Excess of severe autoimmune diseases in women with premature ovarian insufficiency: a population-based study.

STUDY QUESTION: Is there an association between premature ovarian insufficiency (POI) and severe autoimmune diseases before and after POI diagnosis? SUMMARY ANSWER: Women with POI had at least one hospital-treated autoimmune disorder preceding POI diagnosis 2.6 times more often compared with matched female controls, and a 2- to 3-fold risk for these diseases for several years after POI diagnosis. WHAT IS KNOWN ALREADY: It has been suggested that autoimmunity is an important factor in the pathogenesis of POI. Estimations of the prevalence of POI cases with autoimmune origin have ranged from 4% to 50%. STUDY DESIGN, SIZE, DURATION: This population-based registry study included 3972 women diagnosed with spontaneous POI between 1988 and 2017 and 15 708 female population controls and used both case-control and cohort analysis. Autoimmune disease diagnoses were evaluated from childhood until the end of the year 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with POI were identified from the reimbursement registry of the Finnish Social Insurance Institution by their right to hormone replacement therapy (HRT). Four female population controls matched by age and municipality of residence were searched for each POI case to form a reference cohort. Women with a history of cancer or bilateral oophorectomy were excluded. Severe autoimmune disorder diagnoses for the years 1970-2017 were identified from the Hospital Discharge Registry. Odds ratios (ORs) with 95% confidence intervals (CI) were calculated using binary logistic regression for cases of having any, or one or more, specific autoimmune diseases preceding the index date (the date when reimbursement for HRT was granted for the POI) among women with POI as compared to controls. Standardized incidence ratios (SIR) with 95% CIs for getting diagnosed with an autoimmune disease after the index date in 3-year follow-up periods among women with POI (who did not have these diseases prior to the index date) were also calculated. The expected numbers of autoimmune disease cases were based on the incidence of first-onset severe autoimmune disease among the controls. MAIN RESULTS AND THE ROLE OF CHANCE: The prevalence of having at least one severe autoimmune disease in women with POI was 5.6% (n = 233), with an OR of 2.6 (95% CI 2.2, 3.1) when compared to population controls. Women with POI had an increased prevalence of several specific autoimmune diseases prior to the index date compared to controls: polyglandular autoimmune diseases (OR 25.8, 95% CI 9.0, 74.1), Addison's disease (OR 22.9, 95% CI 7.9, 66.1), vasculitis (OR 10.2, 95% 4.3, 24.5), systemic lupus erythematosus (OR 6.3 95% CI 4.2, 20.3), rheumatoid arthritis (OR 2.3, 95% CI 1.7, 3.2), sarcoidosis (OR 2.3, 95% CI 1.2, 4.5), inflammatory bowel diseases (OR 2.2, 95% CI 1.5, 3.3), and hyperthyroidism (OR 1.9, 95% CI 1.2, 3.1); whereas the prevalence of diabetes type 1 and ankylosing spondylitis did not differ between the women with POI and the reference cohort. The SIRs for being diagnosed for the first time with a severe autoimmune disease after POI diagnosis was 2.8 (95% CI 2.3, 3.4), during the first three years after POI diagnosis, decreasing gradually to 1.3 (1.1, 1.6) after 12 years. LIMITATIONS, REASONS FOR CAUTION: This study only included autoimmune disorders diagnosed in specialized health care; hence, the overall prevalence of autoimmune disorders in women with POI may be higher. WIDER IMPLICATIONS OF THE FINDINGS: Severe autoimmune diseases have a strong association with POI, suggesting that immunological mechanisms play a pivotal role in POI. Future studies should focus on specific autoimmune mechanisms behind POI, from both preventive and curative perspectives. STUDY FUNDING/COMPETING INTEREST(S): This work was financially supported by Oulu University Hospital. S.M.S. received grants from the Finnish Menopause Society, the Finnish Medical Foundation, and the Juho Vainio Foundation. H.S. received grants from the Finnish Menopause Society, the Oulu Medical Research Foundation, the Finnish Research Foundation of Gynecology and Obstetrics, UniOGS graduate school, The Finnish Medical Society Duodecim, Orion Research Foundation, and the University of Oulu Scholarship Fund. M.-M.O. received a grant from the Sakari Alhopuro Foundation and the Finnish Diabetes Research Foundation. None of the funders had any involvement in the study design or its execution or reporting. The authors do not have any competing interests to report. TRIAL REGISTRATION NUMBER: N/A.

Association of genetic disorders and congenital malformations with premature ovarian insufficiency: a nationwide register-based study.

