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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.

BACKGROUND: Adverse pregnancy outcomes (APO) contribute to higher risk of maternal cerebrovascular disease, but longitudinal data that include APO and stroke timing are lacking. We hypothesized that APO are associated with younger age at first stroke, with a stronger relationship in those with >1 pregnancy with APO. METHODS: We analyzed longitudinal Finnish nationwide health registry data from the FinnGen Study. We included women who gave birth after 1969 when the hospital discharge registry was established. We defined APO as a pregnancy affected by gestational hypertension, preeclampsia, eclampsia, preterm birth, small for gestational age infant, or placental abruption. We defined stroke as first hospital admission for ischemic stroke or nontraumatic intracerebral or subarachnoid hemorrhage, excluding stroke during pregnancy or within 1 year postpartum. We used Kaplan-Meier survival curves and multivariable-adjusted Cox and generalized linear models to assess the relationship between APO and future stroke. RESULTS: We included 144 306 women with a total of 316 789 births in the analysis sample, of whom 17.9% had at least 1 pregnancy with an APO and 2.9% experienced an APO in ≥2 pregnancies. Women with APO had more comorbidities including obesity, hypertension, heart disease, and migraine. Median age at first stroke was 58.3 years in those with no APO, 54.8 years in those with 1 APO, and 51.6 years in those with recurrent APO. In models adjusted for sociodemographic characteristics and stroke risk factors, risk of stroke was greater in women with 1 APO (adjusted hazard ratio, 1.3 [95% CI, 1.2–1.4]) and recurrent APO (adjusted hazard ratio, 1.4 [95% CI, 1.2–1.7]) compared with those with no APO. Women with recurrent APO had more than twice the stroke risk before age 45 (adjusted odds ratio, 2.1 [95% CI, 1.5–3.1]) compared with those without APO. CONCLUSIONS: Women who experience APO have earlier onset of cerebrovascular disease, with the earliest onset in those with more than 1 affected pregnancy.

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.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a tumor predisposition syndrome caused by germline fumarate hydratase (FH) mutations and characterized by uterine and cutaneous leiomyomas and renal cell cancer. Currently, there is no generally approved method to differentiate FH-deficient uterine leiomyomas from other leiomyomas. Here, we analyzed 3 antibodies (S-(2-succino)-cysteine [2SC], aldo-keto reductase family 1, member B10 [AKR1B10], and FH) as potential biomarkers. The study consisted of 2 sample series. The first series included 155 formalin-fixed paraffin-embedded uterine leiomyomas, of which 90 were from HLRCC patients and 65 were sporadic. The second series included 1590 unselected fresh frozen leiomyomas. Twenty-seven tumors were from known HLRCC patients, while the FH status for the remaining 1563 tumors has been determined by copy number analysis and Sanger sequencing revealing 45 tumors with monoallelic (n=33) or biallelic (n=12) FH loss. Altogether 197 samples were included in immunohistochemical analyses: all 155 samples from series 1 and 42 available corresponding formalin-fixed paraffin-embedded samples from series 2 (15 tumors with monoallelic and 7 with biallelic FH loss, 20 with no FH deletion). Results show that 2SC performed best with 100% sensitivity and specificity. Scoring was straightforward with unambiguously positive or negative results. AKR1B10 identified most tumors accurately with 100% sensitivity and 99% specificity. FH was 100% specific but showed slightly reduced 91% sensitivity. Both FH and AKR1B10 displayed also intermediate staining intensities. We suggest that when patient's medical history and/or histopathologic tumor characteristics indicate potential FH-deficiency, the tumor's FH status is determined by 2SC staining. When aberrant staining is observed, the patient can be directed to genetic counseling and mutation screening.

