Highlights
The glucagon stimulation test (GST) in transition-age patients with childhood-onset growth hormone deficiency (CO-GHD) appears to track the severity of hypothalamic-pituitary damage more closely than adiposity.
Although peak GH after glucagon was inversely correlated with BMI standard deviation score, this association weakened substantially after adjustment for disease category, suggesting confounding by etiology.
Patients with more extensive pituitary hormone deficits and structural central nervous system abnormalities had the lowest GH peaks, supporting the biological validity of GST in persistent organic GHD.
In childhood cancer survivors, as in the broader cohort, hypothalamic-pituitary injury rather than BMI was the dominant determinant of test response.
Background
Reassessment of growth hormone (GH) secretion during transition from pediatric to adult endocrine care remains a clinically important and sometimes contentious step. Many children diagnosed with GH deficiency do not have permanent disease, particularly those with isolated or idiopathic deficiency. By contrast, adolescents with multiple pituitary hormone deficiencies, congenital structural defects, prior cranial irradiation, or other organic hypothalamic-pituitary lesions are much more likely to have persistent GH deficiency into adult life.
Accurate retesting matters because ongoing GH replacement after attainment of near-adult height may improve body composition, bone health, lipid metabolism, and quality of life in appropriately selected patients. At the same time, unnecessary continuation of therapy exposes patients to cost, inconvenience, and possible adverse effects without clear benefit. Dynamic testing is therefore central to transition care.
The insulin tolerance test (ITT) has traditionally been viewed as the reference dynamic test for adult GH deficiency, but it is not always practical or safe. It requires induction of hypoglycemia, close supervision, and is contraindicated in some patients, including those with seizure disorders or cardiovascular risk. The glucagon stimulation test has increasingly been adopted as an alternative because it is easier to administer and generally safer. However, uncertainty remains over its diagnostic cutoffs, especially in adolescents and young adults transitioning from pediatric services.
One major challenge is that obesity suppresses stimulated GH secretion in many testing paradigms, raising concern that BMI may lead to false-positive classifications of persistent GH deficiency. This is well recognized in adult endocrine practice, particularly for GHRH-arginine and, to a lesser extent, other stimulation tests. Whether BMI should materially alter interpretation of GST during transition, especially in patients with known childhood-onset disease and heterogeneous etiologies, has been less clear. The study by Fava and colleagues directly addresses this gap.
Study Design
Fava D, Parodi S, Angelelli A, Tedesco C, Napoli F, Allegri AEM, Patti G, Gastaldi R, Santucci C, Vanorio B, Caridi C, Maiorano NG, Fumo R, Panciroli M, Naim A, Stefani A, De Rose EL, Data E, Maghnie M, Di Iorgi N. GH Response to Glucagon in Transition: Role of Body Mass Index and Etiology in Childhood-onset GH Deficiency. The Journal of Clinical Endocrinology and Metabolism. 2026;111(6):e1493-e1505. PMID: 41521526.
This was a cohort study of 180 patients with childhood-onset GH deficiency undergoing glucagon stimulation testing during transition age. The median age was 17.39 years. The investigators aimed to characterize determinants of peak GH response, with particular focus on BMI and underlying disease severity.
The cohort was clinically stratified into three groups designed to capture increasing probability and severity of permanent hypothalamic-pituitary dysfunction:
1) Isolated GHD: 80 patients.
2) Organic moderate GHD: 63 patients, defined by 1-2 additional pituitary deficiencies and congenital or acquired hypothalamic-pituitary abnormalities.
3) Organic severe GHD: 37 patients, defined by at least 3 pituitary deficiencies and complex central nervous system abnormalities.
Patients were also categorized by BMI using age-appropriate criteria into normal weight, overweight, or obesity. Childhood cancer survivors accounted for 42% of the total cohort, an important subgroup because prior surgery, irradiation, and chemotherapy can produce hypothalamic-pituitary injury and often complicate endocrine interpretation.
The principal endpoint was peak GH concentration during GST. The core analytic question was whether variation in GH response was independently explained by BMI, by disease group and etiology, or by both.
Key Findings
Gradient by disease severity was strong and clinically coherent
The most robust signal in the study was the inverse association between peak GH response and severity of pituitary dysfunction. This relationship was highly statistically significant (P < .001). In practical terms, patients with isolated GHD had higher glucagon-stimulated GH peaks than those with organic moderate disease, while those with organic severe disease had the lowest responses.
This result is clinically intuitive. The more extensive the structural or functional damage to the hypothalamic-pituitary axis, the lower the reserve for stimulated GH secretion. The finding strengthens confidence that GST is not merely generating nonspecific suppression, but is instead capturing biologically meaningful differences in residual somatotroph function across etiologic strata.
