Plasma proteins and persistent postsurgical pelvic pain among adolescents and young adults with endometriosis.

BACKGROUND: Noninvasive biomarkers that predict surgical treatment response would inform personalized treatments and provide insight into potential biologic pathways underlying endometriosis-associated pain and symptom progression. OBJECTIVE: To use plasma proteins in relation to the persistence of pelvic pain following laparoscopic surgery in predominantly adolescents and young adults with endometriosis using a multiplex aptamer-based proteomics biomarker discovery platform. STUDY DESIGN: We conducted a prospective analysis including 142 participants with laparoscopically-confirmed endometriosis from the Women's Health Study: From Adolescence to Adulthood observational longitudinal cohort with study enrollment from 2012-2018. Biologic samples and patient data were collected with modified World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project tools. In blood collected before laparoscopic ablation or excision of endometriosis, we simultaneously measured 1305 plasma protein levels, including markers for immunity, angiogenesis, and inflammation, using SomaScan. Worsening or persistent postsurgical pelvic pain was defined as having newly developed, persistent (ie, stable), or worsening severity, frequency, or persistent life interference of dysmenorrhea or acyclic pelvic pain at 1-year postsurgery compared with presurgery. We calculated odds ratios and 95% confidence intervals using logistic regression adjusted for age, body mass index, fasting status, and hormone use at blood draw. We applied Ingenuity Pathway Analysis and STRING analysis to identify pathophysiologic pathways and protein interactions. RESULTS: The median age at blood draw was 17 years (interquartile range, 15-19 years), and most participants were White (90%). All had superficial peritoneal lesions only and were treated by excision or ablation. One-year postsurgery, pelvic pain worsened or persisted for 76 (54%) of these participants with endometriosis, whereas pelvic pain improved for 66 (46%). We identified 83 proteins associated with worsening or persistent pelvic pain 1-year postsurgery (nominal P<.05). Compared with those with improved pelvic pain 1-year postsurgery, those with worsening or persistent pelvic pain had higher plasma levels of CD63 antigen (odds ratio, 2.98 [95% confidence interval, 1.44-6.19]) and CD47 (odds ratio, 2.68 [95% confidence interval, 1.28-5.61]), but lower levels of Sonic Hedgehog protein (odds ratio, 0.55 [95% confidence interval, 0.36-0.84]) in presurgical blood. Pathways related to cell migration were up-regulated, and pathways related to angiogenesis were down-regulated in those with worsening or persistent postsurgical pelvic pain compared with those with improved pain. When we examined the change in protein levels from presurgery to postsurgery and its subsequent risk of worsening or persistent postsurgical pain at 1-year follow-up, we observed increasing levels of Sonic Hedgehog protein from presurgery to postsurgery was associated with a 4-fold increase in the risk of postsurgical pain (odds ratio [quartile 4 vs 1], 3.86 [1.04-14.33]). CONCLUSION: Using an aptamer-based proteomics platform, we identified plasma proteins and pathways associated with worsening or persistent pelvic pain postsurgical treatment of endometriosis among adolescents and young adults that may aid in risk stratification of individuals with endometriosis.

Plasma proteomic profiles of pain subtypes in adolescents and young adults with endometriosis.

STUDY QUESTION: What are the similarities and differences in the systemic proteomic profiles by endometriosis-associated pain subtypes among adolescents and young adults with endometriosis? SUMMARY ANSWER: Endometriosis-associated pain subtypes exhibited distinct plasma proteomic profiles. WHAT IS KNOWN ALREADY: Endometriosis patients, especially those diagnosed in adolescents and young adults, are often plagued by various pain symptoms. However, it is not clear what biological processes underlie this heterogeneity. STUDY DESIGN, SIZE, DURATION: We conducted a cross-sectional analysis using data and plasma samples from 142 adolescent or young adult participants of the Women's Health Study: From Adolescence to Adulthood cohort with laparoscopically confirmed endometriosis. PARTICIPANTS/MATERIALS, SETTING, METHODS: We measured 1305 plasma protein levels by SomaScan. We classified self-reported endometriosis-associated pain into subtypes of dysmenorrhea, acyclic pelvic pain, life impacting pelvic pain, bladder pain, bowel pain, and widespread pain phenotype. We used logistic regression to calculate the odds ratios and 95% confidence intervals for differentially expressed proteins, adjusting for age, BMI, fasting status, and hormone use at blood draw. Ingenuity Pathway Analysis identified enriched biological pathways. MAIN RESULTS AND THE ROLE OF CHANCE: Our study population consisted mainly of adolescents and young adults (mean age at blood draw = 18 years), with nearly all (97%) scored as rASRM stage I/II at laparoscopic diagnosis of endometriosis, which is a common clinical presentation of endometriosis diagnosed at a younger age. Pain subtypes exhibited distinct plasma proteomic profiles. Multiple cell movement pathways were downregulated in cases with severe dysmenorrhea and life impacting pelvic pain compared to those without (P < 7.5×10-15). Endometriosis cases with acyclic pelvic pain had upregulation of immune cell adhesion pathways (P < 9.0×10-9), while those with bladder pain had upregulation of immune cell migration (P < 3.7×10-8) and those with bowel pain had downregulation (P < 6.5×10-7) of the immune cell migration pathways compared to those without. Having a wide-spread pain phenotype involved downregulation of multiple immune pathways (P < 8.0×10-10). LIMITATIONS, REASONS FOR CAUTION: Our study was limited by the lack of an independent validation cohort. We were also only able to explore any presence of a pain subtype and could not evaluate multiple combinations by pain subtypes. Further mechanistic studies are warranted to elucidate the differences in pathophysiology by endometriosis-pain subtype. WIDER IMPLICATIONS OF THE FINDINGS: The observed variation in plasma protein profiles by pain subtypes suggests different underlying molecular mechanisms, highlighting the need for potential consideration of pain subtypes for effectively treating endometriosis patients presenting with various pain symptoms. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Department of Defense W81XWH1910318 and the 2017 Boston Center for Endometriosis Trainee Award. Financial support for establishment of and data collection within the A2A cohort were provided by the J. Willard and Alice S. Marriott Foundation. N.S., A.F.V., S.A.M., and K.L.T. have received funding from the Marriott Family Foundation. C.B.S. is funded by an R35 MIRA Award from NIGMS (5R35GM142676). S.A.M. and K.L.T. are supported by NICHD R01HD094842. S.A.M. reports serving as an advisory board member for AbbVie and Roche, Field Chief Editor for Frontiers in Reproductive Health, personal fees from Abbott for roundtable participation; none of these are related to this study. Other authors report no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Circulating proteomic profiles associated with endometriosis in adolescents and young adults.

