KRAS mutations and endometriosis burden of disease.

The clinical phenotype of somatic mutations in endometriosis is unknown. The objective was to determine whether somatic KRAS mutations were associated with greater disease burden in endometriosis (i.e. more severe subtypes and higher stage). This prospective longitudinal cohort study included 122 subjects undergoing endometriosis surgery at a tertiary referral center between 2013 and 2017, with 5-9 years of follow-up. Somatic activating KRAS codon 12 mutations were detected in endometriosis lesions using droplet digital PCR. KRAS mutation status for each subject was coded as present (KRAS mutation in at least one endometriosis sample in a subject) or absent. Standardized clinical phenotyping for each subject was carried out via linkage to a prospective registry. Primary outcome was anatomic disease burden, based on distribution of subtypes (deep infiltrating endometriosis, ovarian endometrioma, and superficial peritoneal endometriosis) and surgical staging (Stages I-IV). Secondary outcomes were markers of surgical difficulty, demographics, pain scores, and risk of re-operation. KRAS mutation presence was higher in subjects with deep infiltrating endometriosis or endometrioma lesions only (57.9%; 11/19) and subjects with mixed subtypes (60.6%; 40/66), compared with those with superficial endometriosis only (35.1%; 13/37) (p = 0.04). KRAS mutation was present in 27.6% (8/29) of Stage I cases, in comparison to 65.0% (13/20) of Stage II, 63.0% (17/27) of Stage III, and 58.1% (25/43) of Stage IV cases (p = 0.02). KRAS mutation was also associated with greater surgical difficulty (ureterolysis) (relative risk [RR] = 1.47, 95% CI: 1.02-2.11) and non-Caucasian ethnicity (RR = 0.64, 95% CI: 0.47-0.89). Pain severities did not differ based on KRAS mutation status, at either baseline or follow-up. Re-operation rates were low overall, occurring in 17.2% with KRAS mutation compared with 10.3% without (RR = 1.66, 95% CI: 0.66-4.21). In conclusion, KRAS mutations were associated with greater anatomic severity of endometriosis, resulting in increased surgical difficulty. Somatic cancer-driver mutations may inform a future molecular classification of endometriosis.

Association of Central Sensitization Inventory Scores With Pain Outcomes After Endometriosis Surgery.

Importance: A subset of people who undergo surgery for endometriosis have persistent pain, suggesting that other factors besides the endometriosis, such as central sensitization, may play a role in this pain. The Central Sensitization Inventory, a validated self-reported questionnaire of central sensitization symptoms, may identify individuals with endometriosis who have more pain after surgery due to pain sensitization. Objective: To examine whether greater baseline Central Sensitization Inventory scores are associated with postsurgical pain outcomes. Design, Setting, and Participants: This prospective, longitudinal cohort study performed at a tertiary center for endometriosis and pelvic pain in British Columbia, Canada, included all patients aged 18 to 50 years with diagnosed or suspected endometriosis and a baseline visit between January 1, 2018, and December 31, 2019, who underwent surgery after the baseline visit. Individuals who were menopausal, had a prior hysterectomy, or were missing data for outcomes or measures were excluded. Data analysis was performed from July 2021 to June 2022. Main Outcomes and Measures: The primary outcome was chronic pelvic pain at follow-up measured on a scale of 0 to 10, with 0 to 3 indicating no pain or mild pain, 4 to 6 indicating moderate pain, and 7 to 10 indicating severe pain. Secondary outcomes were deep dyspareunia, dysmenorrhea, dyschezia, and back pain at follow-up. The main variable of interest was baseline Central Sensitization Inventory score (measured from 0 to 100, consisting of 25 self-reported questions rated from 0 to 4 [never, rarely, sometimes, often, and always, respectively]). Results: A total of 239 patients (mean [SD] age, 34 [7] years; 189 [79.1%] White [11 (5.8%) identified as White mixed with another ethnicity], 1 [0.4%] Black or African American, 29 [12.1%] Asian, 2 [0.8%] Native Hawaiian or Pacific Islander, 16 [6.7%] other, and 2 [0.8%] mixed race or ethnicity) with follow-up data at more than 4 months after surgery were included in this study (71.0% follow-up rate). The mean (SD) baseline Central Sensitization Inventory score was 43.8 (18.2), and the mean (SD) follow-up was 16.1 (6.1) months. Higher baseline Central Sensitization Inventory scores were significantly associated with higher chronic pelvic pain (odds ratio [OR], 1.02; 95% CI, 1.00-1.03; P = .02), deep dyspareunia (OR, 1.03; 95% CI, 1.01-1.04; P = .004), dyschezia (OR, 1.03; 95% CI, 1.01-1.04; P < .001), and back pain (OR, 1.02; 95% CI, 1.00-1.03; P = .02) at follow-up, when controlling for baseline pain scores. The Central Sensitization Inventory scores themselves decreased slightly from baseline to follow-up (mean [SD] score, 43.8 [18.2] vs 41.7 [18.9]; P = .05); however, individuals with high baseline Central Sensitization Inventory scores still had high scores at follow-up. Conclusions and Relevance: In this cohort study of 239 patients with endometriosis, higher Central Sensitization Inventory scores at baseline were associated with worse pain outcomes after endometriosis surgery, when controlling for baseline pain scores. The Central Sensitization Inventory could be used to counsel patients with endometriosis on their expected outcomes after surgery.

