Hysterectomy is not associated with increased risk of urinary incontinence-a northern Finland birth cohort 1966 study.

INTRODUCTION: Hysterectomy has been suggested to increase the risk of urinary incontinence (UI), although evidence is controversial. In our population-based cohort study, we aimed to assess the independent effect of hysterectomy on the risk of de novo UI. MATERIAL AND METHODS: This is a population-based cohort study on the women of the Northern Finland Birth Cohort 1966 (n = 5889). We identified all hysterectomies among the cohort (n = 461) using the national Care Register for Health Care and classified them according to surgical approach into laparoscopic (n = 247), vaginal (n = 107), and abdominal hysterectomies (n = 107). Women without hysterectomy formed the reference group (n = 3495). All women with UI diagnoses and operations were identified in the register, and women with preoperative UI diagnosis (n = 36) were excluded from the analysis to assess de novo UI. Data on potential confounding factors were collected from registers and the cohort questionnaire. Incidences of different UI subtypes and UI operations were compared between the hysterectomy and the reference groups, and further disaggregated by different hysterectomy approaches. Logistic regression models were used to analyze the association between hysterectomy and UI, with adjustments for several UI-related covariates. RESULTS: We found no significant difference in the incidence of UI diagnoses or the rate of subsequent UI operations between the hysterectomy and the reference groups (24 [5.6%] vs. 166 [4.7%], p = 0.416 and 14 [3.3%] vs. 87 [2.5%], p = 0.323). Hysterectomy was not significantly associated with the risk of any subtype of UI (overall UI: OR 1.20, 95% CI 0.77-1.86; stress UI (SUI): OR 1.51, 95% CI 0.89-2.55; other UI: OR 0.80, 95% CI 0.36-1.74). After adjusting for preoperative pelvic organ prolapse (POP) diagnoses, the risk was decreased (overall UI: OR 0.54, 95% CI 0.32-0.90; other than SUI: OR 0.40, 95% CI 0.17-0.95). Regarding different hysterectomy approaches, the risks of overall UI and SUI were significantly increased in vaginal, but not in laparoscopic or abdominal hysterectomy. However, adjusting for preoperative POP diagnosis abolished these risks. CONCLUSIONS: Hysterectomy is not an independent risk factor for de novo UI. Instead, underlying POP appears to be a significant risk factor for the incidence of UI after hysterectomy.

AI-algorithm training and validation for identification of endometrial CD138+ cells in infertility-associated conditions; polycystic ovary syndrome (PCOS) and recurrent implantation failure (RIF).

Background: Endometrial CD138+ plasma cells serve as a diagnostic biomarker for endometrial inflammation, and their elevated occurrence correlates positively with adverse pregnancy outcomes. Infertility-related conditions like polycystic ovary syndrome (PCOS) and recurrent implantation failure (RIF) are closely associated with systemic and local chronic inflammatory status, wherein endometrial CD138+ plasma cell accumulation could also contribute to endometrial pathology. Current methods for quantifying CD138+ cells typically involve laborious and time-consuming microscopic assessments of only a few random areas from a slide. These methods have limitations in accurately representing the entire slide and are susceptible to significant biases arising from intra- and interobserver variations. Implementing artificial intelligence (AI) for CD138+ cell identification could enhance the accuracy, reproducibility, and reliability of analysis. Methods: Here, an AI algorithm was developed to identify CD138+ plasma cells within endometrial tissue. The AI model comprised two layers of convolutional neural networks (CNNs). CNN1 was trained to segment epithelium and stroma across 28,363 mm2 (2.56 mm2 of epithelium and 24.87 mm2 of stroma), while CNN2 was trained to distinguish stromal cells based on CD138 staining, encompassing 7345 cells in the object layers (6942 CD138- cells and 403 CD138+ cells). The training and performance of the AI model were validated by three experienced pathologists. We collected 193 endometrial tissues from healthy controls (n = 73), women with PCOS (n = 91), and RIF patients (n = 29) and compared the CD138+ cell percentages based on cycle phases, ovulation status, and endometrial receptivity utilizing the AI model. Results: The AI algorithm consistently and reliably distinguished CD138- and CD138+ cells, with total error rates of 6.32% and 3.23%, respectively. During the training validation, there was a complete agreement between the decisions made by the pathologists and the AI algorithm, while the performance validation demonstrated excellent accuracy between the AI and human evaluation methods (intraclass correlation; 0.76, 95% confidence intervals; 0.36-0.93, p = 0.002) and a positive correlation (Spearman's rank correlation coefficient: 0.79, p < 0.01). In the AI analysis, the AI model revealed higher CD138+ cell percentages in the proliferative phase (PE) endometrium compared to the secretory phase or anovulatory PCOS endometrium, irrespective of PCOS diagnosis. Interestingly, CD138+ percentages differed according to PCOS phenotype in the PE (p = 0.03). On the other hand, the receptivity status had no impact on the cell percentages in RIF samples. Conclusion: Our findings emphasize the potential and accuracy of the AI algorithm in detecting endometrial CD138+ plasma cells, offering distinct advantages over manual inspection, such as rapid analysis of whole slide images, reduction of intra- and interobserver variations, sparing the valuable time of trained specialists, and consistent productivity. This supports the application of AI technology to help clinical decision-making, for example, in understanding endometrial cycle phase-related dynamics, as well as different reproductive disorders.

