Lateral distribution of endometriotic lesions: The anatomical recesses hypothesis. A systematic review and meta-analysis Veronica Bandini, Sonia Cipriani, Chiara Pillinini, Stefano Angioni, Ludovica Bartiromo, et al. Human Reproduction Open, 2026 STUDY QUESTION Are endometriotic lesions affecting bilateral organs or anatomical structures distributed symmetrically on both sides of the body? SUMMARY ANSWER The left-sided preponderance of pelvic endometriotic lesions, and the right-sided dominance of thoracic and inguinal lesions, suggest that endometriotic lesions exhibit a non-random, asymmetric lateral distribution. WHAT IS KNOWN ALREADY Evaluating the anatomical distribution of endometriotic lesions may elucidate the underlying pathogenic mechanism(s) of the disease. If the coelomic metaplasia or embryonic cell remnant theory is correct, a symmetrical right-left pattern would be expected. Conversely, retrograde menstruation would likely result in asymmetrical distribution, influenced by gravity, peritoneal fluid circulation, and anatomical niches. STUDY DESIGN, SIZE, DURATION This systematic review with meta-analysis included full-length, English-language articles published up to 10 June 2024. Literature searches were performed in PubMed/Medline and Embase databases with the keyword ‘endometriosis’, ‘lateral’, ‘distribution’, ‘right’, ‘left’, and ‘asymmetry’. PARTICIPANTS/MATERIALS, SETTING, METHODS The review focused on anatomical structures commonly affected by endometriosis with surgically defined right or left laterality: ovaries, uterosacral ligaments, colon, ureters, inguinal regions, and hemithorax (diaphragm, pleura, lungs). Case reports were excluded. Risk of bias was assessed using ROBINS-I for non-randomized studies and a dedicated tool for case series. Meta-analyses of proportions were conducted in R. Heterogeneity was quantified using the I2 statistic. Funnel plots for publication bias and Egger tests were performed using Stata. MAIN RESULTS AND THE ROLE OF CHANCE Of 6356 articles screened, 154 met the inclusion criteria. A statistically significant left-sided preponderance was observed for ovarian (58%; 95% CI: 57–60%; P < 0.001), uterosacral ligament (56%; 95% CI: 54–59%; P < 0.001), ureteral (71%; 95% CI: 67–76%; P < 0.001), and bowel (72%; 95% CI: 64–79%; P < 0.001) lesions, whereas thoracic (98%; 95% CI: 96–100%; P < 0.001) and inguinal (92%; 95% CI: 83–98%; P < 0.001) lesions were predominantly right-sided. These findings were confirmed in the sensitivity analyses. Egger’s test indicated a possible small study effect only for ovarian lesions (P = 0.012). LIMITATIONS, REASONS FOR CAUTION The preponderance of retrospective studies, the variability in surgical procedures, and the potential difficulties in accurately distinguishing unilateral from bilateral lesions may have influenced the magnitude of the estimated difference. However, the large patient cohorts, geographical diversity, and consistent asymmetry across lesion types strengthen the results’ validity and generalizability. WIDER IMPLICATIONS OF THE FINDINGS The pattern of endometriotic lesion distribution, including the opposite asymmetry observed in the pelvis and upper abdomen/thorax, can be explained by factors influencing dissemination and implantation of refluxed endometrial cells. However, it cannot be explained as well by the coelomic metaplasia or embryonic cell remnant theories. This may have important clinical implications, providing a pathogenic basis for secondary prevention strategies. STUDY FUNDING/COMPETING INTEREST(S) The open access facility of this paper was funded by the Italian Ministry of Health, Current research IRCCS Ca’ Granda Ospedale Maggiore Policlinico. P.V. is a member of the Editorial Board of Human Reproduction Open, Journal of Obstetrics and Gynaecology Canada, and International Editorial Board of Acta Obstetricia et Gynecologica Scandinavica; has received royalties from Wolters Kluwer for chapters in UpToDate. All other authors declare no conflicts of interest. REGISTRATION NUMBER CRD42024511356 (PROSPERO).
Endometriosis and Adenomyosis: Modern Concepts of Their Clinical Outcomes, Treatment, and Management Jessica Ottolina, Roberta Villanacci, Sara D’Alessandro, Xuemin He, Giorgia Grisafi, et al. Journal of Clinical Medicine, 2024 Endometriosis and adenomyosis are complex gynecological conditions characterized by diverse clinical presentations, including superficial peritoneal endometriosis (SPE), ovarian endometrioma (OMA), and deep infiltrating endometriosis (DIE). The hallmark features of these pathologies involve the manifestation of pain symptoms and infertility, and approximately 30% of patients are asymptomatic. Despite ongoing research, definitive treatments for these conditions remain elusive, and clinical management primarily revolves around medical or surgical interventions. Recent advancements in our understanding of the efficacy of various treatment modalities, including medical therapy and surgical interventions, have provided clinicians with valuable insights into pain relief and fertility preservation. This review aims to provide an updated overview of the latest literature on clinical outcomes, treatment options, and management strategies for different types of endometriosis. By synthesizing the newest available data, this review seeks to inform clinicians and guide decision making based on factors such as patients’ symptom severity, childbearing desire, and overall health.
