively. In addition to having a clean background, MUM1 is a more sensitive stain than CD138 for detection of PCs in endometrium.

Transfer of embryos with segmental mosaicism is associated with a significant reduction in live-birth rate.

OBJECTIVE: To evaluate the impact of segmental mosaicism on pregnancy outcomes from the transfer of embryos previously designated as euploid. DESIGN: Retrospective cohort analysis. SETTING: Single, private, high-volume fertility center. PATIENT(S): Three hundred and twenty-seven women who underwent 377 frozen single euploid embryo transfers. INTERVENTION(S): Trophectoderm biopsy of embryos cultured to the blastocyst stage, where all transferred embryos were designated euploid by high-density oligonucleotide array comparative genomic hybridization (aCGH); after ascertaining all outcomes, revaluation of aCGH results for evidence of segmental mosaicism (defined as mosaicism on a portion of a chromosome). MAIN OUTCOME MEASURE(S): Live-birth rate and spontaneous abortion rate. RESULT(S): Of the 377 embryos transferred, 357 were euploid with no mosaicism, and 20 embryos had segmental mosaicism. Segmental mosaics had a statistically significantly lower live-birth rate compared with euploid controls (30.0% vs. 53.8%). When controlling for age and day of Trophectoderm biopsy, the odds for live birth after transfer of segmental mosaics were reduced by 66% compared with euploid controls (0.34; 95% confidence interval, 0.13-0.92). The spontaneous abortion rate was statistically significantly higher after transfer of segmental mosaics compared with euploid controls (40.0% vs. 18.2%). CONCLUSION(S): Blastocysts with segmental mosaicism have reduced reproductive potential but retain the ability to result in live birth. These results support reporting segmental mosaicism to optimize selection of a single embryo for transfer that will maximize the chance of life birth.

Minimal difference in phenotype between adolescents and young adults with polycystic ovary syndrome.

OBJECTIVE: To test the hypothesis that the polycystic ovary syndrome (PCOS) phenotype, or its component features, is less severe in adolescents than in young adult patients, in a referred (clinical) population. DESIGN: Cross-sectional study. SETTING: Tertiary-care academic medical center. PATIENT(S): Two hundred seventy-four adolescents and young adults aged 13.0-24.9 years with PCOS according to the National Institute of Health 1990 criteria. Patients were categorized as adolescents (AD: 13.0-18.9 years; n = 91) and young adults (YA: 19.0-24.9 years; n = 183). Adolescents were further categorized as early adolescents (Early-AD: 13.0-15.9 years; n = 31) and late adolescents (Late-AD: 16.0-18.9 years; n = 60). INTERVENTION(S): History, physical examination, hormonal assays with the use of standardized protocols. MAIN OUTCOME MEASURE(S): Unadjusted and adjusted odds ratios (ORs; adjusted for body mass index [BMI] when applicable) were calculated for biochemical hyperandrogenism (HA), hirsutism (HIR), acne, and degree of oligo/amenorrhea (OA). PCOS phenotypes were classified as HIR+HA+OA, HA+OA, and HIR+OA. RESULT(S): Our analysis demonstrated minimal significant difference in the prevalence of the three PCOS phenotypes, or component features, between AD and YA patients. The risks for obesity were higher for YA versus AD, and the risk of acne was lower for YA versus AD. There was no significant difference between Early-AD and Late-AD. BMI-adjusted models did not significantly modify the main findings. CONCLUSION(S): The present study suggests that the PCOS phenotype is established in early adolescence, remains constant into adulthood, and is not related to BMI.

Sex differences in obesity, lipid metabolism, and inflammation-A role for the sex chromosomes?

BACKGROUND: Sex differences in obesity and related diseases are well established. Gonadal hormones are a major determinant of these sex differences. However, sex differences in body size and composition are evident prior to exposure to gonadal hormones, providing evidence for gonadal-independent contributions attributable to the XX or XY sex chromosome complement. Large-scale genetic studies have revealed male/female differences in the genetic architecture of adipose tissue amount and anatomical distribution. However, these studies have typically neglected the X and Y chromosomes. SCOPE OF THE REVIEW: Here we discuss how the sex chromosome complement may influence obesity, lipid levels, and inflammation. Human sex chromosome anomalies such as Klinefelter syndrome (XXY), as well as mouse models with engineered alterations in sex chromosome complement, support an important role for sex chromosomes in obesity and metabolism. In particular, the Four Core Genotypes mouse model-consisting of XX mice with either ovaries or testes, and XY mice with either ovaries or testes-has revealed an effect of X chromosome dosage on adiposity, hyperlipidemia, and inflammation irrespective of male or female gonads. Mechanisms may include enhanced expression of genes that escape X chromosome inactivation. MAJOR CONCLUSIONS: Although less well studied than effects of gonadal hormones, sex chromosomes exert independent and interactive effects on adiposity, lipid metabolism, and inflammation. In particular, the presence of two X chromosomes has been associated with increased adiposity and dyslipidemia in mouse models and in XXY men. The enhanced expression of genes that escape X chromosome inactivation may contribute, but more work is required.