Uterine Fibroids, or leiomyomata, affect millions of women world-wide, with a high incidence of 75% within women of reproductive age. In ~30% of patients, uterine fibroids cause menorrhagia, or heavy menstrual bleeding, and more than half of the patients experience symptoms such as heavy menstrual bleeding, pelvic pain, or infertility. Treatment is symptomatic with limited options including hysterectomy as the most radical solution. The genetic foundations of uterine fibroid growth have been traced to somatic driver mutations (MED12, HMGA2, FH−/−, and COL4A5-A6). These also lead to downstream expression of angiogenic factors including IGF-1 and IGF-2, as opposed to the VEGF-driven mechanism found in the angiogenesis of hypoxic tumors. The resulting vasculature supplying the fibroid with nutrients and oxygen is highly irregular. Of particular interest is the formation of a pseudocapsule around intramural fibroids, a unique structure within tumor angiogenesis. These aberrations in vascular architecture and network could explain the heavy menstrual bleeding observed. However, other theories have been proposed such as venous trunks, or venous lakes caused by the blocking of normal blood flow by uterine fibroids, or the increased local action of vasoactive growth factors. Here, we review and discuss the evidence for the various hypotheses proposed.

Uterine Fibroids (leiomyomata) and endometriosis affect millions of women world-wide. Although aetiology and natural history of the conditions are markedly different, symptoms can overlap and make differential diagnoses necessary, often using invasive methods such as laparoscopy. Considerable comorbidity exists between the two conditions and needs to be taken into account when treating fibroids and/or endometriosis. The genetic foundations of both uterine fibroids and endometriosis remain to be fully understood but recent evidence suggest common underpinnings. Here, we discuss the comorbidity of uterine fibroids and endometriosis and the implications for diagnosis, treatment and risks.

Uterine leiomyomata (UL) are the most common benign tumours of the female genital tract with an estimated lifetime incidence of up to 70%1. To date, 7 genome-wide association studies (GWASs) have identified 35 loci predisposing to UL. To improve the understanding of the underlying genetic pathways, we conducted the largest genetic association study of UL to date in 426,558 European women from FinnGen and a previously published UL meta-GWAS2. We identified 36 novel and replicated 31 previously reported loci. Annotations of the potential candidate genes suggest involvement of smooth muscle cell (SMC) differentiation and/or proliferation-regulating genes in modulating UL risk. Our results further advocate that genetic predisposition to increased fat-free mass may be causally related to UL risk, underscoring the involvement of altered muscle tissue biology in UL pathophysiology. Overall, our findings provide novel insights into genetic risk factors related to UL, which may aid in developing novel treatment strategies.

Introduction: Hereditary leiomyomatosis and renal cell cancer (HLRCC) constitute a tumor susceptibility syndrome caused by germline mutations in the fumarate hydratase (FH) gene. The most common features are leiomyomas of the uterus and the skin. The syndrome includes a predisposition to early-onset, aggressive renal cell cancer. It is important to identify women with HLRCC among other uterine leiomyoma patients in order to direct them to genetic counseling and to identify other affected family members. Material and methods: We conducted a nationwide historical study to identify typical clinical characteristics, uterine leiomyoma morphology, and immunohistochemistry for diagnosing HLRCC. The study included 20 women with a known FH germline mutation and 77 women with sporadic uterine leiomyomas. The patient records of all women were reviewed to obtain clinical details regarding their leiomyomas. Uterine leiomyoma tissue specimens from 43 HLRCC-related leiomyomas and 42 sporadic leiomyomas were collected and prepared for histology analysis. A morphologic description was performed on hematoxylin & eosin-stained tissue slides, and immunohistochemical analysis was carried out for CD34, Bcl-2, and p53 stainings. Results: The women with HLRCC were diagnosed with uterine leiomyomas at a young age compared with the sporadic leiomyoma group (mean 33.8 years vs. 45.4 years, P < 0.0001), and their leiomyomas occurred as multiples compared with the sporadic leiomyoma group (more than four tumors 88.9% vs. 30.8%, P < 0.0001). Congruently, these women underwent surgical treatment at younger age compared with the sporadic leiomyoma group (mean 37.3 years vs. 48.3 years, P < 0.0001). HLRCC leiomyomas had denser microvasculature highlighted by CD34 immunostaining when compared with the sporadic leiomyoma group (112.6 mean count/high-power field, SD 20.8 vs. 37.4 mean count/high-power field, SD 21.0 P < 0.0001) and stronger anti-apoptotic protein Bcl-2 immunostaining when compared with the sporadic leiomyoma group (weak 4.7%, moderate 44.2%, strong 51.2% vs. 26.2%, 52.4%, 21.4%, respectively, P = 0.003). No differences were observed in p53 staining. Conclusions: Women with HLRCC may be identified through the distinct clinical characteristics: symptomatic and numerous leioymyomas at young age, and morphologic features of FH-mutant leiomyomas, aided by Bcl-2 and CD34 immunohistochemistry. Further, distinguishing individuals with a germline FH mutation enables proper genetic counseling and regular renal monitoring.

