The impact of ovarian stimulation on the human endometrial microenvironment.

STUDY QUESTION: How does ovarian stimulation (OS), which is used to mature multiple oocytes for ART procedures, impact the principal cellular compartments and transcriptome of the human endometrium in the periovulatory and mid-secretory phases? SUMMARY ANSWER: During the mid-secretory window of implantation, OS alters the abundance of endometrial immune cells, whereas during the periovulatory period, OS substantially changes the endometrial transcriptome and impacts both endometrial glandular and immune cells. WHAT IS KNOWN ALREADY: Pregnancies conceived in an OS cycle are at risk of complications reflective of abnormal placentation and placental function. OS can alter endometrial gene expression and immune cell populations. How OS impacts the glandular, stromal, immune, and vascular compartments of the endometrium, in the periovulatory period as compared to the window of implantation, is unknown. STUDY DESIGN, SIZE, DURATION: This prospective cohort study carried out between 2020 and 2022 included 25 subjects undergoing OS and 25 subjects in natural menstrual cycles. Endometrial biopsies were performed in the proliferative, periovulatory, and mid-secretory phases. PARTICIPANTS/MATERIALS, SETTING, METHODS: Blood samples were processed to determine serum estradiol and progesterone levels. Both the endometrial transcriptome and the principal cellular compartments of the endometrium, including glands, stroma, immune, and vasculature, were evaluated by examining endometrial dating, differential gene expression, protein expression, cell populations, and the three-dimensional structure in endometrial tissue. Mann-Whitney U tests, unpaired t-tests or one-way ANOVA and pairwise multiple comparison tests were used to statistically evaluate differences. MAIN RESULTS AND THE ROLE OF CHANCE: In the periovulatory period, OS induced high levels of differential gene expression, glandular-stromal dyssynchrony, and an increase in both glandular epithelial volume and the frequency of endometrial monocytes/macrophages. In the window of implantation during the mid-secretory phase, OS induced changes in endometrial immune cells, with a greater frequency of B cells and a lower frequency of CD4 effector T cells. LARGE SCALE DATA: The data underlying this article have been uploaded to the Genome Expression Omnibus/National Center for Biotechnology Information with accession number GSE220044. LIMITATIONS, REASONS FOR CAUTION: A limited number of subjects were included in this study, although the subjects within each group, natural cycle or OS, were homogenous in their clinical characteristics. The number of subjects utilized was sufficient to identify significant differences; however, with a larger number of subjects and additional power, we may detect additional differences. Another limitation of the study is that proliferative phase biopsies were collected in natural cycles, but not in OS cycles. Given that the OS cycle subjects did not have known endometrial factor infertility, and the comparisons involved subjects who had a similar and robust response to stimulation, the findings are generalizable to women with a normal response to OS. WIDER IMPLICATIONS OF THE FINDINGS: OS substantially altered the periovulatory phase endometrium, with fewer transcriptomic and cell type-specific changes in the mid-secretory phase. Our findings show that after OS, the endometrial microenvironment in the window of implantation possesses many more similarities to that of a natural cycle than does the periovulatory endometrium. Further investigation of the immune compartment and the functional significance of this cellular compartment under OS conditions is warranted. STUDY FUNDING/COMPETING INTERESTS: Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases (R01AI148695 to A.M.B. and N.C.D.), Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD109152 to R.A.), and the March of Dimes (5-FY20-209 to R.A.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or March of Dimes. All authors declare no conflict of interest.

Towards an Improved Understanding of the Effects of Elevated Progesterone Levels on Human Endometrial Receptivity and Oocyte/Embryo Quality during Assisted Reproductive Technologies.

Ovarian stimulation is an indispensable part of IVF and is employed to produce multiple ovarian follicles. In women who undergo ovarian stimulation with gonadotropins, supraphysiological levels of estradiol, as well as a premature rise in progesterone levels, can be seen on the day of hCG administration. These alterations in hormone levels are associated with reduced embryo implantation and pregnancy rates in IVF cycles with a fresh embryo transfer. This article aims to improve the reader's understanding of the effects of elevated progesterone levels on human endometrial receptivity and oocyte/embryo quality. Based on current clinical data, it appears that the premature rise in progesterone levels exerts minimal or no effects on oocyte/embryo quality, while advancing the histological development of the secretory endometrium and displacing the window of implantation. These clinical findings strongly suggest that reduced implantation and pregnancy rates are the result of a negatively affected endometrium rather than poor oocyte/embryo quality. Understanding the potential negative impact of elevated progesterone levels on the endometrium is crucial to improving implantation rates following a fresh embryo transfer. Clinical studies conducted over the past three decades, many of which have been reviewed here, have greatly advanced our knowledge in this important area.

Rhinogenic headache in pediatric and adolescent patients: an evidence-based review.

BACKGROUND: Although some causes of rhinogenic headache, such as acute sinusitis, have clear diagnostic criteria, others, such as "sinus headache" and mucosal contact points, are more nebulous. Misdiagnosis of these entities and primary headaches may result in unnecessary medical or surgical treatment. The purpose of this systematic review is to delineate current understanding of diagnosis and treatment of rhinogenic headaches, including sinus and mucosal contact point headaches, in children. METHODS: PubMed, SCOPUS, and the Cochrane databases were searched for studies on sinus headache and mucosal contact point headaches in children. Studies were assessed for level of evidence, and risk of bias was assessed by Methodological Index for Non-Randomized Studies (MINORS) scoring. Diagnostic criteria, management strategies, and other clinical data were analyzed. RESULTS: Eight studies met the inclusion criteria. Level of evidence was predominantly 4. Forty percent of pediatric patients with migraine had been previously misdiagnosed with sinus headache. Of 327 pediatric patients in two studies, between 55% and 73% had at least 1 cranial autonomic symptom associated with their migraine. For children with mucosal contact point headaches, surgical management in select patients improved headache intensity or severity in 17 (89%) cases. CONCLUSION: The majority of pediatric patients with sinus headache harbor a primary headache disorder, with migraine being most common. Physicians should suspect primary headache disorders in pediatric patients with chronic headaches and a normal exam. Although some case series are supportive of surgical management for mucosal contact point headaches in children, the level of evidence supporting these recommendations is insufficient. High-quality clinical trials are necessary for continuing to improve outcomes in patients with these clinical entities.

Residency Training in Robotic General Surgery: A Survey of Program Directors.

OBJECTIVE: Robotic surgery continues to expand in minimally invasive surgery; however, the literature is insufficient to understand the current training process for general surgery residents. Therefore, the objectives of this study were to identify the current approach to and perspectives on robotic surgery training. METHODS: An electronic survey was distributed to general surgery program directors identified by the Accreditation Council for Graduate Medical Education website. Multiple choice and open-ended questions regarding current practices and opinions on robotic surgery training in general surgery residency programs were used. RESULTS: 20 program directors were surveyed, a majority being from medium-sized programs (4-7 graduating residents per year). Most respondents (73.68%) had a formal robotic surgery curriculum at their institution, with 63.16% incorporating simulation training. Approximately half of the respondents believe that more time should be dedicated to robotic surgery training (52.63%), with simulation training prior to console use (84.21%). About two-thirds of the respondents (63.16%) believe that a formal robotic surgery curriculum should be established as a part of general surgery residency, with more than half believing that exposure should occur in postgraduate year one (55%). CONCLUSION: A formal robotics curriculum with simulation training and early surgical exposure for general surgery residents should be given consideration in surgical residency training.