STUDY QUESTION: What are the systemic molecular profiles of endometriosis diagnosed in adolescents and young adults? SUMMARY ANSWER: Significant enrichment and increased activation of proteins related to angiogenesis and cell migration pathways were observed in endometriosis cases compared to controls (P-value < 2.4 × 10-8). WHAT IS KNOWN ALREADY: Little is known about the pathophysiology of adolescent endometriosis despite the fact that over 50% of adults with endometriosis report onset of severe pelvic pain during adolescence. STUDY DESIGN, SIZE, DURATION: A cross-sectional analysis using data on 142 laparoscopically confirmed endometriosis cases and 74 controls from the observational longitudinal cohort of Women's Health Study: From Adolescence to Adulthood (A2A). PARTICIPANTS/MATERIALS, SETTING, METHODS: We measured 1305 plasma protein levels using the validated, multiplex aptamer-based proteomics discovery platform, SOMAscan. We calculated odds ratios and 95% CIs using logistic regression adjusting for age, BMI, fasting status and hormone use at blood draw for differentially expressed proteins (P < 0.05). Ingenuity Pathway Analysis and STRING analysis were performed to identify biological pathways and protein interactions. We also examined proteins and pathways associated with superficial peritoneal lesion colors (i.e. red, vascularized, white, blue/black, brown). MAIN RESULTS AND THE ROLE OF CHANCE: Average age at blood draw was 18 years for endometriosis cases and 22 years for controls. We identified 63 proteins associated with endometriosis with type-I error set at 0.05, and absolute fold change >1.2, revealing significant enrichment of dysregulated proteins in biological pathways associated with endometriosis. Increased activation of pathways related to angiogenesis and cell migration was observed in plasma from endometriosis cases compared to controls (P-value < 2.4 × 10-8). Furthermore, when we examined proteins and pathways associated with lesion colors, vascularized lesions were associated with upregulation of pathways related to immune cell migration/activation and inflammation, whereas white, blue/black and brown lesions were associated with downregulation of these pathways. LIMITATIONS, REASONS FOR CAUTION: Validation of our results in independent datasets and mechanistic studies are warranted to further our understanding of the pathophysiological characteristics of this common but understudied patient population. WIDER IMPLICATIONS OF THE FINDINGS: To our knowledge, this was the first study to comprehensively examine circulating proteins in predominantly adolescents and young adult women with and without endometriosis. Results from this study provide novel biological insight that will build toward further research to elucidate endometriosis pathophysiology during the earlier course of the disease trajectory. STUDY FUNDING/COMPETING INTEREST(S): This study was supported by the Department of Defense (W81XWH1910318) and the 2017 Boston Center for Endometriosis Trainee Award. Financial support for establishment of and data collection within the A2A cohort were provided by the J. Willard and Alice S. Marriott Foundation. N.S., A.F.V., S.A.M., K.L.T. have received funding from Marriott Family Foundation. S.A.M. and K.L.T. are supported by NICHD (R01 HD94842). S.A.M. serves as an advisory board member for AbbVie and Roche; neither are related to this study. The authors report no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.

Intrauterine device use and risk of ovarian cancer: Results from the New England Case-Control study and Nurses' Health Studies.

Results of studies assessing intrauterine device (IUD) use and ovarian cancer risk are inconsistent. We examined the association between IUD use, including duration, type and timing of use, and ovarian cancer risk using three population-based studies. Data from the New England Case-Control Study (NEC) and two prospective cohort studies, the Nurses' Health Studies (NHS/NHSII), were included in the analysis. Information on IUD use was collected by in-person interview in NEC and by biennial questionnaire in NHS/NHSII. We used unconditional logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI) in NEC and Cox regression to calculate hazard ratios (HR) and 95% CI in NHS/NHSII. We used meta-analysis to combine the NEC and the pooled NHS/NHSII results. Overall, IUD use was not associated with epithelial ovarian cancer risk (OR = 0.96, 95% CI: 0.81-1.14 in NEC; HR = 0.89, 95% CI: 0.69-1.15 in NHS/NHSII; combined RR = 0.94, 95% CI: 0.81-1.08). Among IUD users, older age at first use was associated with increased ovarian cancer risk (P-trend = .03). We did not observe significant associations by IUD type or duration of use. In conclusion, IUD use was not associated with ovarian cancer risk in our study.

