Premature Ovarian Insufficiency in Adolescents and Young Women: A Systematic Review and Meta-analysis of Etiology, Genetic Diagnostic Yield, Autoimmune Associations, and Management Outcomes

Abstract

Background: Premature ovarian insufficiency is characterised by impaired ovarian function before 40 years of age and may present in adolescents and young women with delayed puberty, primary or secondary amenorrhoea, incomplete pubertal progression, hypo-oestrogenism, and elevated gonadotrophins. Early recognition is clinically important because untreated oestrogen deficiency may affect pubertal development, bone mineral accrual, fertility potential, and psychosocial well-being. Objectives: This review aimed to summarise the aetiological distribution of adolescent and young-onset premature ovarian insufficiency, evaluate the diagnostic yield of genetic testing, describe autoimmune associations according to ascertainment method, and review management outcomes related to hormone replacement therapy, bone health, fertility preservation, and emerging therapies. Methods: PubMed/MEDLINE-indexed literature published from January 2000 to December 2025 was reviewed according to systematic review principles. Eligible studies included population-based studies, registry studies, cohort studies, cross-sectional studies, case-control studies, genetic sequencing studies, fertility-preservation cohorts, and clinically relevant case series with extractable numerical data. Guidelines and reviews were used for clinical context but were not included in quantitative pooling. Results: Aetiological distribution was derived from two extractable cohorts including 283 premature ovarian insufficiency cases. Idiopathic disease accounted for 165 cases (58.3%), genetic or chromosomal causes for 31 cases (11.0%), autoimmune causes for 36 cases (12.7%), and iatrogenic causes for 51 cases (18.0%). Across three cohorts, FMR1 premutation was identified in approximately 9 of 445 cases, giving a crude yield of about 2.0%. In one adolescent-only 46,XX cohort, whole-exome sequencing identified premature ovarian insufficiency-related variants in 24 of 63 patients (38.1%). Broader next-generation sequencing or whole-exome sequencing findings across two cohorts showed clinically relevant results in approximately 134 of 438 cases (30.6%). Autoimmune disease burden varied by ascertainment method, with severe registry-defined disease identified in 233 of 3972 women (5.9%) and broader clinically detected disease in 174 of 662 clinic or electronic health record cases (26.3%). Conclusion: Adolescent and young-onset premature ovarian insufficiency is aetiologically heterogeneous. Current evidence supports early diagnosis, systematic aetiological classification, genetic counselling, autoimmune surveillance, physiological hormone replacement therapy, bone protection, fertility-preservation counselling when appropriate, and multidisciplinary long-term care.