Urinary incontinence associates with poor work ability in middle-aged women: A Northern Finland Birth cohort 1966 study.

INTRODUCTION: Urinary incontinence is a common ailment in women and is likely to affect their work ability. We investigated the associations between the different subtypes of urinary incontinence and several dimensions of perceived work ability in middle-aged general population. MATERIAL AND METHODS: Cross-sectional survey at age 46 among participants of the Northern Finland Birth Cohort 1966 study (n = 3706, response rate 72%). Urinary incontinence symptoms and several items of Work Ability Index were collected by postal questionnaire. Work ability was dichotomized as good or poor work ability in general, in relation to physical job demands, to diseases and own 2-year prospect of work ability. The associations between urinary incontinence and work ability measures were assessed using logistic regression models, with further adjustments for biological, behavioral and work-related factors as well as general health. RESULTS: The odds ratio (OR), from lowest to highest, for poor work ability were 1.4-fold among women with stress urinary incontinence (OR 1.37, 95% confidence interval [CI] 1.09-1.72), 2.5-fold with mixed urinary incontinence (OR 2.51, 95% CI 1.68-3.74) and 3.3-fold with urgency urinary incontinence (OR 3.34, 95% CI 1.95-5.70). We note that our results reflect work ability in a Nordic society. CONCLUSIONS: Especially urgency and mixed types of urinary incontinence are associated with poor work ability among middle-aged women.

Long-term results of a prospective randomized trial comparing tension-free vaginal tape versus transobturator tape in stress urinary incontinence.

INTRODUCTION AND HYPOTHESIS: This study was aimed at investigating the long-term effectiveness of minimally invasive mid-urethral sling (MUS) surgery and at comparing the outcomes between retropubic (tension-free vaginal tape, TVT) and transobturator tape (TOT) methods in the treatment of stress urinary incontinence (SUI) and mixed urinary incontinence (MUI) with a predominant stress component in a long-term follow-up of a randomized controlled trial. METHODS: This work is a long-term follow-up study of a previous prospective randomized trial conducted in the Department of Obstetrics and Gynecology at Oulu University Hospital between January 2004 and November 2006. The original 100 patients were randomized into the TVT (n=50) or TOT (n=50) group. The median follow-up time was 16 years, and the subjective outcomes were evaluated using internationally standardized and validated questionnaires. RESULTS: Long-term follow-up data were obtained from 34 TVT patients and 38 TOT patients. At 16 years after MUS surgery, the UISS significantly decreased from a preoperative score in the TVT (11.88 vs 5.00, p<0.001) and TOT (11.05 vs 4.95, p<0.001) groups, showing a good long-term success of the MUS surgery in both groups. In comparing the TVT and TOT procedures, the subjective cure rates did not differ significantly between the study groups in long-term follow-up according to validated questionnaires. CONCLUSION: Midurethral sling surgery had good long-term outcomes in the treatment of SUI and MUI with a predominant stress component. The subjective outcomes of the TVT and TOT procedures were similar after a 16-year follow-up.

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.

Women with polycystic ovary syndrome have poorer work ability and higher disability retirement rate at midlife: a Northern Finland Birth Cohort 1966 study.