BMI showed an inverse unadjusted relationship with GH peak
Across the entire cohort, peak GH during GST correlated negatively with BMI standard deviation score, with a Spearman rho of -0.46 (P < .001). At face value, this suggests that higher adiposity is associated with lower stimulated GH output, consistent with prior literature across GH testing modalities.
This observation is important because, if interpreted in isolation, it could encourage the use of BMI-specific GST cutoffs during transition, as has been debated in adult testing frameworks. The study therefore appropriately moved beyond univariate association to assess whether BMI retained an important independent effect when the clinical context was fully considered.
Adjustment for disease group markedly attenuated the BMI effect
The critical message of the paper is that the apparent impact of BMI was substantially reduced after accounting for disease category. In other words, some of the relationship between higher BMI and lower GH peaks appears to reflect underlying differences in etiology and severity of hypothalamic-pituitary damage rather than adiposity acting as a dominant independent suppressor of the GST response.
This is a clinically meaningful distinction. Adolescents and young adults with complex organic hypopituitarism, prior cancer therapy, or multiple hormonal deficits may have altered body composition and higher BMI for several reasons, including endocrine replacement patterns, hypothalamic dysfunction, reduced physical activity, and prior treatment exposures. Without etiologic adjustment, BMI could therefore seem more influential than it truly is.
Etiology outweighed BMI when analyses were stratified
When patients were examined within etiologic subgroups, including analyses based on childhood cancer survivor status, GH peaks were driven primarily by the extent of hypothalamic-pituitary damage. BMI exerted only a minimal effect. This reinforces the idea that the GST is most informative when interpreted in the context of the underlying disease process.
For the practicing endocrinologist, this means the test cannot be read as a decontextualized number. A low peak GH in an adolescent with obesity and otherwise uncertain isolated childhood GHD does not necessarily carry the same implication as the identical value in a patient with pituitary stalk interruption syndrome, craniopharyngioma treatment history, or multiple anterior pituitary deficits.
Childhood cancer survivors formed a major and clinically relevant subgroup
That 42% of the cohort consisted of childhood cancer survivors deserves emphasis. Transition endocrine care in this population is often complicated by previous cranial irradiation or neurosurgical intervention, evolving endocrine late effects, and altered growth and metabolic trajectories. The present study suggests that in these patients too, GST response largely mirrors hypothalamic-pituitary injury rather than simply body habitus.
This has practical value because obesity is common after some childhood cancer therapies, especially with hypothalamic damage, and clinicians may worry that excess adiposity is causing misleadingly low stimulated GH levels. The data here argue that the anatomic and functional burden of disease should remain the dominant interpretive lens.
Clinical Interpretation
What this study adds to transition medicine
The most useful contribution of this study is not the proposal of a single universal cutoff, but rather a refinement in how GST should be interpreted in transition-age patients with childhood-onset disease. The findings support a hierarchy of determinants: first, the severity and nature of hypothalamic-pituitary pathology; second, BMI, whose effect appears smaller once etiology is incorporated.
This is relevant because transition clinics often struggle with borderline dynamic test results. In many cases, the question is not simply whether the GH peak is low, but whether it is low for a biologically meaningful reason that predicts persistent adult deficiency and likelihood of benefit from continued therapy. The present data argue that structural lesions, multiple pituitary deficiencies, and treatment-related hypothalamic-pituitary injury should weigh heavily in that judgment.
Implications for diagnostic thresholds
The abstract does not present a new GST diagnostic cutoff, and that restraint is appropriate. Cutoffs for dynamic testing are notoriously assay-dependent and population-dependent. They are also affected by age, pubertal stage, body composition, and pretest probability. What the study does suggest is that indiscriminate BMI-based correction of GST interpretation in transition-age CO-GHD may be less helpful than an etiologic framework.
Clinicians should therefore be cautious about transplanting adult obesity-adjusted paradigms directly into transition medicine without accounting for the very different disease spectrum in this population. A patient with severe organic hypopituitarism should not have the significance of a low GST response discounted simply because BMI is elevated.
How to integrate these results into practice
For patients with clear organic disease, especially those with multiple pituitary hormone deficiencies or major structural abnormalities, GST results that show low GH reserve are highly plausible and should be interpreted alongside imaging and endocrine phenotype. In such patients, the test may function more as confirmatory evidence than as a standalone gatekeeper.
