ID #522  Pubertal Development and Hormonal Modulation in Pediatric Low-Grade Gliomas: A Retrospective Cohort Study

Abstract

Pediatric low-grade gliomas (pLGGs) are the most common brain tumors in childhood, usually showing an indolent course and favorable prognosis. Complete surgical resection is often curative, but tumor location may limit feasibility, necessitating additional therapies. Biologically, pLGGs are predominantly driven by MAPK pathway alterations, and targeted therapies with BRAF and MEK inhibitors have improved outcomes. However, the impact of sex hormones, particularly during puberty, remains poorly understood. pLGGs express estrogen (ERα, ERβ, GPER1) and androgen receptors, suggesting hormonal sensitivity. ERα and GPER1 activation promotes proliferation via MAPK/ERK and PI3K/AKT/mTOR pathways, whereas ERβ has a suppressive effect. Androgen receptor signaling may also contribute to tumor growth, while progesterone’s role is less defined. Clinical evidence indicates hormonal modulation can influence tumor behavior. Pubertal suppression with GnRH analogues has been associated with tumor stabilization or regression in patients with optic pathway gliomas and central precocious puberty (CPP), whereas pregnancy in adults can trigger rapid tumor progression. We conducted a retrospective study of 301 children with pLGG treated at Bambino Gesù Children’s Hospital between 2015 and 2025, collecting clinical, radiological, endocrine, and molecular data. Pubertal status was assessed using Tanner staging, and CPP was defined by standard clinical and hormonal criteria. Of 301 patients, 112 (37%) had advanced pubertal stage (>3) at diagnosis, including 18 (6%) with CPP. Among CPP patients, those treated with GnRH analogues (n = 13) had significantly longer progression-free survival (PFS) than untreated patients (n = 5) (p = 0.00038), with 60-month PFS of 78% versus 25%. Tumor progression often coincided with pubertal reactivation. In vitro, patient-derived tumor organoids showed increased proliferation in response to estrogen. These findings indicate that puberty is a biologically relevant modulator of pLGG behavior, highlighting the potential of integrating endocrine-oncologic strategies into pediatric precision medicine.

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