The DOI matches its Crossref record; 40 of the 43 references it cites were found in a registry or an index; none of the 28 sources its claims cite is checked for support yet.
Diagnosis of GH Deficiency as a Late Effect of Radiotherapy in Survivors of Childhood Cancers
Open accessAbstract
Background: Limited guidance exists for selecting a laboratory method for diagnosing GH deficiency (GHD) when it occurs as a late effect of radiotherapy in childhood cancer survivors (CCSs). Methods: We searched Medline, Embase, Cochrane Central Register of Controlled Trials and Database of Systematic Reviews, and Scopus for studies evaluating GHD that used IGF-1 or IGF-binding protein 3 (IGFBP-3) measurements compared with GH dynamic testing. Results: We included 15 studies [IGF-1 (8 studies) and IGFBP-3 (7 studies)] enrolling 477 patients. Comparator tests varied widely. Overall, both IGF-1 and IGFBP-3 had suboptimal diagnostic accuracy but were strongly correlated. The use of both tests simultaneously in the same cohort did not improve the diagnostic accuracy. Despite high variability in the testing protocols, dynamic tests remained the most accurate for appropriately identifying patients with GHD. The insulin tolerance test (ITT) appears to be the most accepted reference test when used alone or in combination with arginine; however, standardized testing strategies among practice groups are absent. GHRH and arginine stimulation performed almost similarly to the ITT; however, in one study GHRH with arginine stimulation had 66% sensitivity and 88% specificity compared with the ITT. Insufficient data were available to assess the accuracy of serial GH testing (nocturnal or over 24 hours). Conclusion: The diagnostic accuracy of various dynamic tests for GHD in CCSs appears to follow the same patterns as those in non-CCSs. Interpreting GHRH stimulation is a challenge given the primarily hypothalamic dysfunction in CCSs. IGF-1 and IGFBP-3 perform poorly in this population.
Overview
CoChat Summary
TL;DR
This systematic review found that dynamic GH testing remains the most accurate approach for diagnosing GH deficiency (GHD) in childhood cancer survivors (CCSs) after radiotherapy, with the insulin tolerance test (ITT) as the most accepted reference. IGF-1 and IGFBP-3 performed poorly in this population, and evidence was limited by high variability and the absence of a gold standard.
Key findings
- Across 15 studies and 477 patients (56% male, n = 266), dynamic tests remained most accurate for identifying GHD; the ITT was the most commonly used reference test. GHRH with arginine stimulation had 66% sensitivity and 88% specificity compared with the ITT in one study.
- IGF-1 and IGFBP-3 had suboptimal diagnostic accuracy: IGF-1 sensitivity varied from 47% to 66% and specificity from 77% to 100%; IGFBP-3 had a low sensitivity of 20%. Using both tests simultaneously did not improve diagnostic accuracy.
- Insufficient data were available to assess serial GH testing (nocturnal or 24-hour profiles). The quality of evidence was moderate, and meta-analysis of sensitivity and specificity could not be performed because studies lacked a single common comparator.
Methods
- Systematic review following Cochrane Collaboration standards and PRISMA reporting; searched Medline, Embase, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Scopus from each database’s inception to 1 March 2016, plus reference screening and taskforce input.
- Included cohort studies and case series evaluating diagnostic accuracy of provocative, dynamic, or static GH testing compared with reference standard tests, with at least 10 patients undergoing any kind of GH testing.
- From 211 citations, 177 full-text studies were reviewed, and 15 studies were included. Reviewers worked independently and in duplicate, used a standardized Web-based form for data collection, assessed risk of bias with QUADAS-2, and evaluated quality of evidence with GRADE.
Limitations
- Stated: included studies span four decades and represent varied testing and clinical consensuses, leading to variability in reporting results and outcomes; there is no gold standard for diagnosing GHD, and calculating diagnostic accuracies from available primary data was not possible.
- Stated: the cohorts could not be combined and index tests could not be compared due to high interstudy variability in testing strategies, cutoff levels, and comparator tests; quality of evidence was moderate because of small sample size and inability to aggregate data.
- Evident from the text: 5 studies did not report age at diagnosis, 3 did not report age at GHD evaluation, and 2 did not report sex proportions; none of the provocative tests evaluated were tested for reproducibility over time.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
0 Valid · 0 Not valid · 20 Not checked · 41 Own results and interpretations
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“All patients received HP, cranial, or craniospinal radiation.”
§ Diagnosis of GH Deficiency as a Late Effect of Radiotherapy in Survivors of Childhood Cancers > Patient characteristics
plainn = 477- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“GHRH and arginine stimulation performed almost similarly to the ITT; however, in one study GHRH with arginine stimulation had 66% sensitivity and 88% specificity compared with the ITT.”
§ Diagnosis of GH Deficiency as a Late Effect of Radiotherapy in Survivors of Childhood Cancers > Abstract
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Overall, homogeneity was observed regarding the protocols used to stimulate GH responses in dynamic tests, which was most notable in terms of dosing regimens and administration route.”
