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Growth hormone secretion, fatigue and quality of life after childhood traumatic brain injury
Open accessAbstract
Context: Traumatic brain injury (TBI) is a recognised cause of hypopituitarism in adults but the prevalence after childhood TBI remains controversial. Objective: To investigate long-term endocrine outcomes and quality of life (PedsQL and QoL-AGHDA (Quality of Life in Adult Growth Hormone Deficiency Assessment)) following childhood TBI. Design: Prospective study. Methods: Participants with moderate/severe TBI (n = 31) and controls (n = 17). Mean (range) age: 19.8 ± 4.2 (11–26), time post TBI: 9 (7–11) years. Detailed endocrine evaluation of stimulated (insulin tolerance test (ITT)) and spontaneous GH secretion (overnight profile) was undertaken in the TBI group; QoL and neuroimaging in both groups. Results: No participant had seizures, short stature, precocious puberty or hypothyroidism. In 6/25 the ITT GH response was below age-defined cut-offs and cortisol <500 nmol/L in 2/25. Mean spontaneous GH secretion was <3.1 µg/L in 16/22 but peak GH was low only in 1/22 profiles. One patient had abnormal spontaneous and stimulated GH secretion and hypogonadism. Fatigue and depression scores were higher in TBI patients (P = .011 and P = .020). Fatigue correlated with measures of spontaneous but not stimulated GH secretion. Overall QoL (PedsQL) did not differ between groups but specific attributes of health state (cognition, memory) were impaired in TBI patients. Pituitary neuroimaging was normal in all participants. Conclusions: Fatigue and depression were common 8–10 years post childhood TBI. One individual had GHD (1/22) using rigorous diagnostic criteria. A single ITT potentially over-diagnosed GHD in 25% (6/25) without clear correlation with symptoms underlying the importance of using two diagnostic tests in TBI survivors.
Overview
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TL;DR
In this prospective KHINES study of childhood moderate/severe TBI survivors assessed about 9 years post-injury, fatigue and depression were common and quality of life was reduced, but true GH deficiency was rare when rigorous criteria were used. A single insulin tolerance test potentially over-diagnosed GHD in 25% of tested TBI participants without clear symptom correlation.
Key findings
In 6/25 TBI participants the ITT GH response was below age-defined cut-offs, and cortisol was <500 nmol/l in 2/25; mean spontaneous GH secretion was <3.1 mcg/l in 16/22, but peak GH was low in only 1/22. One individual had GHD (1/22) using rigorous diagnostic criteria, and one patient had abnormal spontaneous and stimulated GH secretion plus hypogonadism. Fatigue and depression scores were higher in TBI patients (fatigue 3.2±3.3 vs 0.43±0.85, p<.001; significant fatigue 13/28 vs 1/14, p=.011; depression p=.020), and QoL-AGHDA scores in adult TBI patients were poor (10.7±6.9; 8/14 scored >11) and higher than UK general-population data (difference 4.86, 95% CI 1.3–8.3, p<.01). Overall PedsQL did not differ between groups, but cognition and memory were impaired in TBI patients; fatigue correlated with spontaneous but not stimulated GH measures, and mean secretion pulse height was lower in male participants with fatigue (p=.022).
Methods
Prospective study of participants with moderate/severe TBI (n=31) and controls (n=17); mean age was 19.8±4.2 years (range 11–26) and time post-TBI was 9 (7–11) years. TBI participants underwent detailed endocrine evaluation with a 12-hour overnight GH profile sampled every 15 minutes followed by an insulin tolerance test; QoL, fatigue, depression, and neuroimaging were assessed in both groups. GH profiles were analyzed by deconvolution (AutoDecon) and Approximate Entropy; GHD criteria were young adult <3 mcg/l, transition age <5 mcg/l, paediatric <6.7 mcg/l, cortisol 500 nmol/l, and mean overnight GH <3.1 mcg/l.
Limitations
The paper states its main limitation was not having a control group for the endocrine investigation arm involving blood tests. It also states that QoL-AGHDA non-responder bias cannot be entirely ruled out if non-responders had better-than-average scores. Evident from the text: endocrine analyses relied on small subgroups (25 ITT, 22 overnight profiles), and spontaneous GH results were compared with published healthy control data using the same assay but 30-minute rather than 15-minute sampling.
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0 Valid · 1 Not valid · 17 Not checked · 73 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
“Three of these 4 participants had peak overnight GH above the age-related cutoff and IGF-1 SDS above -0.5.”
§ Growth hormone secretion, fatigue and quality of life after childhood traumatic brain injury > Spontaneous Growth Hormone Profiles
plainn = 4- 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
“measures of spontaneous GH secretion (average, maximum, mean secretion pulse mass) correlated with IGF-1 levels (r=.74, r=.52, r=.75, all p<.05).”