Overlap Between Irritable Bowel Syndrome Diagnosis and Endometriosis in Adolescents.

BACKGROUND & AIMS: Gastroenterologic symptoms often are reported by adults with endometriosis, leading to unnecessary diagnostic tests or complicated treatment. We investigated associations between endometriosis and irritable bowel syndrome (IBS) in adolescents and whether concurrent pain disorders affect these. METHODS: We collected data from within The Women's Health Study: Adolescence to Adulthood, which is a US longitudinal study of premenopausal females with and without endometriosis. Our study cohort included participants younger than 21 years enrolled from 2012 to 2018. Participants completed an extensive health questionnaire. Those with IBS based on a self-reported diagnosis or meeting Rome IV diagnostic criteria were considered cases and those without IBS were controls. Subjects without concurrent gastrointestinal disorders or missing pain data (n = 323) were included in the analyses. We calculated adjusted odds ratios using unconditional logistic regression. RESULTS: More adolescents with endometriosis (54 of 224; 24%) had comorbid IBS compared with adolescents without endometriosis (7 of 99; 7.1%). The odds of IBS was 5.26-fold higher among participants with endometriosis than without (95% CI, 2.13-13.0). In girls with severe acyclic pelvic pain, the odds of IBS was 35.7-fold higher in girls without endometriosis (95% CI, 4.67-272.6) and 12-fold higher in girls with endometriosis (95% CI, 4.2-36.3), compared with no/mild pain. For participants with endometriosis, each 1-point increase in acyclic pain severity increased the odds of IBS by 31% (adjusted odds ratio, 1.31; 95% CI, 1.18-1.47). CONCLUSIONS: In an analysis of data from a longitudinal study of girls and women with and without endometriosis, we found significant associations between endometriosis and IBS, and a linear relationship between acyclic pelvic pain severity and the odds of IBS. Increased provider awareness and screening for IBS and endometriosis will improve patient outcomes and increase our understanding of these complex disorders.

Racial/ethnic differences in average CA125 and CA15.3 values and its correlates among postmenopausal women in the USA.

PURPOSE: Among healthy postmenopausal women, levels of CA125 and CA15.3 are influenced by demographic and reproductive factors, including race/ethnicity. In this study, we sought to examine the interaction between race/ethnicity and other correlates of these biomarkers and whether the racial differences observed are simply determined by other correlates with racial differences. METHODS: In archived sera from 946 postmenopausal women who participated in the 2001-2002 cycle of the National Health and Nutrition Examination Survey, we measured CA125 and CA15.3 and examined their associations with health survey and examination data available in this cohort. We used multivariable linear regression to examine the association between CA125 and CA15.3 and race/ethnicity. We then calculated geometric means of these markers by demographic and reproductive factors stratified by race/ethnicity and used likelihood ratio tests to evaluate heterogeneity. RESULTS: Non-white race was associated with lower CA125, with Non-Hispanic Black women being associated with - 29.0% (95% CI - 42.5%, - 12.2%) difference and Mexican American women being associated with - 6.4% (95% CI - 18.1%, 6.9%) difference on average compared to Non-Hispanic White women. Associations between CA125 and age and parity varied by race/ethnicity. Non-Hispanic Black women were associated with higher CA15.3 compared to Non-Hispanic White women, with 17.3% (95% CI - 0.5%, 38.3%) differences on average. Associations between CA15.3 and age, number of births, and age at natural menopause varied by race/ethnicity. CONCLUSIONS: Among postmenopausal women, Non-Hispanic Black women were associated with lower CA125 and higher CA15.3 levels compared to Non-Hispanic White women. Our results support that race/ethnicity should be considered when assigning thresholds for these biomarkers being tested for diagnostic or screening purposes.

Epidemiologic and biologic correlates of serum HE4 and CA125 in women from the National Health and Nutritional Survey (NHANES).

OBJECTIVES: In women with ovarian cancer, tumor features largely determine serum HE4 and CA125 levels, but non-tumor factors may also influence levels and be better understood by studying determinants in a well-characterized sample of women without cancer. METHODS: Serum HE4 and CA125 were measured in 2302 women from the 2001-2002 cohort of the National Heath and Nutritional Survey (NHANES). Publicly-available data on this cohort included demographic/reproductive variables, blood counts, and measurements of C-reactive protein (CRP), total homocysteine (tHcy), cotinine, and creatinine which were examined as predictors of HE4 and CA125 using multivariate models and correlational analyses. RESULTS: HE4 increased non-linearly by age and current smokers had higher HE4. CA125 was lower in postmenopausal women and non-whites and trended downward with increasing BMI. Current-users of oral contraceptives (OCs) had lower HE4 and CA125; and a downward trend for CA125 was seen with increasing OC use. Pregnant women had higher CA125 and nursing women higher HE4. HE4 and CA125 were positively correlated with neutrophils, monocytes, and the neutrophil-to-lymphocyte ratio and inversely correlated with lymphocytes and the lymphocyte-to-monocyte ratio. CRP was positively correlated with both HE4 and CA125 in postmenopausal women. Strong positive correlations existed for HE4 with both tHcy and creatinine. CONCLUSIONS: Serum levels of HE4 and CA125 are influenced by several hormonal or environmental stimuli which affect non-cancerous tissues normally expressing HE4 or CA125. Cytokine co-expression in those tissues may, in turn, affect white cell counts and account for their correlation with HE4 or CA125 levels.

