The association of endometriosis on body size, pain perception, comorbidity and work ability in the Northern Finland Birth cohort 1966:long-term effects of endometriosis on women’s overall health

Abstract Endometriosis is a chronic, benign gynecological disorder affecting 6–10% of women. It is defined by the presence of endometrial tissue outside of the uterine cavity. Endometriosis is an estrogen-dependent condition manifesting as early as adolescence in many cases. On the other hand, the disease symptoms tend to diminish at menopause due to ovarian aging and a lowered effect of estrogen. Clinical manifestations of endometriosis are pain, infertility, and fatigue. Altogether, endometriosis causes considerable burden and decreases quality of life in affected women during their reproductive years. Although earlier studies on endometriosis-related health aspects have been conducted on reproductive-aged women, research on the effect of endometriosis on women’s health during late fertility is comparatively lacking. The aims of this study were to investigate the association between endometriosis and body size from birth up to 46 years of age, to assess pain sensitivity and severity among women with endometriosis at late fertile age as well as the association between endometriosis and non-gynecological comorbidities. Furthermore, work ability and attachment to working life in women with endometriosis at late fertile age were also examined. The study population was derived from the Northern Finland Birth Cohorts 1966 (NFBC1966) with data linkage to several national registers. The results showed that endometriosis was associated with lower body weight and leaner body figure at reproductive age but not in childhood nor in adolescence. At late fertile age, a significant association between lean body size and endometriosis was shown only in cases of peritoneal endometriosis, but not in other subtypes. The results of pain sensitivity analysis showed that still at late fertile age, women with endometriosis had 5.5% lower pressure pain sensitivity and 5.3% lower pressure pain tolerance, and they also had more widespread and disturbing pain, than women without endometriosis. Women with endometriosis were shown to have over twofold increased odds for non-gynecological comorbidities. The association was strongest between endometriosis and allergic, infectious, and pain-causing diseases and non-specific symptoms. Lastly, endometriosis was associated with poor work ability and higher disability days at late fertile age, but not with unemployment or early disability retirement. Altogether, this study shows that even though endometriosis is considered a condition of reproductive age, it does seem to have health- and work-related implications up until late fertile age. Detecting endometriosis behind non-specific symptoms without long diagnostic delay is crucial in order to avoid the prolongation of symptoms. Women with endometriosis should be given more attention in terms of related comorbid conditions and targeted care with a multidisciplinary approach.Tiivistelmä Endometrioosi on krooninen, hyvänlaatuinen gynekologinen sairaus, jota esiintyy 6–10 %:lla fertiili-ikäisistä naisista. Endometrioosi määritellään kohdun limakalvon kaltaisen kudoksen esiintymisenä kohtuontelon ulkopuolella. Endometrioosi on estrogeeniriippuvainen sairaus, ja se puhkeaa yleensä kuukautiskierron käynnistymisen jälkeen. Taudin on ajateltu sammuvan estrogeenituotannon loppuessa vaihdevuosi-iässä. Endometrioosi aiheuttaa oireena mm. kipua, hedelmättömyyttä ja väsymystä, mikä johtaa elämänlaadun heikkenemiseen erityisesti lisääntymisiässä. Aiemmat tutkimukset endometrioosin vaikutuksista naisten terveyteen ovat pääasiassa tapaus-verrokkitutkimuksia ja keskittyvät lisääntymisiässä oleviin naisiin. Väestötason tutkimukset endometrioosin vaikutuksesta naisten terveyteen hedelmällisen iän loppupuolella puuttuvat lähes kokonaan. Tutkimuksen tavoitteena oli arvioida endometrioosin ja kehon koon ja kehon muodon välistä yhteyttä syntymästä 46 ikävuoteen asti. Toiseksi tavoitteenamme oli tutkia endometrioosia sairastavien naisten kipuaistimuksia hedelmällisen iän loppupuolella, sekä endometrioosin ja ei-gynekologisten sairauksien välistä yhteyttä. Lopuksi tutkimme endometrioosia sairastavien naisten työkykyä, työttömyyttä ja varhaista eläköitymistä keski-ikään saakka. Tutkimuksen populaatio koostuu Pohjois-Suomen syntymäkohortti 1966:sta ja aineisto on yhdistetty useisiin kansallisiin rekisteriaineistoihin. Tulokset osoittivat, että lapsuuden ajan ruumiinrakenne on yhtäläinen endometrioosia sairastavilla naisilla verrattuna naisiin, joilla ei ole todettu endometrioosia. Hedelmällisessä iässä endometrioosia sairastavat naiset ovat hoikempia, mutta myöhäisessä hedelmällisessä iässä endometrioosin ja hoikkuuden välinen yhteys ilmeni vain naisilla, jotka sairastivat peritoneaalista endometrioosin alatyyppiä viitaten mahdolliseen endometrioosin alatyyppien välisiin eroihin patogeneesissa. Tarkasteltaessa endometrioosia sairastavien naisten kipumittausten tuloksia havaittiin, että endometrioosia sairastavilla naisilla oli 5,5 % matalampi kipukynnys ja 5,3 % matalampi maksimaalinen kivunsieto. Kipu oli myös laaja-alaisempaa ja häiritsevämpää vielä myöhäisessä hedelmällisessä iässä verrattuna naisiin, joilla ei ole todettua endometrioosia. Endometrioosia sairastavilla naisilla todettiin yli kaksinkertainen riski muihin ei-gynekologisiin sairauksiin, erityisesti allergioihin, infektioihin ja kipusairauksiin sekä autoimmuuni- ja erityyppisiin ei-spesifisiin oireisiin kuin naisilla ilman todettua endometrioosia. Lopuksi, endometrioosilla näytti olevan yhteys heikentyneeseen työkykyyn ja endometrioosia sairastavilla naisilla ilmeni enemmän sairaslomapäiviä vielä myöhäisessä lisääntymisiässä. Toisaalta lisääntynyttä riskiä työkyvyttömyyteen tai varhaiseen eläköitymiseen ei todettu. Tutkimus osoittaa, että endometrioosilla on haitallisia vaikutuksia naisten terveyteen vielä myöhäisessä hedelmällisessä iässä. Endometrioosin varhainen havaitseminen on tärkeää asianmukaisen hoidon tarjoamiseksi ja oireiden pitkittymisen välttämiseksi. On tärkeää tarjota endometrioosia sairastaville naisille asiantuntevaa informaatiota taudin vaikutuksista heidän elämäänsä sekä moniammatillista endometrioosin kokonaisvaltaista hoitoa

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

Abstract 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

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

Abstract 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

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

Abstract 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

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

Abstract 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

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

Abstract 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

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

Abstract 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. Results: 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. Conclusions: 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

Abstract 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