IntroductionEndometriosis is a common gynaecological disease affecting around 10% of fertile-aged women, causing severe pain symptoms. Deep endometriosis is defined as endometriotic implants that infiltrate the underlying organs more than 5 mm in depth. Surgery for deep endometriosis requires advanced multidisciplinary surgical technique, often in very difficult surgical conditions, with increased risks of complications. Robotic surgery offers a high-definition three-dimensional view and articulating instruments that may allow more precise dissection than conventional laparoscopy in the pelvic area. The superiority of robotic surgery has not, however, been provedin randomised controlled studies, and there is a lack of long-term outcome data. Advanced endometriosis surgery offers an excellent platform to study the feasibility and long-term outcomes of robotic surgery compared with conventional laparoscopy.Methods and analysisROBEndo is a prospective, randomised, controlled clinical trial in a single-centre setting. Patients with deep endometriosis verified by MRI needing surgery at Oulu University Hospital (Oulu, Finland) will be considered eligible. 70 patients will be allocated 1:1 to receive either robotic-assisted or conventional laparoscopic surgery in two strata: radical surgery (with the removal of the uterus and adnexae) and gynaecological organ-sparing surgery. The primary outcome will be the surgical outcome as regards to pain symptoms measured on numeric rating scale (NRS) questionnaires at 24 hours and 6, 12 and 24 months postoperatively. As secondary outcomes, intraoperative measures, enhanced recovery after surgery factors, complications, cost and long-term quality of life measured with Endometriosis Health Profile-30 (EHP-30), Female Sexual Function Index (FSFI) and 15-dimensional (15D) questionnaires will be compared.Ethics and disseminationThis study has been approved by the Northern Ostrobothnian Hospital District Ethical Committee at Oulu University Hospital (212/2021). Informed consent will be obtained during the preoperative check-up by the operating gynaecologist. The results will be published in peer-reviewed international journals.Trial registration numberNCT05179109.

Introduction Endometriosis is a common gynecological condition causing chronic pain and infertility. Only limited data exists on body size during childhood and in 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 1) the World Health Organization's International Statistical Classification of Diseases -code documentation from national hospital discharge registers and 2) 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 through postal questionnaires and clinical examinations and included height, weight, and waist and hip circumference measurements. The associations between endometriosis and body size was assessed using logistic regression models. Results The 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 (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 (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.

Background: Uterine leiomyomas from hereditary leiomyomatosis and renal cell cancer (HLRCC) patients are driven by fumarate hydratase (FH) inactivation or occasionally by mediator complex subunit 12 (MED12) mutations. The aim of this study was to analyse whether MED12 mutations and FH inactivation are mutually exclusive and to determine the contribution of MED12 mutations on HLRCC patients' myomagenesis. Methods: MED12 exons 1 and 2 mutation screening and 2SC immunohistochemistry indicative for FH deficiency was performed on a comprehensive series of HLRCC patients' (122 specimens) and sporadic (66 specimens) tumours. Gene expression analysis was performed using Affymetrix GeneChip Human Exon Arrays (Affymetrix, Santa Clara, CA, USA). Results: Nine tumours from HLRCC patients harboured a somatic MED12 mutation and were negative for 2SC immunohistochemistry. All remaining successfully analysed lesions (107/116) were deficient for FH. Of sporadic tumours, 35/64 were MED12 mutation positive and none displayed a FH defect. In global gene expression analysis FH-deficient tumours clustered together, whereas HLRCC patients' MED12 mutation-positive tumours clustered together with sporadic MED12 mutation-positive tumours. Conclusions: Somatic MED12 mutations and biallelic FH inactivation are mutually exclusive in both HLRCC syndrome-associated and sporadic uterine leiomyomas. The great majority of HLRCC patients' uterine leiomyomas are caused by FH inactivation, but incidental tumours driven by somatic MED12 mutations also occur. These MED12 mutation-positive tumours display similar expressional profiles with their sporadic counterparts and are clearly separate from FH-deficient tumours.