Objective: Polycystic ovary syndrome (PCOS) presents with multiple comorbidities potentially affecting function. This was the first general population-based study to evaluate work ability, participation in working life, and disability retirement in middle-aged women with and without PCOS. Design: This is a cohort study. Methods: Women with PCOS (n = 280) and women without PCOS symptoms or diagnosis (n = 1573) were identified in the Northern Finland Birth Cohort in 1966 and were evaluated for self-rated work ability and potential confounders at age 46. Next, incidence rate ratios (IRRs) for disability and unemployment days were extracted from national registers during a prospective 2-year follow-up. Lastly, we assessed hazard ratios (HRs) for disability retirement between 16 and 52 years of age from national registers. Results: The women with PCOS reported poorer ability to work at age 46, especially due to poorer health. During the 2-year follow-up period, the affected women gained on average an additional month of disability and unemployment days, corresponding to an approximately 25% higher risk for both disability (IRR (95% CI): 1.25 (1.22-1.27)) and unemployment days (IRR (95% CI): 1.26 (1.23-1.28)) in models adjusted for health and socioeconomic factors. Lastly, we found a two-fold higher cumulative risk for disability retirement by age 52 compared to non-PCOS women (HR (95% CI): 1.98 (1.40-2.80)), which remained after adjusting for confounding factors (aHR (95% CI): 1.55 (1.01-2.38)). Conclusions: PCOS is associated with lower participation in working life already in midlife. Acknowledging PCOS-related multimorbidity, concerted efforts are needed to support sustainable careers for women with PCOS.

Advancing our understanding of genetic risk factors and potential personalized strategies for pelvic organ prolapse.

Pelvic organ prolapse is a common gynecological condition with limited understanding of its genetic background. In this work, we perform a genome-wide association meta-analysis comprising 28,086 cases and 546,291 controls from European ancestry. We identify 19 novel genome-wide significant loci, highlighting connective tissue, urogenital and cardiometabolic as likely affected systems. Here, we prioritize many genes of potential interest and assess shared genetic and phenotypic links. Additionally, we present the first polygenic risk score, which shows similar predictive ability (Harrell C-statistic (C-stat) 0.583, standard deviation (sd) = 0.007) as five established clinical risk factors combined (number of children, body mass index, ever smoked, constipation and asthma) (C-stat = 0.588, sd = 0.007) and demonstrates a substantial incremental value in combination with these (C-stat = 0.630, sd = 0.007). These findings improve our understanding of genetic factors underlying pelvic organ prolapse and provide a solid start evaluating polygenic risk scores as a potential tool to enhance individual risk prediction.

Artificial intelligence deep learning model assessment of leukocyte counts and proliferation in endometrium from women with and without polycystic ovary syndrome.

OBJECTIVE: To study whether artificial intelligence (AI) technology can be used to discern quantitative differences in endometrial immune cells between cycle phases and between samples from women with polycystic ovary syndrome (PCOS) and non-PCOS controls. Only a few studies have analyzed endometrial histology using AI technology, and especially, studies of the PCOS endometrium are lacking, partly because of the technically challenging analysis and unavailability of well-phenotyped samples. Novel AI technologies can overcome this problem. DESIGN: Case-control study. SETTING: University hospital-based research laboratory. PATIENT(S): Forty-eight women with PCOS and 43 controls. Proliferative phase samples (26 control and 23 PCOS) and luteinizing hormone (LH) surge timed LH+ 7-9 (10 control and 16 PCOS) and LH+ 10-12 (7 control and 9 PCOS) secretory endometrial samples were collected during 2014-2019. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Endometrial samples were stained with antibodies for CD8+ T cells, CD56+ uterine natural killer cells, CD68+ macrophages, and proliferation marker Ki67. Scanned whole slide images were analyzed with an AI deep learning model. Cycle phase differences in leukocyte counts, proliferation rate, and endometrial thickness were measured within the study populations and between the PCOS and control samples. A subanalysis of anovulatory PCOS samples (n = 11) vs. proliferative phase controls (n = 18) was also performed. RESULT(S): Automated cell counting with a deep learning model performs well for the human endometrium. The leukocyte numbers and proliferation in the endometrium fluctuate with the menstrual cycle. Differences in leukocyte counts were not observed between the whole PCOS population and controls. However, anovulatory women with PCOS presented with a higher number of CD68+ cells in the epithelium (controls vs. PCOS, median [interquartile range], 0.92 [0.75-1.51] vs. 1.97 [1.12-2.68]) and fewer leukocytes in the stroma (CD8%, 3.72 [2.18-4.20] vs. 1.44 [0.77-3.03]; CD56%, 6.36 [4.43-7.43] vs. 2.07 [0.65-4.99]; CD68%, 4.57 [3.92-5.70] vs. 3.07 [1.73-4.59], respectively) compared with the controls. The endometrial thickness and proliferation rate were comparable between the PCOS and control groups in all cycle phases. CONCLUSION(S): Artificial intelligence technology provides a powerful tool for endometrial research because it is objective and can efficiently analyze endometrial compartments separately. Ovulatory endometrium from women with PCOS did not differ remarkably from the controls, which may indicate that gaining ovulatory cycles normalizes the PCOS endometrium and enables normalization of leukocyte environment before implantation. Deviant endometrial leukocyte populations observed in anovulatory women with PCOS could be interrelated with the altered endometrial function observed in these women.