Extracellular vesicles secreted by human aneuploid embryos present a distinct transcriptomic profile and upregulate MUC1 transcription in decidualised endometrial stromal cells Sofia Makieva, Elisa Giacomini, Giulia Maria Scotti, Dejan Lazarevic, Valentina Pavone, et al. Human Reproduction Open, 2024 STUDY QUESTION Do extracellular vesicles (EVs) secreted by aneuploid human embryos possess a unique transcriptomic profile that elicits a relevant transcriptomic response in decidualized primary endometrial stromal cells (dESCs)? SUMMARY ANSWER Aneuploid embryo-derived EVs contain transcripts of PPM1J, LINC00561, ANKRD34C, and TMED10 with differential abundance from euploid embryo-derived EVs and induce upregulation of MUC1 transcript in dESCs. WHAT IS KNOWN ALREADY We have previously reported that IVF embryos secrete EVs that can be internalized by ESCs, conceptualizing that successful implantation to the endometrium is facilitated by EVs. Whether these EVs may additionally serve as biomarkers of ploidy status is unknown. STUDY DESIGN, SIZE, DURATION Embryos destined for biopsy for preimplantation genetic testing for aneuploidy (PGT-A) were grown under standard conditions. Spent media (30 μl) were collected from euploid (n = 175) and aneuploid (n = 140) embryos at cleavage (Days 1–3) stage and from euploid (n = 187) and aneuploid (n = 142) embryos at blastocyst (Days 3–5) stage. Media samples from n = 35 cleavage-stage embryos were pooled in order to obtain five euploid and four aneuploid pools. Similarly, media samples from blastocysts were pooled to create one euploid and one aneuploid pool. ESCs were obtained from five women undergoing diagnostic laparoscopy. PARTICIPANTS/MATERIALS, SETTING, METHODS EVs were isolated from pools of media by differential centrifugation and EV-RNA sequencing was performed following a single-cell approach that circumvents RNA extraction. ESCs were decidualized (estradiol: 10 nM, progesterone: 1 µM, cAMP: 0.5 mM twice every 48 h) and incubated for 24 h with EVs (50 ng/ml). RNA sequencing was performed on ESCs. MAIN RESULTS AND THE ROLE OF CHANCE Aneuploid cleavage stage embryos secreted EVs that were less abundant in RNA fragments originating from the genes PPM1J (log2fc = −5.13, P = 0.011), LINC00561 (log2fc = −7.87, P = 0.010), and ANKRD34C (log2fc = −7.30, P = 0.017) and more abundant in TMED10 (log2fc = 1.63, P = 0.025) compared to EVs of euploid embryos. Decidualization per se induced downregulation of MUC1 (log2fc = −0.54, P = 0.0028) in ESCs as a prerequisite for the establishment of receptive endometrium. The expression of MUC1 transcript in decidualized ESCs was significantly increased following treatment with aneuploid compared to euploid embryo-secreted EVs (log2fc = 0.85, P = 0.0201). LARGE SCALE DATA Raw data have been uploaded to GEO (accession number GSE234338). LIMITATIONS, REASONS FOR CAUTION The findings of the study will require validation utilizing a second cohort of EV samples. WIDER IMPLICATIONS OF THE FINDINGS The discovery that the transcriptomic profile of EVs secreted from aneuploid cleavage stage embryos differs from that of euploid embryos supports the possibility to develop a non-invasive methodology for PGT-A. The upregulation of MUC1 in dESCs following aneuploid embryo EV treatment proposes a new mechanism underlying implantation failure. STUDY FUNDING/COMPETING INTEREST(S) The study was supported by a Marie Skłodowska-Curie Actions fellowship awarded to SM by the European Commission (CERVINO grant agreement ID: 79620) and by a BIRTH research grant from Theramex HQ UK Ltd. The authors have no conflicts of interest to declare.