Can Teamwork and High-Volume Experience Overcome Challenges of Lymphadenectomy in Morbidly Obese Patients (Body Mass Index of 40 kg/m2 or Greater) with Endometrial Cancer?: A Cohort Study of Robotics and Laparotomy and Review of Literature.

OBJECTIVE: This study aimed to compare surgical outcomes and the adequacy of surgical staging in morbidly obese women with a body mass index (BMI) of 40 kg/m or greater who underwent robotic surgery or laparotomy for the staging of endometrioid-type endometrial cancer. METHODS: This is a retrospective cohort study of patients who underwent surgical staging between May 2011 and June 2014. Patients' demographics, surgical outcomes, intraoperative and postoperative complications, and pathological outcomes were compared. RESULTS: Seventy-six morbidly obese patients underwent robotic surgery, and 35 underwent laparotomy for surgical staging. Robotic surgery was associated with more lymph nodes collected with increasing BMI (P < 0.001) and decreased chances for postoperative respiratory failure and intensive care unit admissions (P = 0.03). Despite a desire to comprehensively stage all patients, we performed successful pelvic and paraaortic lymphadenectomy in 96% versus 89% (P = 0.2) and 75% versus 60% (P = 0.12) of robotic versus laparotomy patients, respectively. In the robotic group, with median BMI of 47 kg/m, no conversions to laparotomy occurred. The robotic group experienced less blood loss and a shorter length of hospital stay than the laparotomy group; however, the surgeries were longer. CONCLUSIONS: In a high-volume center, a high rate of comprehensive surgical staging can be achieved in patients with BMI of 40 kg/m or greater either by laparotomy or robotic approach. In our experience, robotic surgery in morbidly obese patients is associated with better quality staging of endometrial cancer. With a comprehensive approach, a professional bedside assistant, use of a monopolar cautery hook, and our protocol of treating morbidly obese patients, robotic surgeries can be safely performed in the vast majority of patients with a BMI of 40 kg/m or greater, with lymph node counts being similar to nonobese patients, and with conversions to laparotomy reduced to a minimum.

Mode of conception does not appear to affect placental volume in the first trimester.

OBJECTIVE: To study whether infertility treatments, including IVF and non-IVF fertility treatments, are associated with diseases of placental insufficiency in early gestation. First trimester placental volumes by ultrasound and chorionic villi weight during sampling (CVS) were performed to detect differences between pregnancies conceived spontaneously versus with fertility treatments. DESIGN: Retrospective cohort. SETTING: Academic tertiary center. PATIENT(S): Women with singleton pregnancies undergoing CVS and first trimester ultrasound from April 2007 to November 2015. INTERVENTION(S): Estimated placental volume (EPV) was calculated from ultrasound images using a validated computation and CVS estimated tissue weight was performed using a validated visual analogue scale. MAIN OUTCOME MEASURE(S): Adjusted linear regression was used to compare EPV and CVS weight based on mode of conception. RESULT(S): A total of 1,977 spontaneous and 334 conceived with fertility treatments (133 non-IVF and 201 IVF) pregnancies were included. Significant differences in maternal age, gravidity, hypertension, and smoking status were identified. EPV and CVS weight were correlated with maternal age, gestational age, and maternal hypertension. Adjusted linear regression showed no difference in EPV in pregnancies conceived with fertility treatments versus spontaneously. The CVS weight was significantly lower in the IVF conceptions in unadjusted univariate analyses. However, after adjusted regression, this was no longer significant. CONCLUSION(S): Mode of conception does not appear to affect first trimester placental size. As differences in maternal age, hypertension, and smoking status differ among the groups and are correlated to placental size, it may be the underlying patient population leading to abnormal placentation and insufficiency, not the fertility treatments used.