Decidualized endometrial stromal cells present with altered androgen response in PCOS.

Hyperandrogenic women with PCOS show disrupted decidualization (DE) and placentation. Dihydrotestosterone (DHT) is reported to enhance DE in non-PCOS endometrial stromal cells (eSCCtrl); however, this has not been assessed in PCOS cells (eSCPCOS). Therefore, we studied the transcriptome profile of non-decidualized (non-DE) and DE eSCs from women with PCOS and Ctrl in response to short-term estradiol (E2) and/or progesterone (P4) exposure with/without (±) DHT. The non-DE eSCs were subjected to E2 ± DHT treatment, whereas the DE (0.5 mM 8-Br-cAMP, 96 h) eSCs were post-treated with E2 and P4 ± DHT, and RNA-sequenced. Validation was performed by immunofluorescence and immunohistochemistry. The results showed that, regardless of treatment, the PCOS and Ctrl samples clustered separately. The comparison of DE vs. non-DE eSCPCOS without DHT revealed PCOS-specific differentially expressed genes (DEGs) involved in mitochondrial function and progesterone signaling. When further adding DHT, we detected altered responses for lysophosphatidic acid (LPA), inflammation, and androgen signaling. Overall, the results highlight an underlying defect in decidualized eSCPCOS, present with or without DHT exposure, and possibly linked to the altered pregnancy outcomes. We also report novel factors which elucidate the mechanisms of endometrial dysfunction in PCOS.

The association of endometriosis with work ability and work life participation in late forties and lifelong disability retirement up till age 52: A Northern Finland Birth Cohort 1966 study.

INTRODUCTION: Endometriosis may cause a deterioration of daily functioning due to related symptoms such as pain, fatigue and psychological distress. Accordingly, endometriosis may jeopardize work ability, as suggested in mainly survey-based case-control studies, including clinically established cases at fertile age. This is the first general population-level study to evaluate how endometriosis is associated with (1) self-rated work ability and sick leave dates at age 46 years, (2) registered disability and unemployment days between age 46 and 48 and (3) lifelong emergence of registered disability retirement up to age 52. MATERIAL AND METHODS: Endometriosis case identification was based on the Care Register for Health Care and self-reported diagnosis from a population-based birth cohort, which covers 96% of children born in Northern Finland in 1966. A total of 348 women with endometriosis and 3487 women without endometriosis were identified. Questionnaire data on Work Ability Index Score was collected at age 46. Unemployment and disability days were determined from the Social Insurance Institution of Finland and the Finnish Center for Pensions registers. Finally, each individual's first-ever granted pension decision and diagnoses were collected until age 52 years. The associations between endometriosis and work ability were assessed using logistic regression models. RESULTS: Endometriosis was associated with poor work ability at age 46 (odds ratio [OR] 1.62, 95% confidence interval [CI] 1.06-2.47). Furthermore, the association between endometriosis and over 10 days of absenteeism was increased (OR 1.53; 95% CI 1.05-2.23). Between ages 46 and 48, women with endometriosis had 10 days more disability days (55.5 vs 45.5, p = 0.030) in comparison to women without endometriosis, but 20 days less unemployment days (40.6 vs 59.2 days, p = 0.013). There were no differences in early retirement between the study groups until age 52. CONCLUSIONS: Our study showed that endometriosis associates with poor work ability at age 46. Women with endometriosis have more disability days. However, their employment rate and risk of early retirement are comparable to those of women without endometriosis at late fertile age.

