Cancer Risk in Premature Ovarian Insufficiency: Current Evidence and Clinical Implications

A BSTRACT Premature ovarian insufficiency (POI), defined as loss of ovarian function before 40 years with elevated gonadotropins and oligo/amenorrhea, is increasingly recognized as a systemic condition with long-term health consequences. While cardiovascular, skeletal, and neurocognitive risks are well established, the relationship between POI and cancer risk remains less clearly understood. This mini-review summarizes current evidence on site-specific malignancy risks in women with POI and evaluates the influence of hormone replacement therapy (HRT) on cancer outcomes. Available epidemiological studies, cohort analyses, and guideline recommendations addressing cancer incidence in POI were reviewed, with emphasis on breast, ovarian, endometrial, colorectal, and autoimmune-associated malignancies. Women with spontaneous POI generally demonstrate a reduced risk of breast, ovarian, and endometrial cancers, largely attributed to lower lifetime estrogen exposure and fewer ovulatory cycles. However, cancer risk may vary by etiology: autoimmune POI is associated with increased thyroid cancer incidence, while genetic subgroups such as fragile X mental retardation 1 premutation carriers may exhibit altered ovarian cancer susceptibility. Importantly, physiological HRT in POI differs fundamentally from postmenopausal hormone therapy and does not appear to increase overall cancer risk when continued until the average age of natural menopause. POI is typically associated with lower risks of hormone-dependent malignancies, though subgroup-specific variations exist. Individualized counseling, appropriate progestin opposition, and further POI-specific cohort studies are essential to refine cancer surveillance strategies.