Pituitary volume as a permissive morphological threshold for hypothalamic-pituitary-gonadal axis activation in children: a comprehensive diagnostic prediction study with relative importance decomposition
Year: 2026
Type: article
Study design: Observational Study
Abstract: Objective: The gonadotropin-releasing hormone (GnRH) stimulation test, the reference standard for confirming hypothalamic-pituitary-gonadal axis (HPGA) activation, is invasive and costly. Pituitary volume (PV) on MRI has been proposed as a non-invasive surrogate, yet whether PV constitutes a permissive morphological threshold or is redundant with clinical parameters remains undefined. We evaluated PV as a morphological threshold of HPGA activation and quantified its relative importance, unique information content, and clinical utility. Methods: We retrospectively enrolled 896 children who underwent pituitary MRI and GnRH stimulation testing. PV was measured using the ellipsoid approximation. Out-of-fold cross-validated AUC was the primary performance metric. Predictor importance was quantified by Shapley value decomposition, permutation importance, and Lindeman-Merenda-Gold (LMG) variance partitioning. Morphological-threshold analyses examined HPGA activation across PV deciles. Statistical mediation tested whether insulin-like growth factor 1 (IGF-1) mediated the PV-HPGA association, with formal power analysis for incremental AUC detection. Results: PV exhibited a threshold pattern: HPGA activation was 28.9% (95% CI 20.5-39.0) in the lowest PV decile (≤115 mm³) versus 92.2% (95% CI 84.8-96.2) in the highest (≥335 mm³; OR 4.38, 95% CI 2.60-7.36; per-IQR OR 2.04, 95% CI 1.59-2.62). PV ranked second by Shapley decomposition (+0.065 AUC, 22.2%), carrying unique information (LMG 20.4% of pseudo-R²). At the 203.9 mm³ cutpoint, the diagnostic odds ratio was 4.78, positive likelihood ratio 2.44, and number needed to screen 2.73. PV tertile AUC was 0.693; combined with IGF-1, AUC rose to 0.748. IGF-1 statistically mediated 37.4% of the PV-HPGA association. The full model OOF AUC was 0.801 (95% CI 0.772-0.828) versus 0.798 for the clinical model (ΔAUC +0.003); power was ~5% at N = 896, requiring N ≈ 25360 for 80% power. The age-sex-adjusted PV z-score AUC was 0.592 (95% CI 0.554-0.630). Conclusion: PV serves as a permissive morphological threshold for HPGA activation; while it's not a strictly necessary condition, HPGA activation is physiologically improbable below a critical PV. Although PV is not a standalone predictive tool and its incremental value over clinical parameters is minimal, it functions as a complementary morphological checkpoint that contextualizes hormonal interpretation when pituitary MRI has been conducted to exclude intracranial lesions as per guidelines.
Source: Frontiers in Endocrinology
Language: English
Subfield: Reproductive Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,801
Award: G266464369
OpenAlex ID: W7223181488