Pelvic organ prolapse after 3 modes of hysterectomy: long-term follow-up.

BACKGROUND: There are various indications and approaches for hysterectomy; yet, the difference in long-term risk of subsequent prolapse after surgery is not well studied. OBJECTIVE: To assess the risk of prolapse after abdominal, vaginal, and laparoscopic or robotic hysterectomy for up to 17 years from surgery. STUDY DESIGN: A retrospective chart review study of women undergoing hysterectomy across all indications (benign and malignant) between 2001 and 2008 was conducted. An equivalent random sample of hysterectomy patients was selected each year. We compared demographic and other surgical characteristics data including age, race, parity, body mass index, indication and year of hysterectomy, blood loss, cervix removal, cuff suspension, and complications using chi-square, Kruskal-Wallis test, and Fisher's exact across the 3 groups. Presence and treatment of subsequent prolapse (based on patient symptoms, pelvic exam, International Classification of Diseases, Ninth Revision diagnosis, and current procedural terminology pessary or surgical codes) were compared with Kaplan-Meier survival analysis and Cox proportional hazards regression. RESULTS: Of the 2158 patients, 1459, 375, and 324 underwent open, vaginal, and laparoscopic or robotic hysterectomy, respectively. The vaginal group (56) was older than the abdominal (52) or laparoscopic or robotic (49) groups, with a P value of <.05. Most patients were White with a mean body mass index of 30 kg/m2. The main indication was cancer for abdominal (33%) and laparoscopic or robotic hysterectomy (25%) and prolapse for vaginal hysterectomy (60%). Time to prolapse was shortest after vaginal surgery (27 months) and longest after laparoscopic or robotic surgery (71 months). After controlling for confounders, including surgery indication, the hazard ratio for subsequent prolapse was no different among vaginal (hazard ratio=1.36 [0.77-2.45]), laparoscopic or robotic (hazard ratio=1.47 [0.80-2.69]), or open (reference) hysterectomy. Prolapse grade was similar across the 3 groups. About 50% of women with recurrent prolapse received physical therapy, pessary, or surgical treatment. CONCLUSION: At the 17-year follow-up, the route of hysterectomy is not associated with a difference in recurrence, grade, or subsequent treatment of prolapse when the indication for hysterectomy is considered. Prolapse, as an indication for hysterectomy, increases risk for recurrence. Women planning a hysterectomy should be counseled appropriately about the risk of subsequent prolapse.

A Clinical and Pathologic Exploration of Suspected Peritoneal Endometriotic Lesions.

Endometriosis is generally histopathologically defined as the presence of at least 2 of the following: endometrial stroma, Müllerian epithelium, and/or hemosiderin-laden macrophages (HLM). Despite clinically evident endometriotic lesions, biopsies are frequently nondiagnostic. In this study, we conducted a large-scale review of biopsies of lesions clinically thought to represent endometriosis and correlate the histologic findings with clinical appearance to expand sensitivity of the pathologic definition of endometriosis, particularly in patients on hormonal therapy. In all, 112 biopsies from 78 patients (mean age=25, range 18-39 yr) were reviewed for histopathologic features suggestive of or diagnostic for endometriosis including the presence of endometrial stroma, Müllerian epithelium, dystrophic calcifications, HLM, chronic inflammation, adhesions, and vascular proliferation. Endometriosis was confirmed by pathologic criteria in 37 of 78 patients (47%). Biopsies from patients on hormonal therapy (n=62, 80%) were significantly less likely to meet pathologic criteria for endometriosis (P=0.01). Nondiagnostic biopsies (70/112; 63%) frequently displayed HLM (20%), chronic inflammation (29%), dystrophic calcifications (26%), vascular proliferation (20%), or adhesions (20%) and were significantly more likely to have a vascular clinical appearance (P=0.01). Diagnostic biopsies (42/112; 38%) were more likely to have a blue/black clinical appearance (P=0.03), demonstrate HLM (P=0.004), and display pseudodecidualization (P=0.05). Patients with a high clinical suspicion of endometriosis have a range of histologic findings, with less than half meeting the current histopathologic criteria for diagnosing endometriosis. Given the heterogeneous histopathologic appearance, revision of the histologic criteria may be warranted with further exploration, particularly for lesions with predominantly vascular features.

Differential blood count as triage tool in evaluation of pelvic masses.