Uterine leiomyomas (ULs) are benign tumors that are a major burden to women’s health. A genome-wide association study on 15,453 UL cases and 392,628 controls was performed, followed by replication of the genomic risk in six cohorts. Effects of the risk alleles were evaluated in view of molecular and clinical characteristics. 22 loci displayed a genome-wide significant association. The likely predisposition genes could be grouped to two biological processes. Genes involved in genome stability were represented by TERT, TERC, OBFC1 - highlighting the role of telomere maintenance - TP53 and ATM. Genes involved in genitourinary development, WNT4, WT1, SALL1, MED12, ESR1, GREB1, FOXO1, DMRT1 and uterine stem cell marker antigen CD44, formed another strong subgroup. The combined risk contributed by the 22 loci was associated with MED12 mutation-positive tumors. The findings link genes for uterine development and genetic stability to leiomyomagenesis, and in part explain the more frequent occurrence of UL in women of African origin., eLife digest Fibroids – also known as uterine leiomyomas, or myomas – are a very common form of benign tumor that grows in the muscle wall of the uterus. As many as 70% of women develop fibroids in their lifetime. About a fifth of women report symptoms including severe pain, heavy bleeding during periods and complications in pregnancy. In the United States, the cost of treating fibroids is estimated to be $34 billion each year. Despite the prevalence of fibroids in women, there are few treatments available. Drugs to target them have limited effect and often an invasive procedure such as surgery is needed to remove the tumors. However, a better understanding of the genetics of fibroids could lead to a way to develop better treatment options. Välimäki, Kuisma et al. used a genome-wide association study to seek out DNA variations that are more common in people with fibroids. Using data from the UK Biobank, the genomes of over 15,000 women with fibroids were analyzed against a control population of over 392,000 individuals. The analysis revealed 22 regions of the genome that were associated with fibroids. These regions included genes that may well contribute to fibroid development, such as the gene TP53, which influences the stability of the genome, and ESR1, which codes for a receptor for estrogen – a hormone known to play a role in the growth of fibroids. Variation in a set of genes known to control development of the female reproductive organs was also identified in women with fibroids. The findings are the result of the largest genome-wide association study on fibroids, revealing a set of genes that could influence the development of fibroids. Studying these genes could lead to more effective drug development to treat fibroids. Revealing this group of genes could also help to identify women at high risk of developing fibroids and help to prevent or manage the condition.

Are there differences in estrogen and progesterone secretion in singleton pregnancies, up to Week 11, between spontaneous pregnancies, after controlled ovarian hyperstimulation and fresh embryo transfer (COH + ET) and after frozen embryo transfer in a spontaneous cycle (FET)?Serum progesterone and estradiol (E2) concentrations after COH + ET were higher in early pregnancy, lasting up to Week 7-8, than FET and spontaneous pregnancies, while hormone levels after FET did not differ from spontaneous pregnancies.The risk of adverse perinatal outcomes after COH + ET seems to be increased when compared with spontaneous pregnancies. One of the reasons suggested for this is related to ovarian hyperstimulation.This was a prospective cohort study consisting of three different groups of pregnant women which were followed-up weekly until Week 11 of their pregnancies. The spontaneous pregnancy group consisted of 41 women, the COH + ET group consisted of 39 and the FET group consisted of 30 women.Women in the control group with spontaneous conception were recruited from local prenatal clinics. Women in the COH + ET and FET groups were recruited from the Reproductive Unit of Oulu University Hospital. At each visit, a three-dimensional ultrasonography was performed to examine the ovarian volumes and vascularization. A blood sample was drawn to analyse progesterone and E2 levels. The pregnancy outcome was included in the analysis.At pregnancy Week 5, the serum progesterone levels were higher after the COH + ET (median 312, inter-quartile range 183-480 nmol/l), when compared with the spontaneous (63, 52-80 nmol/l; P0.001) and FET (74, 48-96 nmol/l; P0.001) pregnancies. At Week 11, the P (189, 124-260 nmol/l) was still higher in the COH + ET group (FET 101, 78-120 nmol/l, P0.001; spontaneous 115, 80-139 nmol/l, P0.01) than the other two groups. The E2 levels at Week 5 were also significantly higher after COH + ET (4.1, 2.2-6.6 nmol/l) than in the spontaneous pregnancies (1.1, 0.7-1.6 nmol/l, P0.001) or after FET (0.7, 0.6-0.9 nmol/l, P0.001). The volume of the ovaries and the intraovarian vasculature in the COH + ET group were significantly higher when compared with the other two groups (P0.001). The birthweight was negatively correlated with the serum P (R -0.340, P0.01) and E2 (R= -0.275, P0.05) in pregnancy Weeks 5-8. In the multivariate analysis evaluating the factors affecting birthweight of the newborn, the significant factors were the length of gestation, maternal height and progesterone or E2 secretion during Weeks 5-8.Because of the low number of patients in this study, larger cohort studies are required to confirm the findings.The findings here indicate that COH-induced increased luteal activity should be evaluated by measuring steroid levels or the ovarian size or vascularity, rather than number of oocytes retrieved. If unphysiologically high steroid activity during pregnancy after COH contributes to the risk of adverse perinatal outcomes after fresh embryo transfer, milder stimulation protocols or even freezing of all of the embryos should be considered.This study was supported by a research grant from the Academy of Finland. The authors declare no conflicts of interest.