§ Diagnosis of GH Deficiency as a Late Effect of Radiotherapy in Survivors of Childhood Cancers > Provocative test protocols
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
In the paper
“in one study GHRH with arginine stimulation had 66% sensitivity and 88% specificity compared with the ITT.”
- Also stated in: § Performance · plain
“in one study, GHRH in combination with arginine stimulation was 66% sensitive and 88% specific in comparison with the ITT (16).”
§ Diagnosis of GH Deficiency as a Late Effect of Radiotherapy in Survivors of Childhood Cancers > Abstract
What the sources say
- Not checked yetcites [16] Björk, 2005, The utility of the growth hormone (GH) releasing hormone-arginine test for diagnosing GH deficiency in adults with childhood acute lymphoblastic leukemia treated with cranial irradiation, J Clin Endocrinol Metab source
plainstates an association- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Rests on an assumption not shown here.
- Also stated in: § Performance · plain
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Comparator tests varied widely.”
- Also stated in: § Study characteristics · plain
“There was high variability in the confirmatory test performed in each study and in the testing strategies.”
§ Diagnosis of GH Deficiency as a Late Effect of Radiotherapy in Survivors of Childhood Cancers > Abstract
plainn = 477- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Also stated in: § Study characteristics · plain
30 more claims
Create a free account to see all 61 claims and to verify the 27 references still open.
- Probably not a substantial claim. 11
- It may state two separate claims as one. 20
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Diagnosis of GH Deficiency as a Late Effect of Radiotherapy in Survivors of Childhood Cancers > GHRH.
“Arginine used in isolation or in combination with GHRH was administered at a dosage of either 20 g/m 2 or 0.5 g/kg via intravenous infusion over 30 minutes”
§ Diagnosis of GH Deficiency as a Late Effect of Radiotherapy in Survivors of Childhood Cancers > Conclusion
“| Lissett et al. 2001 (17) Cross | Arginine | 20 mg/m 2 | ,8 mg/L | ITT | 0.2 U/kg IV | | ,8 mg/L | |”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Diagnosis of GH Deficiency as a Late Effect of Radiotherapy in Survivors of Childhood Cancers > GHRH.
“Arginine used in isolation or in combination with GHRH was administered at a dosage of either 20 g/m 2 or 0.5 g/kg via intravenous infusion over 30 minutes”
§ Diagnosis of GH Deficiency as a Late Effect of Radiotherapy in Survivors of Childhood Cancers > Conclusion
“| Shalet et al. 1976 (10) | Cross-sectional | Arginine stimulation | Bovril 20 g/ 1.5 m 2 oral | ,6.67 mg/L | ITT | 0.1-0.2 U/kg IV | ,6.67 mg/L | |”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Diagnosis of GH Deficiency as a Late Effect of Radiotherapy in Survivors of Childhood Cancers > Cutoff values
“The various cutoff values used by the studies evaluated ranged from 4.67 mg/L to 10 mg/L”
§ Diagnosis of GH Deficiency as a Late Effect of Radiotherapy in Survivors of Childhood Cancers > Conclusion
“| Bj örk et al. 2005 (16) Cross- | GHRH + Arginine | GHRH 1 mg/kg | ,9 mg/L | ITT | 0.1-0.2 U/kg IV | ,3 mg/L | | |”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Diagnosis of GH Deficiency as a Late Effect of Radiotherapy in Survivors of Childhood Cancers > Abstract
“We included 15 studies [IGF-1 (8 studies) and IGFBP-3 (7 studies)] enrolling 477 patients.”
§ Diagnosis of GH Deficiency as a Late Effect of Radiotherapy in Survivors of Childhood Cancers > Study characteristics
“Nonprovocative tests included IGF-1 in 10 studies, IGFBP-3 in 9 studies, and continuous GH profiles in 3 studies”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Diagnosis of GH Deficiency as a Late Effect of Radiotherapy in Survivors of Childhood Cancers > Eligibility criteria
“We included studies reporting .10patients undergoing any kind of GH testing.”