OBJECTIVE: Triaging patients with presumptive ovarian cancer to the appropriate specialist may improve survival. Therefore, there is increasing interest in complementary diagnostic markers to the standard serum CA125. In patients with pelvic masses, we examined the ability of epidemiologic variables and preoperative differential blood counts to improve detection of ovarian cancer over CA125 alone. METHODS: From pathology reports, patients were classified as having: epithelial ovarian cancer (n=743), including fallopian tube and primary peritoneal cancer, non-epithelial ovarian cancers (n=46), non-ovarian cancers (n=122), or benign disease (1,129). From women with epithelial ovarian cancer, we excluded those who received prior neoadjuvant chemotherapy (n=19). Women were also excluded if they did not have a serum CA125 or complete blood count measured within 180 days prior to surgery (n=1099) or did not have both tests within 90 days of each other (n=13). Categorizing patients by menopausal status, we calculated Pearson correlations between differential counts or ratios and CA125, and used t tests to identity univariate predictors of malignancy and stepwise logistic regression and likelihood ratio tests to create models best distinguishing epithelial ovarian cancer from benign disease. RESULTS: 337 women with epithelial ovarian cancer and 365 with benign disease were included in the analysis. Compared with cancers, women with benign disease had lower average: age, 52.5 versus 58.4 years (p<0.0001); serum CA125, 20 versus 239 U/mL (p<0.0001), neutrophil-to-lymphocyte ratio, 2.4 versus 3.5 (p<0.0001); and platelet-to-lymphocyte ratio, 158 versus 222 (p<0.0001); but greater average body mass index, 28.5 versus 26.8 kg/m2 (p=0.004), and lymphocyte-to-monocyte ratio, 5.6 versus 3.9 (p<0.0001). Correlations between counts and ratios and serum CA125 were seen in both epithelial ovarian cancer and benign disease groups and differed by menopausal status. In premenopausal women, a multivariate model including serum CA125, smoking, family history, lymphocytes, and monocytes performed similarly to the model with lymphocyte-to-monocyte ratio replacing counts. In postmenopausal women, a model including body mass index, parity, monocytes, and basophils performed similarly to the model replacing counts with platelet-to-lymphocyte ratio and lymphocyte-to-monocyte ratio. Models including epidemiologic variables and either counts or ratios were better at fitting data than models with serum CA125 and menopausal status alone. A single model applying to all women overstated performance for premenopausal women and understated performance for postmenopausal women. CONCLUSIONS: Epidemiologic variables and differential counts or ratios better distinguished between benign and malignant disease when compared with serum CA125 alone using separate models for pre- and postmenopausal women.

Loop Electrosurgical Excision Procedure in Managing Persistent Low-Grade Abnormality or Human Papillomavirus Positivity.

OBJECTIVES: The aims of the study were to estimate the rate and to identify predictors of high-grade abnormalities among women with persistent low-grade abnormalities or high-risk human papillomavirus (hrHPV) positivity for at least 2 years stratified by presence (high risk) or absence (low risk) of previous high-grade results or HPV 16/18. MATERIALS AND METHODS: A retrospective cohort study of patients who underwent a loop electrosurgical excision procedure (LEEP) for persistent low-grade or hrHPV positivity was performed. Patients were stratified based on whether they had a history of high-grade and/or HPV 16/18 positivity. Rates of high-grade or worse abnormalities on LEEP were compared using Fisher exact tests. Logistic regression was used to evaluate the associations between patient characteristics and high-grade results on the LEEP. RESULTS: Three hundred eleven LEEPs were performed for persistent low-grade or hrHPV positivity. The rates of occult high grade were 12% and 22% among the low- and high-risk groups, respectively. Compared with those 45 years and older, the adjusted odds of high grade was 3.79 (95% CI = 1.19-12.1) for women aged 25-29 years. The odds of high grade was higher among current versus never smokers (6.40; 95% CI = 2.01-20.4) and those with a history of high-grade abnormality (2.23; 95% CI = 1.12-4.43). At 2 years, approximately half had an abnormal cytology and/or hrHPV positivity result independent of whether high grade was identified on their LEEP specimen. CONCLUSIONS: Patients with persistent low-grade abnormalities or persistent hrHPV should be counseled on the risks and benefits of a LEEP given that 12%-22% have a risk of occult high grade, especially if they have a history of high-grade dysplasia.

Trends in Patient Demographics and Diagnostic Yield at an Academic Colposcopy Clinic From 2008 to 2018.

OBJECTIVE: The aim of the study was to review trends in colposcopy rates and diagnoses of high-grade dysplasia and cancer for the past 10 years at an academic colposcopy clinic. MATERIALS AND METHODS: A registry of patients seen January 2008 to December 2018 at an academic colposcopy clinic was queried to examine trends in patient characteristics, cytology and histology results, and interventions during the study period, which coincided with the implementation of revised national guidelines. Differences in characteristics were examined with analysis of variance and χ tests. Trends in diagnoses were examined with logistic regression. Trends in interventions were modeled with binomial distribution, logit link, Poisson distribution, and log link. RESULTS: Among 5,103 women referred for abnormal pap testing, human papillomavirus, or dysplasia, the mean age increased over time (30.6 in 2008 to 38.4 in 2018, p < .0001) and fewer pregnant patients were served (11.3% in 2008 vs 2.8% in 2018, p < .0001). There were decreased rates of low-grade cytology (81.3% in 2008 vs 73.6% in 2018, p = .006) and increased rates of human papillomavirus positivity (4.1% in 2008 vs. 14.4% in 2018, p < .0001) on referral. Fewer colposcopies were performed per patient per year (1.2 in 2008 vs. 0.7 in 2018, p < .0001), and with this targeted intervention, there was an increased percentage of patients diagnosed with high-grade histology over time (adjusted p = .05). CONCLUSIONS: Over time, the number of colposcopies performed per patient decreased, especially in younger and pregnant women. Meanwhile, the percentage of patients diagnosed with high-grade histology increased, suggesting that guidelines decreased unnecessary procedures while increasing the percentage of patients diagnosed with precancerous lesions.