Design and methodology of the ‘endometriosis and pelvic floor dysfunction’ (EndoPFD) multicenter cross-sectional study Eleonora Russo, Maria F. Brancalion, Tiziana Fidecicchi, Maria M. Montt-Guevara, Giulia Misasi, et al. Gynecological Endocrinology, 2024 OBJECTIVE To assess the prevalence and the characteristics of pelvic floor dysfunction (PFD) in women with endometriosis. METHODS This is a methodological paper that describes the 'Endometriosis and Pelvic Floor Dysfunction' (EndoPFD) multicenter study protocol. It involves three sites: the University Hospital of Pisa, the San Raffaele Hospital of Milan and the Vanvitelli University Hospital of Naples. Women are recruited through web links and are asked whether they want to participate to the clinical evaluation or only to the web survey. The web survey gathers personal history, endometriosis history and symptoms, and performs a subjective evaluation of PFD through questionnaires: Urinary Distress Inventory 6, Colorectal-Anal Distress Inventory 8, Wexner Scale for Fecal Incontinence, Wexner Constipation Scoring System, and Female Sexual Function Index. Those interested in the clinical evaluation will add to the questionnaires the following exams: gynecological and proctological exam, pelvic ultrasound, urodynamic test, and anorectal manometry. PRELIMINARY RESULTS Recruitment for the web survey was completed. A total of 1,149 women signed the electronic consent, 329 were excluded due to inclusion/exclusion criteria; hence, 525 completed all the questionnaires (response rate of 64.02%). Recruitment for the clinical evaluation is ongoing. DISCUSSION This study protocol offers the possibility to define the prevalence of PFD in endometriosis patients with a subjective and an objective assessment of signs and symptoms. This may pave the way for changing the approach to patients with endometriosis. Moreover, it demonstrates the validity of the method used (online survey and recruitment) to reach a high number of patients.
CO2 fiber laser vaporization for endometrioma treatment results in preserved ovarian responsiveness and improved embryo quality in infertile women undergoing ART Massimo CANDIANI, Stefano M. FERRARI, Noemi SALMERI, Carolina DOLCI, Roberta VILLANACCI, et al. Minerva Obstetrics and Gynecology, 2023 BACKGROUND Infertile women carrying ovarian endometriomas can be managed either with surgery or by in vitro fertilization (IVF). The objective of this study is to compare ovarian responsiveness to controlled ovarian stimulation (COS) in assisted reproduction techniques (ART) in infertile women carrying small intact endometriomas and those managed by endometrioma cystectomy or CO2 fiber laser ablation. METHODS Retrospective case-control study of prospectively collected data including women underwent ART for endometriosis-related infertility. The study group consisted of infertile women undergoing endometriomas CO2 fiber laser vaporization before ART ('ART after laser CO2' group). Controls were infertile women with endometrioma managed by cystectomy before ART ('ART after cystectomy' group) and infertile women with small endometriomas undergoing ART as first approach ('ART only' group). RESULTS Of the 86 included patients, 27 (31.4%) belonged to 'ART after laser CO2' group, 37 (43%) to 'ART after cystectomy' group and 22 (25.6%) to 'ART only' group. Surgical groups had larger endometriomas than patients referred to 'ART only' group. No between-groups differences were observed in terms of COS protocol, gonadotropins starting and total doses and length of COS. While women belonged to 'ART after cystectomy' group had fewer recruited follicles (p = .014), oocytes (p = .042), MII oocytes (p = .042) and formed embryos (p = .004) compared to women of 'ART only' group, no significant differences were found between patients of 'ART only' group 'ART after laser CO2' group. A greater number of good-quality embryos were observed in surgical groups. No between-groups differences were found in clinical pregnancy rates. CONCLUSIONS Our results demonstrate encouraging findings on IVF/ICSI outcomes after laser CO2 endometrioma ablation in terms of both quantity and quality of developed embryos.
Minimally invasive surgery for ovarian endometriosis as a mean of improving fertility: Cystectomy vs. CO2 fiber laser ablation what do we know so far? Massimo Candiani, Jessica Ottolina, Noemi Salmeri, Sara D’Alessandro, Iacopo Tandoi, et al. Frontiers in Surgery, 2023 Minimally invasive surgery emerged in the 1980s as a safe and effective technique which requires smaller incisions and, usually, a shorter hospital stay compared to traditional surgery. Since then, minimally invasive surgery has expanded in many surgical specialties. One of its newest application in gynecology stands in the infertility management of young women with unexplained infertility or suspected endometriosis. In these cases, laparoscopy allows to diagnose and treat the disease aiming to increase at best the chances of spontaneous pregnancy or trough assisted reproductive technology. Nowadays, minimally invasive surgical approach of ovarian endometriosis consists of either laparoscopic cystectomy or ablative techniques such as laparoscopic CO2 fiber laser vaporization. Although cystectomy represents the gold standard according to the latest Cochrane review, some endometriosis experts are worried about its detrimental effect on healthy ovarian parenchyma and suggest preferring a less aggressive approach such as CO2 fiber laser vaporization. The aim of this review is to give an overview of the available evidences about the impact of the two surgical procedures on ovarian reserve markers and pregnancy outcome.