HLRCC is an autosomal dominant tumor predisposition syndrome characterized by cutaneous and uterine leiomyomas (ULs), and increased risk for aggressive type 2 papillary renal cell carcinoma (RCC). The syndrome is caused by germline mutations in fumarate hydratase (FH). Loss of FH causes dysfunction of the Crebs cycle and an increase of succinated proteins, which can be detected using anti-2-succinocysteine (2SC) antibody. Recently, we have observed that aldo-keto reductase family 1, member B10 (AKR1B10) is overexpressed in RNA-level in ULs with biallelic loss of FH. Here, we compared anti-AKR1B10, anti-2SC, and anti-FH antibodies in detection of FH loss in protein-level in HLRCC-associated ULs. The study material consisted of 142 formalin-fixed paraffin-embedded (FFPE) UL samples collected at the University hospitals in Finland. The sample series include 77 FH-deficient UL samples from 25 HLRCC patients and 65 sporadic conventional ULs. HLRCC background was verified by detected germline mutation of FH. Four 0.8 mm cores of representative FFPE tumor tissue were used to construct tissue microarrays. Immunohistochemistry (IHC) was executed using an anti-AKR1B10 (1:300, H00057016-M01, Abnova), anti-2SC (1:2000, provided by Dr. Norma Frizzell), and anti-FH (1:1000, sc-100743, Santa Cruz Biotechnology, Inc) antibodies. Expression was detected by BrightVision (Immunologic) and DAB Quanto (Thermo Fisher Scientific) systems. Pathologist specialized in gynecological pathology evaluated the IHC staining from the smooth muscle tumor cells. AKR1B10 and 2SC detected all 77 HLRCC samples. AKR1B10 displayed either mild (12/77, 16%) or strong (65/77, 84%) expression and succination level was strong in all cases. Loss of FH expression was displayed in 68/77 (88%) of the FH-deficient ULs. All conventional ULs displayed negative AKR1B10 and 2SC staining and expressed FH. FH was expressed either mildly (15/65, 23%) or strongly (50/65, 77%) in the samples. Reliable methods for FH-deficient UL detection in the clinics are currently lacking. Here, comparison of AKR1B10, 2SC, and FH showed that all three biomarkers identified HLRCC-ULs with 100% specificity. The sensitivity was 100% with AKR1B10 and 2SC, and 88% with FH. It seems that even with known mutation in FH, in some cases the likely inactive protein is retained in tumor cells and is thus detectable by anti-FH. To conclude, we show that anti-AKR1B10 and anti-2SC detect FH-deficient ULs with 100% specificity and sensitivity. Anti-FH is lacking sensitivity in 12% of HLRCC cases. Reliable detection of FH-deficient ULs enables the patients and their families to be directed to genetic counseling, family planning, and regular renal monitoring. Citation Format: Terhi Ahvenainen, Outi Uimari, Anne Ahtikoski, Kati Kämpjärvi, Ralf Bützow, Pia Vahteristo. Comparison of AKR1B10, 2SC, and FH as biomarkers for HLRCC detection [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3992.