For patients with isolated or idiopathic childhood GHD, especially those with overweight or obesity and no corroborating MRI or pituitary deficits, clinical interpretation remains more nuanced. BMI may still contribute to lower GH peaks, even if the present study suggests its independent effect is relatively modest after adjustment. These are the patients in whom repeat testing strategy, assay-specific reference standards, IGF-1 interpretation, and longitudinal clinical context remain particularly important.
Strengths and Limitations
Strengths
The study has several notable strengths. First, the sample size of 180 patients is substantial for a transition endocrine cohort. Second, the investigators used a clinically meaningful stratification of disease severity based on both hormone deficits and neuroimaging findings. Third, the large childhood cancer survivor subgroup increases the relevance of the findings to a growing population seen in tertiary endocrine practice. Fourth, the focus on confounding between BMI and etiology addresses a real-world interpretive problem that often arises in clinic.
Limitations
As with any observational study, residual confounding remains possible. The abstract does not provide full details on assay methodology, sampling schedule, pubertal status, sex distribution, prior GH washout duration, or whether sex steroid priming or replacement status influenced results. These factors can affect stimulated GH concentrations and generalizability.
The study also appears focused on physiological test response rather than long-term clinical outcomes. It therefore does not directly answer whether GST performance in different subgroups predicts response to adult GH replacement, changes in body composition, bone accrual, or quality of life. In addition, without head-to-head comparison against ITT or another accepted reference test in the same cohort, the paper informs interpretation more than absolute diagnostic accuracy.
Finally, the abstract does not report detailed effect estimates for multivariable models or subgroup-specific thresholds. Those data would be useful for clinicians trying to operationalize the results in daily practice.
Relation to Existing Literature and Guidelines
Current endocrine guidance generally recommends retesting many adolescents with childhood-onset GH deficiency after linear growth is complete, while recognizing that some patients with unequivocal organic disease may have a very high likelihood of permanent deficiency. Prior guideline and consensus documents have emphasized the importance of pretest probability, structural lesions, and the presence of multiple pituitary hormone deficits when interpreting dynamic testing.
The present study aligns with that framework. It reinforces the notion that disease context should come before body habitus when judging a GST result in transition. This does not negate the known suppressive effect of obesity on GH secretion, but it suggests that in a heterogeneous CO-GHD population, BMI may be less decisive than the depth of hypothalamic-pituitary injury.
These findings are also directionally consistent with broader GH physiology: obesity can blunt spontaneous and stimulated GH secretion, but irreversible hypothalamic-pituitary structural disease produces a more direct and clinically durable loss of secretory capacity. In transition-age endocrine practice, where both phenomena may coexist, the more fundamental lesion appears to dominate.
Expert Commentary
This study is especially useful because it addresses a common overcorrection in endocrine reasoning. Once clinicians become aware that obesity lowers GH responses, there can be a tendency to attribute any low stimulated value in a heavier patient to adiposity. Fava and colleagues show why that shortcut can be misleading in childhood-onset disease. In this setting, BMI may be a marker traveling with organic pathology rather than the primary explanation for the low response.
Another important message is methodological: endocrine dynamic tests are rarely interpreted well outside their clinical substrate. A single number detached from MRI findings, number of hormonal deficits, prior irradiation history, and cancer survivorship status is often insufficient. The study argues for a layered diagnostic model rather than a one-threshold-fits-all approach.
For centers managing childhood cancer survivors, the work is particularly timely. Survivorship clinics increasingly face questions about persistent GH deficiency, metabolic risk, and whether obesity is obscuring endocrine diagnosis. The data support keeping hypothalamic-pituitary injury at the center of decision-making.
Conclusion
In transition-age patients with childhood-onset GH deficiency, the glucagon stimulation test appears to reflect the burden of hypothalamic-pituitary disease more strongly than BMI. Although higher BMI is associated with lower GH peaks on unadjusted analysis, this effect becomes much smaller after accounting for etiology and severity of pituitary dysfunction. The practical implication is clear: GST interpretation during transition should be anchored primarily in disease context, especially the presence of organic lesions, multiple pituitary hormone deficits, and prior cancer-related hypothalamic-pituitary injury.
Future research should define assay-specific GST cutoffs across etiologic strata, compare GST directly with ITT and other dynamic tests in transition cohorts, and examine whether these physiological findings translate into better prediction of adult treatment benefit. Until then, this study supports a clinically grounded approach: in childhood-onset GH deficiency, know the pituitary first, then interpret the peak.
Funding and ClinicalTrials.gov
The abstract information provided does not specify funding sources or a ClinicalTrials.gov registration number. Readers should consult the full published article for these details.
References
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