Long-term endocrine and reproductive outcomes in female adolescent and young adult survivors after hematopoietic stem cell transplantation for hematological malignancies during childhood or adolescence.
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BACKGROUND: Cancer treatment during childhood and adolescence, particularly hematopoietic stem cell transplantation (HSCT), may adversely affect long-term reproductive and endocrine health in female adolescent and young adult (AYA) survivors, leading to premature ovarian insufficiency (POI), which may be associated with impaired pubertal development, low bone mass, and reproductive complications. METHODS: This study included 34 female survivors treated with HSCT for hematological malignancies during childhood or adolescence (median age 10.8 years). The median follow-up from HSCT to the last gynecological assessment was 8.5 years. Hormonal assessment, pelvic ultrasound, and bone mineral density (BMD) evaluation were performed. Patients were classified as having normal ovarian function, transient ovarian insufficiency (TOI), or persistent POI. RESULTS: At the last follow-up, normal ovarian function was observed in 15 patients (44.1%), TOI in 7 (20.6%), and persistent POI in 12 (35.3%). Patients with normal ovarian function were significantly older at HSCT (p = 0.0432), whereas premenarchal status was associated with impaired ovarian outcome (p = 0.0066). In multivariable analysis including cyclophosphamide equivalent dose (CED), radiotherapy, and menarchal status at HSCT, postmenarchal status was associated with markedly lower odds of ovarian insufficiency (adjusted OR 0.056, 95% CI 0.005-0.566; p = 0.0147). All postmenarchal patients received GnRHa, precluding separation of the effects of menarchal status and GnRHa exposure; GnRHa-treated survivors had higher AMH concentrations (p =0.0032). AMH and FSH concentrations differed significantly between groups (both p < 0.01). Uterine and mean ovarian volumes, antral follicle count (AFC), and BMD were significantly lower in patients with TOI and POI (all p < 0.05). Radiotherapy exposure was associated with both lower uterine and ovarian volumes, while puberty induction was also associated with lower uterine volume (all p <0.05). Two patients diagnosed with POI achieved spontaneous pregnancies during follow-up, one resulting in a live birth. CONCLUSIONS: Ovarian dysfunction is highly prevalent after childhood HSCT, although partial recovery of ovarian function may occur even in patients with a diagnosis of POI. Persistent POI is associated with impaired uterine development and lower BMD despite ongoing hormone replacement therapy, underscoring the need for timely and long-lasting individualized endocrine and reproductive care in AYA survivors.