STUDY QUESTION Do genome-wide association study (GWAS) data for endometriosis provide insight into novel biological pathways associated with its pathogenesis? SUMMARY ANSWER GWAS analysis uncovered multiple pathways that are statistically enriched for genetic association signals, analysis of Stage A disease highlighted a novel variant in MAP3K4, while top pathways significantly associated with all endometriosis and Stage A disease included several mitogen-activated protein kinase (MAPK)-related pathways. WHAT IS KNOWN ALREADY Endometriosis is a complex disease with an estimated heritability of 50%. To date, GWAS revealed 10 genomic regions associated with endometriosis, explaining

STUDY QUESTION: Are uterine fibroids associated with increased cardiovascular risk? SUMMARY ANSWER: This study reports an association between increased serum lipids and metabolic syndrome with an increased risk of uterine fibroids. WHAT IS KNOWN ALREADY: Recent studies suggest similarities in biological disease mechanisms and risk factors for fibroids and atherosclerosis: obesity, hypertension and abnormal serum lipids. These findings are awaiting confirmation that a population-based follow-up study could offer with extensive health examination data collection linked with a national hospital discharge register. STUDY DESIGN, SIZE, DURATION: The Northern Finland Birth Cohort (NFBC1966) is a population-based long-term follow-up study including all children with estimated date of delivery in 1966 in the Northern Finland area. The data were collected from national registries, postal questionnaires and clinical health examinations. The study population for this study comprised all females included in the NFBC1966 that underwent an extensive clinical health examination at age 46 years (n = 3635). PARTICIPANTS/MATERIALS, SETTING, METHODS: All females included in the NFBC1966 who were alive and traceable (n = 5118) were invited for the 46-year follow-up study; 3268 (63.9%) responded, returned the postal questionnaire and attended the clinical examination. Uterine fibroid cases were identified through the national hospital discharge register that has data on disease diagnoses based on WHO ICD-codes. Uterine fibroid codes, ICD-9: 218 and ICD-10: D25 were used for case identification. Self-reported fibroid cases were identified through the postal questionnaire. MAIN RESULTS AND THE ROLE OF CHANCE: A total of 729 fibroid cases were identified, including 293 based on hospital discharge registries. With adjustment for BMI, parity, education and current use of exogenous hormones the risk of prevalent fibroids rose significantly for every 1 mmol/l increase in LDL (OR = 1.13, 95% CI: 1.02-1.26 for all cases) and triglycerides (OR = 1.27, 95% CI: 1.09-1.49 for all cases). Metabolic syndrome associated with hospital discharge-based fibroid diagnosis (OR = 1.48, 95% CI: 1.09-2.01). Additionally every 1 unit increase in waist-hip ratio associated with fibroids (OR = 1.32, 95% CI: 1.10-1.57). LIMITATIONS, REASONS FOR CAUTION: The case ascertainment may present some limitations. There was likely an under-identification of cases and misclassification of some cases as controls; this would have diluted the effects of reported associations. The data analysed were cross-sectional and therefore cause and effect for the associations observed cannot be distinguished. WIDER IMPLICATIONS OF THE FINDINGS: Increased serum lipids and metabolic syndrome are associated with increased risk of uterine fibroids. Along with central obesity these findings add to an increased risk for cardiovascular disease among women with fibroids. These observations may suggest that there are shared predisposing factors underlying both uterine fibroids and adverse metabolic and cardiac disease risk, or that metabolic factors have a role in biological mechanisms underlying fibroid development. STUDY FUNDING/COMPETING INTERESTS: This study was supported by the Academy of Finland, University Hospital Oulu, University of Oulu, Finland, Northern Finland Health Care Foundation, Duodecim Foundation, ERDF European Regional Development Fund-Well-being and health: Research in the Northern Finland Birth Cohort 1966. The authors declare no conflict of interest.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a tumor predisposition syndrome characterized by cutaneous and uterine leiomyomas and renal cell cancer. HLRCC is caused by heterozygous germline mutations in the fumarate hydratase (FH) gene. A Finnish family with nine closely related women with uterine leiomyomas was detected by an alert gynecologist. No cutaneous or renal cell tumors were reported in the family when it was referred to genetic analyses. Samples were available from seven patients, and a novel germ- line FH mutation was detected in five of them. Mutation carriers were symptomatic, had multiple tumors and were diagnosed at an early age. This study emphasizes the importance of considering FH mutation screening when gynecologists encounter families with multiple severe uterine leiomyoma cases. Due to possibility of phenocopies more than one patient should be tested. Early mutation detection allows regular screening of the mutation carriers and enables early detection of possible highly aggressive renal tumors. It may also affect family planning as multiple myomas at early age may significantly reduce fertility.

