Endometrial carcinoma: The perioperative and long-term outcomes of robotic surgery in the morbidly obese.

BACKGROUND AND METHODS: To evaluate surgical and pathologic outcomes of robotic assisted versus open hysterectomy for women with at least class II (BMI >35) and class III (BMI >40) obesity with endometrial cancer. Women with endometrial cancer and class II obesity, treated with open or robotic hysterectomy between 3/2005 and 3/2013 were eligible for inclusion in this retrospective cohort. Patients with class III obesity were reviewed both within the cohort of class II and as a separate subset. Data were collected on demographics, operative statistics, pathology, post-operative complications, and oncologic outcomes. Tests of significance used Chi-square, Fisher's exact test, t-test, and Wilcoxon rank-sum. RESULTS: One hundred and thirty-six women with BMI >35 who underwent hysterectomy (56 robotic and 80 abdominal) were included. Patients undergoing robotic hysterectomies had fewer post-operative complications, shorter hospital stays, and lower blood loss compared to the abdominal group. A subset (83 of 136) with class III obesity had similar findings. Operative times, lymph node dissection rates, and lymph node yield (both pelvic and para-aortic) were similar between open and robotic surgery in both obesity classes. Oncologic outcomes and use of adjuvant treatment was not compromised. CONCLUSIONS: Robotic hysterectomy is a safe and effective option for morbidly obese women with endometrial cancer. J. Surg. Oncol. 2016;114:884-887. © 2016 2016 Wiley Periodicals, Inc.

A GREB1-steroid receptor feedforward mechanism governs differential GREB1 action in endometrial function and endometriosis.

Cellular responses to the steroid hormones, estrogen (E2), and progesterone (P4) are governed by their cognate receptor's transcriptional output. However, the feed-forward mechanisms that shape cell-type-specific transcriptional fulcrums for steroid receptors are unidentified. Herein, we found that a common feed-forward mechanism between GREB1 and steroid receptors regulates the differential effect of GREB1 on steroid hormones in a physiological or pathological context. In physiological (receptive) endometrium, GREB1 controls P4-responses in uterine stroma, affecting endometrial receptivity and decidualization, while not affecting E2-mediated epithelial proliferation. Of mechanism, progesterone-induced GREB1 physically interacts with the progesterone receptor, acting as a cofactor in a positive feedback mechanism to regulate P4-responsive genes. Conversely, in endometrial pathology (endometriosis), E2-induced GREB1 modulates E2-dependent gene expression to promote the growth of endometriotic lesions in mice. This differential action of GREB1 exerted by a common feed-forward mechanism with steroid receptors advances our understanding of mechanisms that underlie cell- and tissue-specific steroid hormone actions.

Embryo Cryopreservation in a Patient with Sickle Cell Disease Utilizing Letrozole and Enoxaparin: A Case Report.

PURPOSE: To describe a patient with sickle cell disease, a prothrombotic disorder, who underwent successful embryo cryopreservation for the purposes of fertility preservation prior to hematopoietic stem cell transplant. METHODS: To report a successful case of gonadotropin stimulation and embryo cryopreservation using the aromatase inhibitor letrozole to maintain low serum estradiol to minimize thrombotic risk in a patient with sickle cell disease (SCD) and history of retinal artery thrombosis planning hematopoietic stem cell transplant (HSCT). The patient was given letrozole (5 mg daily) as well as prophylactic enoxaparin while undergoing gonadotropin stimulation with an antagonist protocol to preserve fertility prior to HSCT. After the oocyte retrieval, letrozole was continued for one additional week. RESULTS: The patient's peak serum estradiol concentration was 172 pg/mL during gonadotropin stimulation. Ten mature oocytes were retrieved and a total of 10 blastocysts were cryopreserved. The patient required pain medication and intravenous fluids after oocyte retrieval due to pain but had significant improvement at the scheduled post-operative day one follow-up. No embolic events occurred during stimulation or 6 months thereafter. CONCLUSION: The utilization of definitive treatment for SCD with stem cell transplant is increasing. We successfully used letrozole to maintain low serum estradiol during gonadotropin stimulation along with prophylactic enoxaparin in a patient with SCD to minimize her risk of thrombosis. This approach will allow patients planning definitive treatment with stem cell transplant the opportunity to preserve their fertility safely.

SF3B1-dependent alternative splicing is critical for maintaining endometrial homeostasis and the establishment of pregnancy.