Statin therapy and association with ovarian cancer risk in the New England Case Control (NEC) study.

Statins are widely used to lower blood cholesterol and reduce risk for cardiovascular diseases, but attention has recently focused on a role in cancer prevention or therapy. Here we present data from a large case-control study addressing whether statin use can lower the risk for epithelial ovarian cancer (EOC). Between 1992 and 2008, data including medications used for at least 6 months were collected from 2,040 cases with EOC and 2,100 frequency-matched controls without the disease who participated in the New England Case Control study. We used unconditional logistic regression controlling for matching factors and potential confounders to examine the association between statin use and the risk for EOC. Overall, women who used statins had 32% lower risk of ovarian cancer compared to non-users (Odds ratio (OR) 0.68, 95% Confidence Interval (CI): 0.54-0.85), adjusting for the matching factors and other covariates. The reduced risk was most apparent in women taking a lipophilic statin who began use after age 49, and who had used them 2-4.9 years. Statin use was associated with lower risks for both serous and non-serous histologic subtypes with the strongest effect seen for mucinous and mixed epithelial subtypes. The association became apparent about a decade after the introduction of statins and did not appear to be confounded by indications for use of statins or medications used concomitantly. In this case-control study, statins were found to lower the risk for both serous and non-serous EOC and especially mucinous EOC.

Persistence of Symptoms After Total vs Supracervical Hysterectomy in Women with Histopathological Diagnosis of Adenomyosis.

STUDY OBJECTIVE: To compare symptom persistence in women with adenomyosis based on retention or removal of the cervix at the time of hysterectomy. DESIGN: Retrospective cohort study and follow-up survey (Canadian Task Force classification xx). SETTING: Tertiary care academic hospital in Boston, Massachusetts. PATIENTS: Women (n = 1580) who underwent laparoscopic hysterectomy for benign indications between 2008 and 2012 at Brigham and Women's Faulkner Hospital and Brigham and Women's Hospital. INTERVENTION: Retrospective chart review and follow-up survey. MEASUREMENTS AND MAIN RESULTS: Among the 1580 women contacted, 762 (48%) responded to the postoperative symptom resolution survey. Of these 762 women, 623 agreed to participate in the study. Menopausal women or those who had undergone bilateral salpingo-oophorectomy were excluded. Adenomyosis was identified on histopathologic evaluation of the uterus in 171 of the remaining 443 women (39%). Compared with women without adenomyosis, those with adenomyosis were older on average (mean age, 46.6 ± 6.8 years vs 45.0 ± 5.5 years; p = .009) and more likely to report that abnormal bleeding and pain led to their hysterectomy (87.7% vs 79.8%; p = .03 and 64.9% vs 51.4%; p = .009, respectively). The rates of total and supracervical hysterectomies were similar in the 2 groups. Following surgery, women with adenomyosis were less likely than those without adenomyosis to report persistent pain (adjusted odds ratio [aOR], 0.43; 95% confidence interval [CI], 0.20-0.93; p = .03). Persistent bleeding was similar in the 2 groups (aOR, 0.97; 95% CI, 0.49-1.93; p = .94). Among women with adenomyosis, multivariable logistic regression showed no difference in persistence of symptoms with cervical removal or retention at the time of hysterectomy. CONCLUSION: Compared with women without adenomyosis, those with histopathologically proven adenomyosis were less likely to report persistent pain following hysterectomy. Retention of the cervix does not appear to increase the risk of symptom persistence or postprocedure patient satisfaction.

Menstrual pain and risk of epithelial ovarian cancer: Results from the Ovarian Cancer Association Consortium.

Menstrual pain, a common gynecological condition, has been associated with increased risk of ovarian cancer in some, but not all studies. Furthermore, potential variations in the association between menstrual pain and ovarian cancer by histologic subtype have not been adequately evaluated due to lack of power. We assessed menstrual pain using either direct questions about having experienced menstrual pain, or indirect questions about menstrual pain as indication for use of hormones or medications. We used multivariate logistic regression to calculate the odds ratio (OR) for the association between severe menstrual pain and ovarian cancer, adjusting for potential confounders and multinomial logistic regression to calculate ORs for specific histologic subtypes. We observed no association between ovarian cancer and menstrual pain assessed by indirect questions. Among studies using direct question, severe pain was associated with a small but significant increase in overall risk of ovarian cancer (OR = 1.07, 95% CI: 1.01-1.13), after adjusting for endometriosis and other potential confounders. The association appeared to be more relevant for clear cell (OR = 1.48, 95% CI: 1.10-1.99) and serous borderline (OR = 1.31, 95% CI: 1.05-1.63) subtypes. In this large international pooled analysis of case-control studies, we observed a small increase in risk of ovarian cancer for women reporting severe menstrual pain. While we observed an increased ovarian cancer risk with severe menstrual pain, the possibility of recall bias and undiagnosed endometriosis cannot be excluded. Future validation in prospective studies with detailed information on endometriosis is needed.

Ovarian cancer early detection by circulating CA125 in the context of anti-CA125 autoantibody levels: Results from the EPIC cohort.