Uterine leiomyomas are benign smooth muscle tumors that cause considerable morbidity. They are among the most common human tumors and are the leading indication for hysterectomy. Genetic factors play an important role in the development of these hormone-dependent tumors. First-degree relatives of uterine leiomyoma patients are at increased risk for developing leiomyomas. Twin studies have shown that an inherited predisposition is likely to contribute to the formation of these lesions. Furthermore, the clinical and molecular features of familial leiomyomas differ from those of sporadic cases. Thus far, the only known high risk predisposition defect is dominantly inherited loss of function mutations in fumarate hydratase (FH) that underlie a tumor predisposition syndrome hereditary leiomyomatosis and renal cell cancer (HLRCC). The aim of this study is to identify novel candidate high risk susceptibility genes for uterine leiomyomas. The study material consists of five FH mutation-negative families, which have at least four individuals diagnosed with uterine leiomyomas, originating from Northern Finland. Genomic DNA extracted from peripheral blood lymphocytes from one affected individual from each family has been exome sequenced. Exome sequencing data have been analyzed for rare non-synonymous variants with allele frequencies less than 0.1% in 4 019 controls. All protein-truncating variants as well as missense and splice site variants affecting the same gene in at least two individuals that are predicted to be protein-damaging have been included for further analysis. Preliminarily 25 candidate susceptibility genes have been shortlisted. Relevant variant calls will be verified by direct sequencing, followed by segregation analysis and assessment of loss of heterozygosity in the corresponding tumor samples. Identification of novel genes predisposing to familial uterine leiomyomas may provide a better understanding into the tumorigenic mechanisms and could lead to new prevention approaches and personalized medical treatments in the future. Citation Format: Hanna-Riikka Heinonen, Outi Uimari, Jaana Tolvanen, Markku Ryynänen, Lauri A. Aaltonen, Pia Vahteristo. Identification of candidate predisposition genes for familial uterine leiomyomas. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4800. doi:10.1158/1538-7445.AM2015-4800

Objective To study the natural history of myomas in familial cases and to compare the tendencies of myomas between familial and non-familial cases. Study design Subjects with familial and non-familial myomas were identified from the hospital records and the reliable details of the myomas were collected. Results In the familial cases there are several myomas, four or more. In the non-familial cases, there is usually only one single myoma, which is bigger than in familial cases. In the familial group, the diagnosis and surgery was made earlier. In the familial group, there were more pregnancies and less infertility problems. Conclusion There is a significant difference in the natural history of the familial and non-familial cases. In familial cases, subjects have four or more myomas while in non-familial cases the fibroid is single and large.

Objectives : Endometriosis and uterine fibroids are common gynecological disorders in fertile women. It has been suggested that these two disorders may be associated with each other. In this study, we tested whether this connection exists. In addition, we wanted to evaluate whether they both affect fertility independently of each other. Materials and Methods : The prevalence of endometriosis and uterine fibroids was investigated in three groups of patients: Symptomatic patients requiring surgery either for endometriosis (n=182), or for uterine fibroids (n=240) and asymptomatic patients undergoing laparoscopic sterilization (n=183). The prevalences were examined in three age groups: 35-39 yrs, 40-44 yrs and ≥ 45 yrs. The significance of both diagnoses on fertility was assessed using logistic regression analysis. Results :Uterine fibroids were detected in 25.8% (47/182) of patients with endometriosis. Endometriosis was detected in 19.6% (47/240) of patients with uterine fibroids. 5.5% (10/183) women undergoing sterilization had endometriosis and 19.3% (17/183) had uterine fibroids. Both uterine fibroids and endometriosis were, independently of each other, related to subfertility (OR, 95% CI: 3.8, 2.3-6.5; 6.8, 4.0-11.6, respectively). Conclusions : The results suggest that symptomatic endometriosis appears together with symptomatic uterine fibroids. Both diseases seem to decrease female fertility independently of each other.