§ Diagnosis of GH Deficiency as a Late Effect of Radiotherapy in Survivors of Childhood Cancers > Conclusion
“| Shalet et al. | United Kingdom | N/A | 10 (7-14) | 6 (66.67) | 4 y (2-10) | Medulloblastoma (4) | 9 | Cranial or | 10 to 42.5 |”
Citations
Cites
QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies
Whiting, P. F., Rutjes, A. W. S., Westwood, M. E., Mallett, S., Deeks, J. J., Reitsma, J. B., Leeflang, M. M. G., Sterne, J. A. C., Bossuyt, P. M. M., & the QUADAS-2 Group* (2011) · Annals of Internal Medicine · doi:10.7326/0003-4819-155-8-201110180-00009 · Cited by 14,199
Childhood and adolescent cancer statistics, 2014
Ward, E., DeSantis, C., Robbins, A., Kohler, B., & Jemal, A. (2014) · CA: A Cancer Journal for Clinicians · doi:10.3322/caac.21219 · Cited by 2,412
Molitch, M. E., Clemmons, D. R., Malozowski, S., Merriam, G. R., & Vance, M. L. (2011) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-0179 · Cited by 1,047
Grimberg, A., DiVall, S. A., Polychronakos, C., Allen, D. B., Cohen, L. E., Quintos, J. B., Rossi, W. C., Feudtner, C., Murad, M. H., & on behalf of the Drug and Therapeutics Committee and Ethics Committee of the Pediatric Endocrine Society (2016) · Hormone Research in Paediatrics · doi:10.1159/000452150 · Cited by 697
Self-citationSensitivity and specificity of six tests for the diagnosis of adult GH deficiency
Biller, B. M. K., Samuels, M. H., Zagar, A., Cook, D. M., Arafah, B. M., Bonert, V., Stavrou, S., Kleinberg, D. L., Chipman, J. J., & Hartman, M. L. (2002) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.87.5.8509 · Cited by 423
Murad, M. H. (2017) · Mayo Clinic Proceedings · doi:10.1016/j.mayocp.2017.01.001 · Cited by 386
Self-citationClemmons, D. R. (2011) · Clinical Chemistry · doi:10.1373/clinchem.2010.150631 · Cited by 353
Society, G. R. (2000) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.85.11.6984 · Cited by 349
Ghigo, E. (1996) · Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.81.9.3323 · Cited by 303
Chemaitilly, W., Li, Z., Huang, S., Ness, K. K., Clark, K. L., Green, D. M., Barnes, N., Armstrong, G. T., Krasin, M. J., Srivastava, D. K., et al. (2015) · Journal of Clinical Oncology · doi:10.1200/jco.2014.56.7933 · Cited by 281
Self-citation
Cited by
Yuen, K. C. J., Biller, B. M. K., Radovick, S., Carmichael, J. D., Jasim, S., Pantalone, K. M., & Hoffman, A. R. (2019) · Endocrine Practice · doi:10.4158/gl-2019-0405 · Cited by 298
Self-citationGrowth hormone therapy in children; research and practice – A review
Collett‐Solberg, P. F., Jorge, A. A. L., Boguszewski, M. C. D. S., Miller, B. S., Choong, C. S., Cohen, P., Hoffman, A. R., Luo, X., Radovick, S., & Saenger, P. H. (2018) · Growth Hormone & IGF Research · doi:10.1016/j.ghir.2018.12.004 · Cited by 103
Wit, J. M., Kamp, G. A., Oostdijk, W., & on behalf of the Dutch Working Group on Triage and Diagnosis of Growth Disorders in Children (2019) · Hormone Research in Paediatrics · doi:10.1159/000499915 · Cited by 68
Hypothalamic-Pituitary and Other Endocrine Surveillance Among Childhood Cancer Survivors
van Iersel, L., Mulder, R. L., Denzer, C., Cohen, L. E., Spoudeas, H. A., Meacham, L. R., Sugden, E., Schouten-van Meeteren, A. Y. N., Hoving, E. W., Packer, R. J., et al. (2022) · Endocrine Reviews · doi:10.1210/endrev/bnab040 · Cited by 66
Self-citationBoguszewski, M. C. D. S., Cardoso-Demartini, A. D. A., Boguszewski, C. L., Chemaitilly, W., Higham, C., Johannsson, G., & Yuen, K. C. J. (2021) · Pituitary · doi:10.1007/s11102-021-01173-0 · Cited by 43
Self-citation
Metadata
- Authors
- Sfeir, J. G., Kittah, N. E. N., Tamhane, S. U., Jasim, S., Chemaitilly, W., Cohen, L. E., & Murad, M. H.
- Affiliations
- Mayo Clinic (US)
- St. Jude Children's Research Hospital (US)
- Boston Children's Hospital (US)
- Corresponding author
- Murad, M Hassan
- Venue
- The Journal of Clinical Endocrinology & Metabolism
- Publisher
- The Endocrine Society
- Published
- 2018-06-29
- Volume
- 103
- Issue
- 8
- Pages
- 2785-2793
- ISSN
- 0021-972X (ISSN-L)
- 1945-7197
- OpenAlex
- W2811100230
- Semantic Scholar
- 0459f99cde4f0b924597f9aed23b9db8a8ef908d
- Cited by
- 35
- References
- 43
- Citations by year
- 2026: 4 · 2025: 2 · 2024: 5 · 2023: 3 · 2022: 4 · 2021: 5 · 2020: 3 · 2019: 7 · 2018: 2
- FWCI
- 0.59
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Clinical Endocrinology & Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Pfizer
- Novo Nordisk
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Pituitary Gland Disorders and Treatments
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Childhood Cancer Survivors' Quality of Life
- Keywords
- growth hormone deficiency, childhood cancer survivors, late radiation effects, insulin-like growth factor I, IGFBP-3, insulin tolerance test, GHRH stimulation, arginine stimulation, diagnostic accuracy, hypothalamic dysfunction
- MeSH terms
- Cancer Survivors, Adult, Child, Diagnostic Techniques, Endocrine, Growth Disorders, Humans, Predictive Value of Tests, Radiation Injuries, Radiotherapy, Reproducibility of Results, Age of Onset, Human Growth Hormone
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
A language model drew the claims from the paper on 2026-11-14, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-11-14 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
Data sources
Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