The remarkable potential of human endometrium to undergo spontaneous remodeling is shaped by controlled spatiotemporal gene expression patterns. Although hormone-driven transcription shown to govern these patterns, the post-transcriptional processing of these mRNA transcripts, including the mRNA splicing in the endometrium is not studied yet. Here, we report that the splicing factor, SF3B1 is central in driving alternative splicing (AS) events that are vital for physiological responses of the endometrium. We show that loss of SF3B1 splicing activity impairs stromal cell decidualization as well as embryo implantation. Transcriptomic analysis revealed that SF3B1 depletion decidualizing stromal cells led to differential mRNA splicing. Specifically, a significant upregulation in mutually exclusive AS events (MXEs) with SF3B1 loss resulted in the generation of aberrant transcripts. Further, we found that some of these candidate genes phenocopy SF3B1 function in decidualization. Importantly, we identify progesterone as a potential upstream regulator of SF3B1-mediated functions in endometrium possibly via maintaining its persistently high levels, in coordination with deubiquitinating enzymes. Collectively, our data suggest that SF3B1-driven alternative splicing plays a critical role in mediating the endometrial-specific transcriptional paradigms. Thus, the identification of novel mRNA variants associated with successful pregnancy establishment may help to develop new strategies to diagnose or prevent early pregnancy loss.

Association of the human semen DNA virome with successful in vitro fertilization.

OBJECTIVE: To comprehensively characterize the DNA virome in semen samples collected for in vitro fertilization (IVF). DESIGN: A descriptive clinical study. SETTING: Single academic fertility center. PATIENT(S): Twenty-four male partners from couples undergoing IVF. INTERVENTION(S): Couples were randomized to receive 1 g of azithromycin (standard of care) or no azithromycin at the time of baseline IVF assessment. Semen samples were collected at the time of the female partners' egg retrieval, and 100 µL of the sample was used for the virome analysis. MAIN OUTCOME MEASURE(S): Detection of viruses by ViroCap enrichment of viral nucleic acid and sequencing. Association between the virome, semen parameters, and pregnancy outcomes. RESULT(S): We detected viruses in 58% of the participants. Viruses included polyomaviruses, papillomaviruses, herpesviruses, and anelloviruses. Viromes detected in semen had little overlap with the viromes detected in vaginal samples from their female partners collected at the time of embryo transfer, which were analyzed in a previous study. A lower viral diversity in semen samples was positively associated with pregnancy (Hodges-Lehmann estimate of difference, 1; 95% confidence interval, 2-0.00003). There was no association between viral diversity and sperm concentration, motility, or fertilization rates. CONCLUSION(S): This comprehensive characterization of the DNA virome in semen reveals an association between virome diversity and pregnancy in couples undergoing IVF. However, no association was found with specific semen parameters or fertilization rates, suggesting that viral exposure may negatively affect pregnancy after fertilization. Future studies should be undertaken to evaluate the associations between the semen virome with IVF outcomes in larger cohorts.

Machine-learning algorithm incorporating capacitated sperm intracellular pH predicts conventional in vitro fertilization success in normospermic patients.

OBJECTIVE: To measure human sperm intracellular pH (pHi) and develop a machine-learning algorithm to predict successful conventional in vitro fertilization (IVF) in normospermic patients. DESIGN: Spermatozoa from 76 IVF patients were capacitated in vitro. Flow cytometry was used to measure sperm pHi, and computer-assisted semen analysis was used to measure hyperactivated motility. A gradient-boosted machine-learning algorithm was trained on clinical data and sperm pHi and membrane potential from 58 patients to predict successful conventional IVF, defined as a fertilization ratio (number of fertilized oocytes [2 pronuclei]/number of mature oocytes) greater than 0.66. The algorithm was validated on an independent set of data from 18 patients. SETTING: Academic medical center. PATIENT(S): Normospermic men undergoing IVF. Patients were excluded if they used frozen sperm, had known male factor infertility, or used intracytoplasmic sperm injection only. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Successful conventional IVF. RESULT(S): Sperm pHi positively correlated with hyperactivated motility and with conventional IVF ratio (n = 76) but not with intracytoplasmic sperm injection fertilization ratio (n = 38). In receiver operating curve analysis of data from the test set (n = 58), the machine-learning algorithm predicted successful conventional IVF with a mean accuracy of 0.72 (n = 18), a mean area under the curve of 0.81, a mean sensitivity of 0.65, and a mean specificity of 0.80. CONCLUSION(S): Sperm pHi correlates with conventional fertilization outcomes in normospermic patients undergoing IVF. A machine-learning algorithm can use clinical parameters and markers of capacitation to accurately predict successful fertilization in normospermic men undergoing conventional IVF.