§ Growth hormone secretion, fatigue and quality of life after childhood traumatic brain injury > Spontaneous Growth Hormone Profiles
plainstates an association- 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
“One post-pubertal female with secondary amenorrhea following TBI had low levels of oestradiol (<50 pmol/L), gonadotropins, IGF-1 and IGFBP3 (-2.4 and -2.1 SDS respectively).”
§ Growth hormone secretion, fatigue and quality of life after childhood traumatic brain injury > Baseline endocrine function
plainSingle case- 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
“IGF-1 levels were also lower in the subgroup of TBI patients with mean, overnight GH secretion under 3.1 mcg/l (33.4±7.1 vs 45.7±7.1 nmol/L, p=.003, 95% CI of difference 4.62-19.87).”
§ Growth hormone secretion, fatigue and quality of life after childhood traumatic brain injury > Spontaneous Growth Hormone Profiles
plainstates an association- 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
“IGF-1 SDS was not different between participants with normal and abnormal stimulated GH response (-.48±1.1 vs -.74 ±.82, p=.86)”
§ Growth hormone secretion, fatigue and quality of life after childhood traumatic brain injury > Stimulated Growth hormone and cortisol secretion
plainn = 31- 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.
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Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“Traumatic brain injury affecting the hypophysis can lead to secondary hypogonadism [44].”
From An Approach to Traumatic Brain Injury-Related Hypopituitarism: Overcoming the Pediatric Challenges (2023) · cites this paper as [44]
In the citing paper
“Based on evaluation of existing reports, between 9.1% and 47.8% of children and adolescents with TBI may develop GHD (Supplementary Table S2).26,45,60-63,65-67”
In the citing paper
“This analysis revealed that PTHP may be present in 10 to 58% of pediatric and adolescent patients at any time during the chronic phase of TBI (Supplementary Table S1).26,45,59–66”
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 major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ Growth hormone secretion, fatigue and quality of life after childhood traumatic brain injury > Endocrine Investigations
“Mean spontaneous, nocturnal GH secretion in this group was 6.7±2.9 (3.1-15.6 mcg/l) (14).”
§ Growth hormone secretion, fatigue and quality of life after childhood traumatic brain injury > Spontaneous Growth Hormone Profiles
“Overall, mean GH secretion was significantly lower compared to that reported in healthy individuals (2.2±1.3 vs 6.1±2.6 mcg/l, p<.0001) (14).”
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
§ Growth hormone secretion, fatigue and quality of life after childhood traumatic brain injury > Abstract
“Fatigue and depression scores were higher in TBI patients (p=.011 and p=.020).”
§ Growth hormone secretion, fatigue and quality of life after childhood traumatic brain injury > Fatigue
“Fatigue scores were higher in TBI (3.2±3.3)vs control group (.43 ±.85) using bimodal scoring (scale 0-11) (p<.001).”
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
§ Growth hormone secretion, fatigue and quality of life after childhood traumatic brain injury > Fatigue
“In TBI participants 15/35 scans were abnormal.”
§ Growth hormone secretion, fatigue and quality of life after childhood traumatic brain injury > Fatigue
“Neuroimaging 35/48 participants (14 controls, 21 TBI) had a head MRI scan”
Citations
Cites
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Approximate entropy (ApEn) as a complexity measure
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Measuring fatigue in clinical and community settings
Cella, M., & Chalder, T. (2010) · Journal of Psychosomatic Research · doi:10.1016/j.jpsychores.2009.10.007 · Cited by 376
Pincus, S. M., Mulligan, T., Iranmanesh, A., Gheorghiu, S., Godschalk, M., & Veldhuis, J. D. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.24.14100 · Cited by 337
McKenna, S. P., Doward, L. C., Alonso, J., Kohlmann, T., Niero, M., Prieto, L., & Wíren, L. (1999) · Quality of Life Research · doi:10.1023/a:1008987922774 · Cited by 263
Growth Hormone (GH) Provocative Testing Frequently Does Not Reflect Endogenous GH Secretion*
BERCU, B. B., SHULMAN, D., ROOT, A. W., & SPILIOTIS, B. E. (1986) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem-63-3-709 · Cited by 227
Anterior pituitary dysfunction following traumatic brain injury (TBI)
Agha, A., & Thompson, C. J. (2006) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2006.02517.x · Cited by 108
Fatigue after TBI: Association with neuroendocrine abnormalities
Bushnik, T. L., Englander, J., & Katznelson, L. J. (2007) · Brain Injury · doi:10.1080/02699050701426915 · Cited by 93
Endocrine dysfunction following traumatic brain injury in children
Kaulfers, A.-M. D., Backeljauw, P. F., Reifschneider, K., Blum, S., Michaud, L., Weiss, M., & Rose, S. R. (2010) · The Journal of Pediatrics · doi:10.1016/j.jpeds.2010.07.004 · Cited by 84
Permanent hypopituitarism is rare after structural traumatic brain injury in early childhood
Heather, N. L., Jefferies, C., Hofman, P. L., Derraik, J. G. B., Brennan, C., Kelly, P., Hamill, J. K. M., Jones, R. G., Rowe, D. L., & Cutfield, W. S. (2012) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2011-2284 · Cited by 62 · cited 1×
“In a study of 198 paediatric survivors of TBI with MRI changes, all participants had normal pituitary function using two stimulation tests (5) while in a more recent study, GHD was confirmed in 5/61 children with severe TBI who were retested 5 years postTBI (6).”