CA125 is the best ovarian cancer early detection marker to date; however, sensitivity is limited and complementary markers are required to improve discrimination between ovarian cancer cases and non-cases. Anti-CA125 autoantibodies are observed in circulation. Our objective was to evaluate whether these antibodies (1) can serve as early detection markers, providing evidence of an immune response to a developing tumor, and (2) modify the discriminatory capacity of CA125 by either masking CA125 levels (resulting in lower discrimination) or acting synergistically to improve discrimination between cases and non-cases. We investigated these objectives using a nested case-control study within the European Prospective Investigation into Cancer and Nutrition cohort (EPIC) including 250 cases diagnosed within 4 years of blood collection and up to four matched controls. Circulating CA125 antigen and antibody levels were quantified using an electrochemiluminescence assay. Adjusted areas under the curve (aAUCs) by 2-year lag-time intervals were calculated using conditional logistic regression calibrated toward the absolute risk estimates from a pre-existing epidemiological risk model as an offset-variable. Anti-CA125 levels alone did not discriminate cases from controls. For cases diagnosed <2 years after blood collection, discrimination by CA125 antigen was suggestively higher with higher anti-CA125 levels (aAUC, highest antibody tertile: 0.84 [0.76-0.92]; lowest tertile: 0.76 [0.67-0.86]; phet = 0.06). We provide the first evidence of potentially synergistic discrimination effects of CA125 and anti-CA125 antibodies in ovarian early detection. If these findings are replicated, evaluating CA125 in the context of its antibody may improve ovarian cancer early detection.

Early life abuse and risk of endometriosis.

STUDY QUESTION: Is there an association between physical and sexual abuse occurring in childhood or adolescence and risk of laparoscopically-confirmed endometriosis? SUMMARY ANSWER: Early life sexual and physical abuse was associated with an increased risk of endometriosis. WHAT IS KNOWN ALREADY: Previous studies have reported that physical and sexual abuse are associated with chronic pelvic pain (CPP). However, only one study has examined the association between childhood physical abuse and laparoscopically-confirmed endometriosis, and did not observe an association with endometriosis risk. STUDY DESIGN, SIZE, DURATION: Prospective cohort study using data collected from 60 595 premenopausal women from 1989 to 2013 as part of the Nurses' Health Study II cohort. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants completed an exposure to violence victimization questionnaire in 2001. Cases were restricted to laparoscopically-confirmed endometriosis. Cox proportional hazards models were used to calculate rate ratios (RR) and 95% confidence intervals (CI). MAIN RESULTS AND THE ROLE OF CHANCE: Three thousand three hundred and ninety-four cases of laparoscopically-confirmed endometriosis were diagnosed during 24 years of follow-up. Compared to those reporting no physical or sexual abuse, the risk of endometriosis was greater among those who experienced severe physical abuse (RR = 1.20; 95% CI = 1.06, 1.37) or severe sexual abuse (RR = 1.49; 95% CI = 1.24, 1.79). There was a 79% increased risk of laparoscopically-confirmed endometriosis for women reporting severe-chronic abuse of multiple types (95% CI = 1.44, 2.22). The associations between abuse and endometriosis were stronger among women presenting without infertility, a group that was more likely to have been symptomatic with respect to pain. LIMITATIONS, REASONS FOR CAUTION: The violence exposure was recalled by the study participants and thus is subject to misclassification as well as recall bias for the cases who were diagnosed prior to 2001. However, our results were similar in a sensitivity analysis including only endometriosis cases incident after their violence history report. In addition, residual or unmeasured confounding is a possibility; however, we were able to adjust for a variety of potential early life confounders. Finally, selection bias is also a possibility if those who chose to return the violence questionnaire did so based jointly on abuse history and endometriosis risk. WIDER IMPLICATIONS OF THE FINDINGS: Early life sexual and physical abuse was associated with an increased risk of endometriosis. Severity, chronicity and accumulation of types of abuse were associated with greater risk. Understanding the mechanisms underlying these relations may better define the biologic impacts of abuse and the related pathophysiology of endometriosis. STUDY FUNDING/COMPETING INTEREST(s): This work was supported by National Institute of Child Health and Human Development [Grant numbers HD48544, HD52473, HD57210 and CA50385] and the Atlanta Clinical and Translational Science Institute [Grant number ULRR025008]. The Nurses' Health Study II is supported by the National Institutes of Health grant UM1 CA176726 from the National Cancer Institute. H.R.H. is supported by the National Cancer Institute, National Institutes of Health [Grant number K22 CA193860]. Authors report no conflict of interest.

Spectrum of symptoms in women diagnosed with endometriosis during adolescence vs adulthood.

