Primary ovarian insufficiency: Genetic etiology, in vitro follicle activation mechanisms, and clinical management perspectives

Abstract

Introduction: Menstrual irregularities or amenorrhea affect at least 17.4 million women worldwide. Symptoms in young patients may be atypical, and imaging and serum hormone levels are sometimes insufficient to explain the condition. Objectives: This review synthesizes current evidence to improve diagnostic and treatment strategies, reduce misdiagnosis of primary ovarian insufficiency (POI), facilitate timely treatment, and support earlier recognition and individualized follow-up to preserve reproductive function. Methods: We conducted a narrative review of studies addressing the genetic basis, molecular mechanisms, follicular activation pathways, and clinical management of POI. Particular attention was given to single-gene variants, chromosomal abnormalities, phosphoinositide 3-kinase (PI3K), mechanistic target of rapamycin (mTOR), and Hippo signaling pathways, as well as acquired or functional conditions that may mimic genetic POI. Results: POI is a heterogeneous reproductive endocrine disorder involving chromosomal abnormalities, X-linked factors, folliculogenesis-related genes, meiotic and chromosomal stability defects, and DNA damage repair pathways. Representative genes such as FMR1, BMP15, GDF9, NR5A1, HFM1, STAG3, and BRCA2 illustrate the diverse mechanisms that impair ovarian reserve or cause follicular dysfunction. In vitro activation of dormant follicles is biologically supported by PI3K/phosphatase and tensin homolog/protein kinase B/FOXO3a, mTOR, and Hippo signaling pathways, but its clinical application remains limited and requires further validation. Functional hypothalamic amenorrhea, drug exposure, metabolic abnormalities, endocrine tumors, and autoimmune conditions should also be considered in the differential diagnosis. Conclusion: POI in young women should not be simply attributed to stress, emotional factors, or menstrual irregularity. Early etiological evaluation, appropriate genetic testing, differential diagnosis, reproductive counseling, hormone replacement therapy when indicated, fertility preservation planning, and long-term multidisciplinary follow-up may improve clinical management. In vitro activation-related mechanisms provide a potential biological rationale for future fertility-preserving strategies, but broader clinical use requires stronger evidence.