Single-cell transcriptomic analysis of endometriosis.

Endometriosis is a common condition in women that causes chronic pain and infertility and is associated with an elevated risk of ovarian cancer. We profiled transcriptomes of >370,000 individual cells from endometriomas (n = 8), endometriosis (n = 28), eutopic endometrium (n = 10), unaffected ovary (n = 4) and endometriosis-free peritoneum (n = 4), generating a cellular atlas of endometrial-type epithelial cells, stromal cells and microenvironmental cell populations across tissue sites. Cellular and molecular signatures of endometrial-type epithelium and stroma differed across tissue types, suggesting a role for cellular restructuring and transcriptional reprogramming in the disease. Epithelium, stroma and proximal mesothelial cells of endometriomas showed dysregulation of pro-inflammatory pathways and upregulation of complement proteins. Somatic ARID1A mutation in epithelial cells was associated with upregulation of pro-angiogenic and pro-lymphangiogenic factors and remodeling of the endothelial cell compartment, with enrichment of lymphatic endothelial cells. Finally, signatures of ciliated epithelial cells were enriched in ovarian cancers, reinforcing epidemiologic associations between these two diseases.

Central sensitization inventory in endometriosis.

ABSTRACT: A key clinical problem is identifying the patient with endometriosis whose pain is complicated by central nervous system sensitization, where conventional gynecologic treatment (eg, hormonal therapy or surgery) may not completely alleviate the pain. The Central Sensitization Inventory (CSI) is a questionnaire previously validated in the chronic pain population. The objective of this study was an exploratory proof-of-concept to identify a CSI cutoff in the endometriosis population to discriminate between individuals with significant central contributors (identified by central sensitivity syndromes [CSS]) to their pain compared to those without. We analyzed a prospective data registry at a tertiary referral center for endometriosis, and included subjects aged 18 to 50 years with endometriosis who were newly or re-referred to the center in 2018. The study sample consisted of 335 subjects with a mean age of 36.0 ± 7.0 years. An increasing number of CSS was significantly correlated with dysmenorrhea, deep dyspareunia, dyschezia, and chronic pelvic pain scores (P < 0.001), and with the CSI score (0-100) (r = 0.731, P < 0.001). Receiver operating characteristic analysis indicated that a CSI cutoff of 40 had a sensitivity of 78% (95% CI: 72.7%-84.6%) and a specificity of 80% (95% CI: 70.3%-84.5%) for identifying a patient with endometriosis with ≥3 CSS. In the group with CSI ≥ 40, 18% retrospectively self-reported pain nonresponsive to hormonal therapy and 40% self-reported daily pain, compared with 6% and 20% in the CSI < 40 group (P = 0.003 and 0.002, respectively). In conclusion, a CSI ≥ 40 may be a practical tool to help identify patients with endometriosis with pain contributors related to central nervous system sensitization.