BACKGROUND: Endometriosis symptoms often start at a young age, and the time between symptom onset and endometriosis diagnosis can be several years. It is not clear whether the symptoms that are experienced by adolescents differ from adults. Better understanding may shorten the often lengthy delay in diagnosis. OBJECTIVE: The purpose of the study was to further elucidate the symptom presentation of adolescents as compared with adults to determine whether differences existed, based on age at surgical diagnosis that could impact time to diagnosis. STUDY DESIGN: This investigation was a cross-sectional study at enrollment within a longitudinal cohort of adolescents and women with endometriosis. The population-based cohort was recruited from 2 tertiary care centers and the surrounding communities. Participants included adolescents (diagnosed at ≤18 years old; n=295) and adults (diagnosed at >18 years old; n=107) with surgically confirmed endometriosis who were enrolled into The Women's Health Study: From Adolescence to Adulthood. Participants completed an expanded version of the World Endometriosis Research Foundation Endometriosis Phenome and Biobanking Harmonization Project standard clinical questionnaire that included items regarding menstrual history, associated symptoms, and pain. Chi-square or Fisher's exact tests were applied to categoric data; Wilcoxon rank sum tests were applied to continuous data. RESULTS: Most participants (90%) experienced moderate-severe menstrual pain. On average, 3 doctors were seen before diagnosis, regardless of age at presentation (range, 0-25 years). Time from symptoms to diagnosis averaged 2 years for adolescents and 5 years for adults (P<.001). More adolescents (50%) than adults (33%) reported pain starting at menarche (P=.002) and nausea accompanying pain (69% vs 53%; P=.01). Noncyclic, general pelvic pain was prevalent. One-half of the participants reported relief of their general pelvic pain after a bowel movement. Pain interfered with work/school, daily activities, exercise, and sleep to a moderate-extreme degree; difficulties were similar by age at diagnosis. CONCLUSIONS: Pelvic pain was severe and noncyclic and negatively impacted quality of life. At our tertiary care centers, symptoms of endometriosis did not differ between women surgically diagnosed during adolescence compared with those diagnosed as adults. Adolescents had more nausea and symptom onset at menarche. Multi-year delays in diagnosis were common. Clinicians should be aware of these alternate symptom patterns and include endometriosis in their differential diagnosis for both adolescent and young adult women who experience noncyclic pelvic pain and nausea.

A prospective cohort study of meat and fish consumption and endometriosis risk.

BACKGROUND: Only 2 case-control studies have examined the associations between consumption of meat products and endometriosis risk with inconsistent results. Consumption of animal products has the potential to influence endometriosis risk through effects on steroid hormones levels. OBJECTIVE: We sought to determine whether higher intake of red meat, poultry, fish, and seafood are associated with risk of laparoscopically confirmed endometriosis. STUDY DESIGN: A total of 81,908 participants of the prospective Nurses' Health Study II were followed up from 1991 through 2013. Diet was assessed via food frequency questionnaire every 4 years. Cox proportional hazards models were used to calculate rate ratios and 95% confidence intervals. RESULTS: During 1,019,294 person-years of follow-up, 3800 cases of incident laparoscopically confirmed endometriosis were reported. Women consuming >2 servings/d of red meat had a 56% higher risk of endometriosis (95% confidence interval, 1.22-1.99; Ptrend < .0001) compared to those consuming ≤1 serving/wk. This association was strongest for nonprocessed red meats (rate ratio, 1.57; 95% confidence interval, 1.35-1.83 for ≥2 servings/d vs ≤1 servings/wk; Ptrend < .0001), particularly among women who had not reported infertility (Pinteraction = .0004). Women in the highest category of processed red meat intake also had a higher risk of endometriosis (rate ratio, 1.20; 95% confidence interval, 1.06-1.37 for ≥5 servings/wk vs <1 serving/mo; Ptrend = .02). Intakes of poultry, fish, shellfish, and eggs were unrelated to endometriosis risk. CONCLUSION: Our prospective analysis among premenopausal US nurses suggests that red meat consumption may be an important modifiable risk factor for endometriosis, particularly among women with endometriosis who had not reported infertility and thus were more likely to present with pain symptoms. Well-designed dietary intervention studies among women with endometriosis could help confirm this observation.

Extramammary Paget Disease of the Vulva: A Case Series Examining Treatment, Recurrence, and Malignant Transformation.

OBJECTIVES: Extramammary Paget disease (EMPD) of the vulva is a rare lesion with a high recurrence rate ranging from 12% to 61%. The rate of underlying adenocarcinoma varies, but in the largest series was reported at 4%. Given the rarity of the disease there is a paucity of data to optimize treatment. This study aims to describe the management and recurrence patterns in a tertiary care setting and to offer suggestions for management in a modern-day setting. METHODS: Patients with pathologically confirmed EMPD treated from 2000 to 2015 were retrospectively identified using an IRB approved database. Clinical data were abstracted from the electronic medical record. Pathology underwent central review. RESULTS: Forty-four patients met criteria and underwent central pathology review. Forty-two patients were treated with surgical excision. Alternative treatment modalities included Mohs surgery in 3 patients and medical therapy in 20 patients. The median number of surgical procedures was 1 and the number of procedures ranged from 1 to 16. Twenty-five patients (56.8%) had recurrent disease with a median of 2 (1-6) recurrences per patient. The median disease-free interval was 28.7 months with a median follow up of 45.8 months (1.2-178.9 months). Three patients (7%) had invasive cancer and 7 patients (16%) were diagnosed with a separate malignancy at or following diagnosis of EMPD. Despite radical resection, the majority of patients had positive margins and there was no significant difference in disease recurrence between simple and radical resection (P = 0.69). CONCLUSIONS: Patients with EMPD in this series have a high rate of recurrence. Many undergo multi-modal therapy often with multiple providers. However, patients experience relatively long disease-free intervals with a low rate of associated malignancy. We propose an algorithm for management that focuses on symptom control and minimizing morbidity of treatment intervention once invasive disease has been excluded.