Body size during adulthood, but not in childhood, associates with endometriosis, specifically in the peritoneal subtype-population-based life-course data from birth to late fertile age.

INTRODUCTION: Endometriosis is a common gynecological condition causing chronic pain and infertility. Only limited data exist on body size during childhood and adolescence in affected women. A leaner body shape has been associated with endometriosis in adults. However, longitudinal follow-up data from birth to adulthood are lacking. The aim of this study was to assess the association between body size and endometriosis from birth to age 46 years. We also performed in-depth analysis of the endometriosis subtypes. MATERIAL AND METHODS: This was a population-based study including 96% of the children born in Northern Finland in 1966. Endometriosis case identification was based on (a) the World Health Organization's International Statistical Classification of Diseases code documentation from national hospital discharge registers and (b) self-reported diagnosis. A total of 348 women with endometriosis (203 in subtype analysis) and 3487 women without endometriosis were identified. Pregnancy, birth, and growth data up to adolescence were collected from welfare clinical records. Follow-up data of the Northern Finland Birth Cohort 1966 were collected at ages 14, 31, and 46 years through postal questionnaires and clinical examinations and included height, weight, and waist and hip circumference measurements. The associations between endometriosis and body size were assessed using logistic regression models. RESULTS: Body sizes in childhood and adolescence were comparable between women developing endometriosis and those not developing endometriosis. On average, the risk for endometriosis was 2% lower for every kilogram of weight (odds ratio [OR] 0.98, 95% CI 0.97-1.00) and 6% lower for every body mass index unit (OR 0.94, 95% CI 0.90-0.99) at age 31. By age 46, a lower risk for peritoneal endometriosis was observed with greater weight (OR 0.95, 95% CI 0.92-0.98), weight gain from age 14 to age 46 years (OR 0.97, 95% CI 0.93-1.00), body mass index (OR 0.90, 95% CI 0.82-0.98), waist circumference (OR 0.95, 95% CI 0.92-0.99), and waist-hip ratio (OR 0.41, 95% CI 0.21-0.78). CONCLUSIONS: This study provides further evidence of the associations between endometriosis and body size and adiposity, specifically in women with peritoneal endometriosis. The associations are evident in adulthood but not in childhood or adolescence.

The Long-Term Footprint of Endometriosis: Population-Based Cohort Analysis Reveals Increased Pain Symptoms and Decreased Pain Tolerance at Age 46 Years.

Previous studies have shown increased pain sensitivity in fertile-aged women with endometriosis in response to mechanical stimuli. As yet, population-based studies on the association of endometriosis with pain sensation and pain symptoms in late fertile age are lacking. The main objective of this population-based cohort study was to investigate whether a history of endometriosis is associated with altered pain sensation and musculoskeletal pain symptoms at age 46 years. Our data are derived from the Northern Finland Birth Cohort 1966, which contains postal questionnaire data (72% response rate) as well as clinical data assessing pressure-pain threshold and maximal pain tolerance. The study population consisted of 284 women with endometriosis and 3,390 controls. Our results showed that at age 46 women with a history of endometriosis had a 5.3% lower pressure-pain threshold and 5.1% lower maximal pain tolerance compared with controls. The most significant contributors besides endometriosis were anxiety, depression, and current smoking status. Women with endometriosis also reported an increased number of pain sites (0 pain sites, 9.6 vs 17.9%; 5-8 pain sites, 24.8 vs 19.1%, endometriosis vs controls respectively; P < .001), and their pain was more troublesome and intense. The results were adjusted for body mass index, smoking, depressive/anxiety symptoms, education, and use of hormonal contraceptives. These unique data revealed an altered pain sensation and a greater likelihood of reporting musculoskeletal pain at age 46 years among women with a history of endometriosis. The results imply that endometriosis has a long-term footprint on affected women, thus underlying the need for psychological support and medical treatment beyond fertile age. PERSPECTIVE: This population-based cohort study showed decreased pain threshold and maximal pain tolerance in women with endometriosis in the late fertile age of 46 years. The pain was also found to be more bothersome and intense compared with controls.