Pubertal Dysfunctions in Intracranial Germ Cell Tumors

In 60 kids with intracranial germ cell tumors, 45% developed a puberty disorder—too early, too late, or both in sequence

Journal: Frontiers in Endocrinology | Published: 2026-05-19 | Type: Retrospective cohort | PMID: 42238235 Authors: Partenope C, Criscuolo S, Carceller F, Albanese A (Royal Marsden NHS Foundation Trust / University of Piemonte Orientale) Funding/COI: Not listed; authors declared no commercial or financial conflicts of interest

Summary

Intracranial germ cell tumors (IC-GCTs) sit directly on or near the hypothalamic-pituitary axis, so disrupting puberty is almost inevitable—but how and when varies wildly. This single-center retrospective study from the Royal Marsden tracked 60 pediatric patients over 27 years and found 45% developed some form of pubertal disorder. The most clinically interesting finding is the sequential pattern: HCG-secreting tumors can drive pseudo-precocious puberty at diagnosis, which resolves with tumor treatment, only for hypogonadotropic hypogonadism to appear years later as a treatment sequela.

Claims

• 27 of 60 patients (45%) developed at least one pubertal disorder; 16 male, 11 female
• Pseudo-precocious puberty (PPP): 5 patients at diagnosis, all male, all with HCG-secreting GCTs; 3 of 5 resolved spontaneously with tumor treatment and HCG normalization
• 1 PPP case progressed to central precocious puberty (CPP); 1 additional PPP case was managed with bicalutamide + anastrozole before also progressing to CPP
• CPP developed in 3 patients total; managed with GnRH agonist therapy
• Hypogonadotropic hypogonadism (HH): 20 cases, mean onset age 17.5 years in males and 15.1 years in females; only 2 had HH at diagnosis—the rest emerged post-treatment
• Zero cases of hypergonadotropic hypogonadism attributable to chemotherapy
• Suprasellar location (59% of cohort) carried the highest risk of pubertal dysfunction; pineal tumors (30%) less so
• 90% received radiotherapy; 78% received chemotherapy; 11% surgery alone

Study Quality

This is a retrospective single-center chart review spanning 1996–2023—standard for rare pediatric tumor populations where prospective enrollment isn't feasible. The 60-patient cohort from a high-volume UK specialist center carries inherent selection bias: sicker or more complex patients are more likely to be referred to the Royal Marsden. Hormonal workup appears systematic (LH, FSH, sex steroids, thyroid, adrenal), and pubertal staging used Tanner classification, which is reasonably objective. Statistical analysis is purely descriptive—medians, IQRs, and counts—appropriate for a cohort this small, but no regression modeling means confounders (tumor location, treatment intensity, age at diagnosis) aren't formally disentangled.

The 27-year enrollment window is a double-edged sword: it provides sample size for a rare condition, but treatment protocols evolved substantially from 1996 to 2023—craniospinal irradiation doses, chemotherapy regimens, and surgical approaches all shifted—making the cohort heterogeneous in ways the paper doesn't fully account for.

Red Flags

• Median follow-up of only 22.9 months; 32% of patients had fewer than 3 years of follow-up—the paper's own discussion notes that endocrine complications frequently emerge 1–10 years post-therapy, meaning this cohort likely underestimates incidence
• Single center; referral center selection bias inflates severity compared to community populations
• No control arm; no way to disaggregate tumor-direct effects from treatment effects from baseline risk
• Heterogeneous treatments across 27 years make subgroup comparisons unreliable
• N=60 is underpowered for any subgroup analysis (e.g., pineal vs. suprasellar risk comparison produces small cell counts)
• Descriptive statistics only; no multivariate analysis of risk factors

Strengths

• Long institutional follow-up window (1996–2023) provides rare longitudinal data on a rare tumor type
• Systematic hormonal profiling at diagnosis and follow-up
• Clear classification framework distinguishing PPP, CPP, and HH—conditions that are often conflated in less rigorous case series
• Captures the dynamic, sequential nature of pubertal dysfunction over time, which is clinically important and underreported
• No commercial COI declared

Verdict

For a 60-patient chart review, this paper punches above its weight on clinical relevance. The sequential PPP → resolution → HH trajectory—and the implication that persistent or recurrent PPP might be an early signal of tumor recurrence—is a genuinely useful observation for clinicians managing these patients. The short median follow-up is a real problem that the authors acknowledge: HH prevalence of 33% in this cohort will almost certainly be higher in longer-term follow-up, as the paper's own cited literature suggests ~40% of childhood cancer survivors develop endocrine disorders. Read it as a hypothesis-generating case series from a credible institution, not as definitive incidence data.