A Quantitative Analysis of Sleep Quality in Women with Endometriosis.

Background: Endometriosis is a complex condition that can negatively affect a woman's quality of life, including her sleep. This study aims to assess the multifactorial variables associated with poorer quality of sleep in women with endometriosis. Materials and Methods: Data from the Endometriosis Pelvic Pain Interdisciplinary Cohort (EPPIC) data registry were analyzed for women who underwent surgery at the BC Women's Center for Pelvic Pain and Endometriosis with histopathological confirmation of endometriosis (June 2015 to June 2017). The primary outcome was quality of sleep preoperatively, from the Chronic Pain Sleep Inventory (0-100 VAS). Bivariate analysis and multivariable linear regression were done to determine any significant associations between preoperative patient variables and overall quality of sleep, based on p-value of 0.05. Results: Two hundred and seventy-five women met the study criteria. Poorer overall quality of sleep was independently associated with poorer functional quality of life (EHP-30) (b = -0.18, p = 0.0026), more depressive symptoms (PHQ-9) (b = -1.62, p < 0.001), and painful bladder syndrome (PBS) (b = -5.82, p = 0.035). This indicates that a 1 point increase in the EHP-30 (worsening quality of life), a 1 point increase in the PHQ-9 (worsening depression), and the presence of PBS increased the primary outcome (i.e., toward poorer quality of sleep) by 0.18, 1.62, and 5.82 points. Conclusions: Poorer quality of sleep in women with endometriosis is associated with poorer quality of life, more depressive symptoms, and bladder pain. Research into interventions that improve sleep is warranted as part of the management of some women with endometriosis.

Endometriosis and Negative Perception of the Medical Profession.

OBJECTIVE: This study sought to identify factors independently associated with a negative impression of the medical profession in patients with endometriosis who were presenting to a tertiary referral centre. METHODS: A cross-sectional analysis was conducted on a prospective data registry between December 2013 and June 2017 at a tertiary referral centre for pelvic pain and endometriosis. The main outcome variable, negative impression about the medical profession, was measured with the four-item subscale of the Endometriosis Health Profile-30 and divided into three groups: no (0), some (1-8), and many (9-16) negative impressions. Patients with a surgical and histological diagnosis of endometriosis were included. Postmenopausal women were excluded. Bivariate analyses determined significant associations (P < 0.05) between variables from the registry and the main outcome. Variables with a significant association were put into ordinal logistic regression with sequential backwards elimination. RESULTS: Negative impression of the medical profession was independently associated with previous surgery that did not help symptoms (adjusted odds ratio [aOR] 1.77; 95% confidence interval [CI] 1.09-2.87; P = 0.021), presentation to an emergency room in the past 3 months (aOR 1.90; 95% CI 1.17-3.07; P = 0.009), and previous visits to a complementary health care provider (aOR 2.16; 95% CI 1.42-3.29; P < 0.0005), while controlling for an endometriosis pain-related morbidity composite variable. CONCLUSION: Negative perception of the medical profession in women with endometriosis was associated with surgical treatment failure, emergency room use, and accessing complementary health care. Each identified factor offers an opportunity for intervention to improve the perception of the medical profession among women with endometriosis.

Plasminogen activator inhibitor-1 (PAI-1) expression in endometriosis.