Public reporting of IVF outcomes influences medical decision-making and physician training.

BACKGROUND: Since 1992 ART clinics have been required to report outcome data. Our objective was to assess practitioners' opinions of the impact of public reporting of assisted reproductive technology (ART) outcomes on treatment strategies, medical decision-making, and fellow training. METHODS: Survey study performed in an academic medical center. Members of the Society of Reproductive Endocrinology and Infertility and the Society of Reproductive Surgery were recruited to participate in an online survey in April 2012.: Categorical survey responses were expressed as percentages. Written responses were categorized according to common themes regarding effects of reporting on participants' medical management of patients. The study was primarily qualitative and was not powered to make statistical conclusions. RESULTS: Of 1019 surveys sent, 323 participants (31.7%) responded from around the United States, and 275 provided complete data. Nearly all (273 of 282; 96.8%) participants responded that public reporting sometimes or always affected other providers' practices, and 264 of 281 (93.9%) responded that other practitioners were motivated to deny care to poor-prognosis patients to improve reported success rates. However, only 121 of 282 (42.9%) indicated that public reporting influenced their own medical management. The majority of respondents agreed that public reporting may hinder adoption of single embryo transfer practices (194 of 299; 64.9%) and contribute to the persistent rate of twinning in in vitro fertilization (187 of 279; 67%). A small majority (153 of 279; 54.8%) felt that public reporting did not benefit fellow training, and 58 (61.7%) of the 94 participants who trained fellows believed that having fellows perform embryo transfers reduced pregnancy rates. A small majority (163 of 277; 58.8%) of respondents reported their ART success rates on clinical websites. However, the majority (200 of 275; 72.7%) of respondents compared their success rates with those of other clinics. Finally, most respondents (211 of 277; 76%) believed that most centers that advertised their success rates did so in ways that were misleading to patients. CONCLUSIONS: Public reporting of ART clinical outcomes is intended to drive improvement, promote trust between patients and providers, and inform consumers and payers. However, providers reported that they modified their practices, felt others denied care to poor-prognosis patients, and limited participation of trainees in procedures in response to public reporting of ART outcomes.

Complications of Assisted Reproductive Technology.

Although only accounting for a small percentage of infants born in the United States each year, assisted reproductive technology (ART) has become a more common means of conception since the first in vitro fertilization baby was born in 1978. An understanding of the ART process, medications, and complications is becoming essential for emergency medicine practice. Much of the surveillance data focuses on ART complications that are likely to be less relevant in the acute care setting, but ovarian hyperstimulation syndrome, ectopic pregnancy, and ovarian torsion are 3 diagnoses with high potential morbidity and mortality that emergency physicians should not miss.

Membrane Potential Determined by Flow Cytometry Predicts Fertilizing Ability of Human Sperm.

Infertility affects 10 to 15% of couples worldwide, with a male factor contributing up to 50% of these cases. The primary tool for diagnosing male infertility is traditional semen analysis, which reveals sperm concentration, morphology, and motility. However, 25% of infertile men are diagnosed as normozoospermic, meaning that, in many cases, normal-appearing sperm fail to fertilize an egg. Thus, new information regarding the mechanisms by which sperm acquire fertilizing ability is needed to develop a clinically feasible test that can predict sperm function failure. An important feature of sperm fertilization capability in many species is plasma membrane hyperpolarization (membrane potential becoming more negative inside) in response to signals from the egg or female genital tract. In mice, this hyperpolarization is necessary for sperm to undergo the changes in motility (hyperactivation) and acrosomal exocytosis required to fertilize an egg. Human sperm also hyperpolarize during capacitation, but the physiological relevance of this event has not been determined. Here, we used flow cytometry combined with a voltage-sensitive fluorescent probe to measure absolute values of human sperm membrane potential. We found that hyperpolarization of human sperm plasma membrane correlated positively with fertilizing ability. Hyperpolarized human sperm had higher in vitro fertilization (IVF) ratios and higher percentages of acrosomal exocytosis and hyperactivated motility than depolarized sperm. We propose that measurements of human sperm membrane potential could be used to diagnose men with idiopathic infertility and predict IVF success in normozoospermic infertile patients. Patients with depolarized values could be guided toward intracytoplasmic sperm injection, preventing unnecessary cycles of intrauterine insemination or IVF. Conversely, patients with hyperpolarized values of sperm membrane potential could undergo only conventional IVF, avoiding the risks and costs associated with intracytoplasmic sperm injection.