Method
Research works printed but not linked: 9
- Kraus JF, Rock A, Hemyari P. Brain injuries among infants, children, adolescents, and young adults. American journal of diseases of children. 1990;144(6):684-91.
- Tanriverdi F, De Bellis A, Ulutabanca H, Bizzarro A, Sinisi AA, Bellastella G, Amoresano Paglionico V, Dalla Mora L, Selcuklu A, Unluhizarci K, et al. A five year prospective investigation of anterior pituitary function after traumatic brain injury: is hypopituitarism long-term after head trauma associated with autoimmunity? Journal of neurotrauma. 2013;30(16):1426-33.
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- McCarthy ML, MacKenzie EJ, Durbin DR, Aitken ME, Jaffe KM, Paidas CN, Slomine BS, Dorsch AM, Berk RA, Christensen JR, et al. The Pediatric Quality of Life Inventory: an evaluation of its reliability and validity for children with traumatic brain injury. Archives of physical medicine and rehabilitation. 2005;86(10):1901-9.
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- Leal-Cerro A, Povedano J, Astorga R, Gonzalez M, Silva H, Garcia-Pesquera F, Casanueva FF, Dieguez C. The growth hormone (GH)-releasing hormone-GH-insulin-like growth factor-1 axis in patients with fibromyalgia syndrome. The Journal of clinical endocrinology and metabolism. 1999;84(9):3378-81.
Cited by
Pathophysiology of Pediatric Traumatic Brain Injury
Serpa, R. O., Ferguson, L., Larson, C., Bailard, J., Cooke, S., Greco, T., & Prins, M. L. (2021) · Frontiers in Neurology · doi:10.3389/fneur.2021.696510 · Cited by 62
Greenham, M., Botchway-Commey, E. N., Knight, S., Bonyhady, B., Tavender, E. J., Scheinberg, A. M., Anderson, V. A., & Muscara, F. (2020) · Disability and Rehabilitation · doi:10.1080/09638288.2020.1849425 · Cited by 32
Yuen, K. C. J., Masel, B. E., Reifschneider, K. L., Sheffield-Moore, M., Urban, R. J., & Pyles, R. B. (2020) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/clinem/dgaa398 · Cited by 24
Wexler, T. L., Reifschneider, K., Backeljauw, P., Cárdenas, J. F., Hoffman, A. R., Miller, B. S., & Yuen, K. C. J. (2023) · Journal of Neurotrauma · doi:10.1089/neu.2022.0384 · Cited by 19
Pituitary dysfunction after traumatic brain injury: prevalence and screening strategies
Ntali, G., & Tsagarakis, S. (2020) · Expert Review of Endocrinology & Metabolism · doi:10.1080/17446651.2020.1810561 · Cited by 17
Metadata
- Authors
- Daskas, N., Sharples, P., Likeman, M., Lightman, S., & Crowne, E. C.
- Affiliations
- University Hospitals Bristol NHS Foundation Trust (GB)
- University of Bristol (GB)
- Corresponding author
- Crowne, E C
- Venue
- European Journal of Endocrinology
- Publisher
- Oxford University Press (OUP)
- Published
- 2019-09
- Volume
- 181
- Issue
- 3
- Pages
- 331-338
- ISSN
- 0804-4643 (ISSN-L)
- 1479-683X
- OpenAlex
- W2964275005
- Cited by
- 12
- References
- 18
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 2 · 2022: 1 · 2021: 2 · 2020: 4
- FWCI
- 0.92
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- European Journal of Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Explore Bristol Research (publishedVersion, other-oa)
- Bristol Research (University of Bristol) (submittedVersion, other-oa)
- Funders
- Engineering and Physical Sciences Research Council (EP/N014391/1)
- 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 › Clinical Neurology › Traumatic Brain Injury Research
- Keywords
- pediatric traumatic brain injury, growth hormone deficiency, hypopituitarism, fatigue, depression, quality of life, insulin tolerance test, pituitary function, cognitive impairment
- MeSH terms
- Brain Injuries, Traumatic, Adolescent, Adult, Child, Depression, Fatigue, Female, Humans, Male, Quality of Life, Human Growth Hormone, Young Adult
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- Daskas, N., Sharples, P., Likeman, M., Lightman, S., & Crowne, E. C. (2019). Growth hormone secretion, fatigue and quality of life after childhood traumatic brain injury. European Journal of Endocrinology. https://doi.org/10.1530/eje-19-0166
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