Reflections on GnRH analogues dosage in the context of escape phenomenon: a case report of hypothalamic hamartoma with central precocious puberty and literature review

OBJECTIVES: Gonadotropin-releasing hormone analogues (GnRHa) are the standard treatment for central precocious puberty (CPP), with well-established efficacy but uncommon escape phenomena. We report an escape case in hypothalamic hamartoma (HH)-related CPP and review the literature on HH-related CPP and idiopathic central precocious puberty (ICPP), analyzing characteristics of escape cases. CASE PRESENTATION: A 15-month-old boy with HH-related CPP experienced escape during GnRHa therapy. Despite dose escalation and switching the drug type and formulation, suppression of the hypothalamic-pituitary-gonadal (HPG) axis remained incomplete. Combination therapy with an aromatase inhibitor and an androgen receptor antagonist ultimately controlled hyperandrogenic symptoms, including acne and frequent erections, while decelerating growth velocity and bone age progression. He developed epilepsy at 38 months of age and is scheduled for surgery. Literature review indicates that approximately 8.9 % of HH-related CPP cases experience escape, some of which are associated with impaired drug absorption or inadequate dosing. In ICPP, escape is predominantly a mild, biochemical phenomenon without significant impact on long-term outcomes like bone age control or predicted adult height. CONCLUSIONS: Patients with HH-related CPP should be monitored for the risk of escape during GnRHa therapy. The underlying mechanism may involve relatively inadequate GnRHa exposure, potentially attributable to abnormal neuroendocrine activity of the HH lesion itself. Within safe limits, individualized dose titration is a rational approach to achieving adequate suppression. For patients refractory to GnRHa, combining therapy with peripheral androgen inhibitors is a potential option; however, given the current lack of long-term safety data, a monitoring protocol for adverse effects is essential.