Abstract

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.