Whole-exome sequencing reveals candidate high-risk susceptibility genes for endometriosis.

BACKGROUND: Endometriosis is a common, chronic disease among fertile-aged women. Disease course may be highly invasive, requiring extensive surgery. The etiology of endometriosis remains elusive, though a high level of heritability is well established. Several low-penetrance predisposing loci have been identified, but high-risk susceptibility remains undetermined. Endometriosis is known to increase the risk of epithelial ovarian cancers, especially of endometrioid and clear cell types. Here, we have analyzed a Finnish family where four women have been diagnosed with surgically verified, severely symptomatic endometriosis and two of the patients also with high-grade serous carcinoma. RESULTS: Whole-exome sequencing revealed three rare candidate predisposing variants segregating with endometriosis. The variants were c.1238C>T, p.(Pro413Leu) in FGFR4, c.5065C>T, p.(Arg1689Trp) in NALCN, and c.2086G>A, p.(Val696Met) in NAV2. The only variant predicted deleterious by in silico tools was the one in FGFR4. Further screening of the variants in 92 Finnish endometriosis and in 19 endometriosis-ovarian cancer patients did not reveal additional carriers. Histopathology, positive p53 immunostaining, and genetic analysis supported the high-grade serous subtype of the two tumors in the family. CONCLUSIONS: Here, we provide FGFR4, NALCN, and NAV2 as novel high-risk candidate genes for familial endometriosis. Our results also support the association of endometriosis with high-grade serous carcinoma. Further studies are required to validate the findings and to reveal the exact pathogenesis mechanisms of endometriosis. Elucidating the genetic background of endometriosis defines the etiology of the disease and provides opportunities for expedited diagnostics and personalized treatments.

Increased overall morbidity in women with endometriosis: a population-based follow-up study until age 50.

OBJECTIVE: To investigate whether there is an association between endometriosis and nongynecological diseases in the general female population by age 50? DESIGN: A prospective cohort study. SETTING: Study participants with and without endometriosis were identified from a general population-based birth cohort. The analyzed data, linking to the national hospital discharge registers, spanned up to the age of 50 years. PATIENT(S): Endometriosis case identification was based on national register data and self-reported diagnoses, producing a study population of 349 women with endometriosis and 3,499 women without endometriosis. MAIN OUTCOME MEASURE(S): International Classification of Diseases diagnosis codes from 1968 to 2016 were accumulated from the Finnish national Care Register for Health Care, whereas self-reported symptoms and continuous medication usage data were collected from the questionnaires distributed at age 46. The associations between endometriosis and comorbidities were assessed using logistic regression models that included several covariates. The odds ratios and 95% confidence intervals (CIs) were modeled. Endometriosis subtype and temporal analyses were also performed. RESULT(S): Women with endometriosis were on average twice as likely to have hospital-based nongynecological diagnoses as women without endometriosis (adjusted odds ratio [aOR] 2.32; 95% CI, 1.07-5.02). In more detail, endometriosis was associated with allergies, infectious diseases, pain-causing diseases, and respiratory diseases. Moreover, the affected women presented with nonspecific symptoms and signs (aOR 3.56; 95% CI, 2.73-4.64), especially abdominal and pelvic pain (aOR 4.33; 95% CI, 3.13-4.76) more often compared with nonendometriosis controls. The temporal analysis revealed that diagnoses accumulated at a significantly younger age among women with endometriosis than in nonendometriosis counterparts. CONCLUSION(S): Women with endometriosis have a high risk for several chronic diseases compared with women without endometriosis, underlying the need for awareness and targeted resources for these women in the health care system. Moreover, endometriosis should be considered in the presence of nonspecific symptoms and abdominal pain, as they may conceal the disease and cause considerable delay in diagnosis and treatment.

Robotic versus laparoscopic surgery for severe deep endometriosis: protocol for a randomised controlled trial (ROBEndo trial).