PURPOSE: Deep infiltrating endometriosis (DIE) is defined as an endometriotic lesion penetrating to a depth of >5 mm and is associated with pelvic pain, but the underlying mechanisms are unclear. Our objective is to investigate whether plasminogen activator inhibitor-1 expression (PAI-1) in endometriotic tissues is increased in women with DIE. METHODS: In this blinded in vitro study, immunohistochemistry and Histoscore were used to examine the expression of PAI-1 in glandular epithelium (GECs) and stroma (SCs) in a total of 62 women: deep infiltrating uterosacral/rectovaginal endometriosis (DIE; n = 13), ovarian endometrioma (OMA; n = 14), superficial peritoneal uterosacral/cul-de-sac endometriosis (SUP; n = 23), uterine (eutopic) endometrium from women with endometriosis (UE; n = 6), and non-endometriosis eutopic endometrium (UC; n = 6). The following patient characteristics were also collected: age, American Fertility Society stage, hormonal suppression, phase of menstrual cycle, dysmenorrhea score and deep dyspareunia score. RESULTS: PAI-1 expression in GECs and SCs of the DIE group was significantly higher than that of SUP group (p = 0.01, p = 0.01, respectively) and UE group (p = 0.03, p = 0.04, respectively). Interestingly, increased PAI-1 expression in GECs and SCs was also significantly correlated with increased dysmenorrhea (r = 0.38, p = 0.01; r = 0.34, p = 0.02, respectively). CONCLUSIONS: We found higher expression of PAI-1 in DIE, and an association between PAI-1 and worse dysmenorrhea.

Deep Dyspareunia in Endometriosis: Role of the Bladder and Pelvic Floor.

INTRODUCTION: The etiology of endometriosis-associated deep dyspareunia may include direct endometriosis-specific factors (eg, stage or invasiveness of disease) and/or indirect contributors such as bladder/pelvic floor dysfunction (eg, related to myofascial mechanisms or nervous system sensitization). AIM: This study aimed to determine whether bladder/pelvic floor tenderness and painful bladder syndrome were associated with severity of deep dyspareunia in women with endometriosis, regardless of Stage (I/II vs III/IV) or other endometriosis-specific factors. METHODS: Observational study from a prospective patient registry (January 2014 to December 2016) at a tertiary centre for endometriosis. Included were women aged 18 to 49 years who had surgical removal and histopathologic confirmation of endometriosis at the centre. Cases with Stage I/II vs Stage III/IV endometriosis were analyzed separately. Bivariate associations with the primary outcome (severity of deep dyspareunia) were tested for bladder/pelvic floor tenderness, painful bladder syndrome, as well as endometriosis-specific factors identified at the time of laparoscopic surgery (eg, deep infiltrating endometriosis) and demographic factors (eg, age). Multivariable ordinal logistic regression was carried out to adjust for factors associated with the primary outcome. MAIN OUTCOME MEASURE: Primary outcome was severity of deep dyspareunia on an 11-point numeric rating scale, categorized as none/mild (0-3), moderate (4-6), and severe (7-10), from a preoperative self-reported questionnaire. RESULTS: Overall, 411 women had surgically confirmed endometriosis: 263 had Stage I/II and 148 had Stage III/IV endometriosis. Among women with Stage I/II endometriosis, severity of deep dyspareunia was associated with both bladder/pelvic floor tenderness and painful bladder syndrome (AOR = 1.94, 95% CI: 1.11-3.38, P = .019 and AOR = 1.99, 95% CI: 1.15-3.44, P = .013, respectively), independent of endometriosis-specific factors or other factors associated with deep dyspareunia severity. Similar associations were found in women with Stage III/IV endometriosis (bladder/pelvic floor tenderness AOR =2.51, 95% CI: 1.25-5.02, P = .01, painful bladder syndrome: AOR = 1.90, 95% CI: 1.01-3.57, P = .048). CLINICAL IMPLICATIONS: Myofascial or nervous system mechanisms may be important for deep dyspareunia in women with endometriosis, even in those with moderate-to-severe disease (Stage III/IV). STRENGTHS & LIMITATIONS: Strengths include the prospective registry, and histological confirmation of endometriosis and staging by experienced endometriosis surgeons. Limitations include assessment of only one pelvic floor muscle (levator ani). CONCLUSION: In women with Stage I/II or Stage III/IV endometriosis, severity of deep dyspareunia was strongly associated with bladder/pelvic floor tenderness and painful bladder syndrome, independent of endometriosis-specific factors, which suggests the role of myofascial or sensitization pain mechanisms in some women with deep dyspareunia. Orr NL, Noga H, Williams C, et al. Deep Dyspareunia in Endometriosis: Role of the Bladder and Pelvic Floor. J Sex Med 2018;15:1158-1166.