STUDY QUESTION: Are genetic disorders and congenital malformations associated with premature ovarian insufficiency (POI)? SUMMARY ANSWER: A wide range of genetic disorder and congenital malformation diagnoses are associated with POI, especially early onset POI. WHAT IS KNOWN ALREADY: POI is known to be associated with some genetic disorders, such as Turner syndrome and Fragile X premutation. Multiple genetic syndromes, such as ataxia teleangiectasia and galactosemia, have also been associated with an increased risk of POI, and many of these genetic syndromes manifest with various congenital malformations. In previous studies, a genetic aetiology has been found for 7-15% of POI cases. STUDY DESIGN, SIZE, DURATION: This population-based study included 5011 women diagnosed with POI in 1988-2017. The data were collected from various national registries and covers women with POI nationwide. PARTICIPANTS/MATERIALS, SETTING, METHODS: We identified 5011 women diagnosed with POI from 1988 to 2017 from the drug reimbursement registry of the Social Insurance Institution of Finland. Women with surgical POI (bilateral oophorectomy for benign indications) were not included. We selected four population controls per woman with POI matched by month and year of birth and municipality of residence. Diagnostic codes for genetic disorders and congenital malformations (GD/CM) for the cases and controls were searched from the Hospital Discharge Register. Binary logistic regression was used to compare the odds for GD/CM among cases and controls. To minimize bias, for the statistical analyses, we excluded diagnoses which were reported <2 years prior to the index date. MAIN RESULTS AND THE ROLE OF CHANCE: Of the women with POI, 15.9% (n = 797) had at least one diagnostic code for GD or CM. The odds ratio (OR) for Turner syndrome was 275 (95% CI 68.1-1110), and for other sex chromosome abnormalities, it was 12.7 (95% CI 4.1-39.1). For autosomal single gene disorders, the OR was 16.5 (95% CI 6.2-43.7). Women with POI had a higher odds of having a GD/CM diagnosis in all categories. The OR for GD/CM diagnoses was highest among the youngest POI patients (10-14 years old, OR 24.1, 95% CI 15.1-38.2). The odds of having POI were higher the more GD or CM diagnoses a woman had. LIMITATIONS, REASONS FOR CAUTION: Some women with POI might not have sought help for their symptoms and therefore remain undiagnosed. Due to the register-based nature of our study, we did not have access to more specific genetic diagnoses than international classification of diseases offers. WIDER IMPLICATIONS OF THE FINDINGS: GD/CM diagnoses were strongly associated with POI, especially when POI was diagnosed at a young age. The risk of POI was highest in women with multiple GD/CM diagnoses. Early onset POI can be a sign of underlying genetic disorder or congenital anomaly, and this should serve as a reminder for clinicians to consider further examinations. To avoid unnecessary delay in the diagnosis of POI and starting relevant hormone replacement therapy treatment, clinicians should be aware of these associations. STUDY FUNDING/COMPETING INTEREST(S): Oulu University Hospital financially supported this work. H.S. has received personal grants from the Finnish Menopause Society, Oulu Medical Research Foundation, and Finnish Research Foundation of Gynaecology and Obstetrics. S.S. has received grants from the Finnish Menopause Society, the Finnish Medical Foundation, and the Juho Vainio Foundation. None of the authors have any competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.

Incidence and familial risk of premature ovarian insufficiency in the Finnish female population.

STUDY QUESTION: What is the incidence of premature ovarian insufficiency (POI), has the incidence of POI changed over time, and what is the risk of POI among relatives of POI women? SUMMARY ANSWER: The incidence of POI increased among females aged 15-19 years from 2007 onwards and decreased in older age groups, and among relatives of women with POI the risk of POI is significantly increased. WHAT IS KNOWN ALREADY: So far, there has been no good quality, nationwide studies of the incidence of POI. Early menopause has been associated with the elevated risk of early menopause among relatives, but the knowledge of the familial risk of POI is scarce. Lower socioeconomic status has been associated with lower age at natural menopause. STUDY DESIGN, SIZE, DURATION: Population-based study with 5011 women diagnosed with POI in 1988-2017. The data were collected from national registries and covers POI subjects in entire Finland. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women with hormone replacement therapy reimbursement for POI were identified from Social Insurance Institution (SII). We calculated POI incidence in different age groups and studied the changes in the incidence rate over time in 5-year segments. Four population-based controls were selected from the Digital and Population Data Services Agency (DVV) for each POI woman. Family members of the POI cases and controls were identified from the DVV and linked to SII reimbursement data to identify POI diagnoses among them. The familial risk of POI was estimated with a logistical regression model. MAIN RESULTS AND THE ROLE OF CHANCE: The incidence was highest in the 35-39 age group, ranging from 73.8/100 000 women-years in 1993-1997 to 39.9/100 000 women-years in 2013-2017. From 2007, the incidence among 15- to 19-year-olds rose from 7.0 to 10.0/100 000 women-years in 2015-2017. Cumulative incidence of POI for women under 40 years in 1988-2017 was 478/100 000 women. The relative risk of POI among relatives of women with POI was 4.6 (95% CI 3.3-6.5) compared to relatives of women without POI. POI women tended to have slightly lower socioeconomic status and level of education compared to controls. LIMITATIONS, REASONS FOR CAUTION: For some women with POI, diagnosis or reimbursement may be lacking. However, we presume that these women represent a minority due to the nature of the disease and the economic benefits of reimbursement. Some changes in the incidence of POI can reflect changes in clinical practice and changing treatments and reimbursement criteria. WIDER IMPLICATIONS OF THE FINDINGS: The risk of developing POI is significantly higher in women who have first-degree relatives diagnosed with POI. Raising awareness of the increased risk might lead to earlier diagnosis and initiation of hormonal replacement therapy, possibly preventing adverse effects of low oestrogen levels, such as osteoporosis. STUDY FUNDING/COMPETING INTEREST(S): This work was financially supported by the Oulu University Hospital. H.S. received a grant from Finnish Menopause Society. S.M.S. received a grant from the Finnish Menopause Society, the Finnish Medical Foundation and the Juho Vainio Foundation. The authors do not have any competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.