INTRODUCTION: Endometriosis is a common gynaecological disease affecting around 10% of fertile-aged women, causing severe pain symptoms. Deep endometriosis is defined as endometriotic implants that infiltrate the underlying organs more than 5 mm in depth. Surgery for deep endometriosis requires advanced multidisciplinary surgical technique, often in very difficult surgical conditions, with increased risks of complications. Robotic surgery offers a high-definition three-dimensional view and articulating instruments that may allow more precise dissection than conventional laparoscopy in the pelvic area. The superiority of robotic surgery has not, however, been provedin randomised controlled studies, and there is a lack of long-term outcome data. Advanced endometriosis surgery offers an excellent platform to study the feasibility and long-term outcomes of robotic surgery compared with conventional laparoscopy. METHODS AND ANALYSIS: ROBEndo is a prospective, randomised, controlled clinical trial in a single-centre setting. Patients with deep endometriosis verified by MRI needing surgery at Oulu University Hospital (Oulu, Finland) will be considered eligible. 70 patients will be allocated 1:1 to receive either robotic-assisted or conventional laparoscopic surgery in two strata: radical surgery (with the removal of the uterus and adnexae) and gynaecological organ-sparing surgery. The primary outcome will be the surgical outcome as regards to pain symptoms measured on numeric rating scale (NRS) questionnaires at 24 hours and 6, 12 and 24 months postoperatively. As secondary outcomes, intraoperative measures, enhanced recovery after surgery factors, complications, cost and long-term quality of life measured with Endometriosis Health Profile-30 (EHP-30), Female Sexual Function Index (FSFI) and 15-dimensional (15D) questionnaires will be compared. ETHICS AND DISSEMINATION: This study has been approved by the Northern Ostrobothnian Hospital District Ethical Committee at Oulu University Hospital (212/2021). Informed consent will be obtained during the preoperative check-up by the operating gynaecologist. The results will be published in peer-reviewed international journals. TRIAL REGISTRATION NUMBER: NCT05179109.

Laparoscopically guided transversus abdominis plane block versus local wound analgesia in laparoscopic surgery for peritoneal endometriosis: study protocol for a prospective randomized controlled double-blinded LTAP-trial.

BACKGROUND: Ultrasound-guided transversus abdominis plane block (TAP) performed by anesthesiologist has been shown to be an effective and safe analgesia method in abdominal surgery, reducing postoperative opioid consumption. Recently, there has been growing interest to insert TAP under laparoscopic vision (LTAP) by surgeon. LTAP has been used in laparoscopic gastrointestinal surgery, but studies on LTAP in gynecologic laparoscopic surgery are sparse and inconsistent. The purpose of this study is to compare the efficacy of LTAP and local wound analgesia in laparoscopic surgery due to suspected or diagnosed superficial peritoneal endometriosis. METHODS: The LTAP-trial is a prospective randomized controlled double-blinded study comparing the efficacy and safety of LTAP with local wound analgesia in laparoscopic endometriosis surgery. Patients are randomized to receive LTAP with levobupivacaine and wound infiltration with placebo or wound infiltration with levobupivacaine and LTAP with placebo. The primary outcome is postoperative opioid consumption measured by patient-controlled analgesia (PCA) pump. Secondly, subjective postoperative pain up to 24 h postoperatively will be measured by Numeric Rating Scale (NRS). Additional outcome measures are factors related to recovery and length of stay in the hospital as well as a 6-month follow-up survey regarding pain (NRS) and endometriosis-related wellbeing (endometriosis-related health profile, EHP-30) after surgery. A total of 46 patients will be randomized in a proportion of 1:1. DISCUSSION: Patients with peritoneal endometriosis are often prone to severe postoperative pain that may prohibit their enhanced recovery after laparoscopy. Thus, there is a need for effective postoperative pain management with minimal side-effects. This study focusing on laparoscopically inserted transversus abdominis plane block may provide new insight in dealing with postoperative pain after laparoscopic endometriosis surgery as well as after other gynecologic surgery. TRIAL REGISTRATION: The LTAP-trial -protocol has been prospectively registered to ClinicalTrials.gov , ID: NCT04735770 . Registered on February 2021.

Childhood growth of term singletons born after frozen compared with fresh embryo transfer.

RESEARCH QUESTION: Is the growth of term singletons born after frozen embryo transfer (FET) comparable to those born after fresh embryo transfer and natural conception up to 5 years of age? DESIGN: Observational cohort study in an academic medical centre and municipal child health clinics with repeated measurements carried out by medical professionals. Term singletons born after FET (n = 110) and fresh embryo transfer (n = 181) and their matched natural conception controls (n = 543) born in Oulu, Northern Finland, were included. Mean weights, lengths, heights and head circumferences at the ages of 4, 8 and 18 months and 3 and 5 years were compared. At 3 and 5 years, body mass indices were compared. RESULTS: Childhood growth did not differ between term singletons born after FET, fresh embryo transfer and natural conception, correcting for exact age at measurement and adjusting for maternal body mass index and paternal height. CONCLUSIONS: Similar growth between children born after FET, fresh embryo transfer and natural conception offers reassurance of the safety and feasibility of the steadily increasing use of embryo cryopreservation in assisted reproduction.