Evaluating Quality of Life Effects after Growth Hormone Replacement in Individuals with Moderate-to-Severe Traumatic Brain Injury and Growth Hormone Deficiency

Abstract

Traumatic brain injury (TBI) is a leading cause of long-term disability, with chronic complications including growth hormone deficiency (GHD). Growth hormone replacement therapy (GHRT) has shown promise in improving these outcomes, but evidence specific to moderate-to-severe TBI (msTBI) populations using TBI-specific quality of life (QoL) measures remains limited. This prospective cohort study evaluated the impact of 1 year of GHRT on QoL in 69 adults with msTBI and GHD, using the QoL after Brain Injury (QOLIBRI) questionnaire. GHD was diagnosed via glucagon stimulation testing at least 1-year postinjury. GHRT was initiated and titrated to achieve therapeutic insulin-like growth factor 1 levels, with QOLIBRI scores collected at baseline, 6 months, and 12 months. Statistical analyses included Friedman tests and multivariate mixed-effects models. Results demonstrated significant improvements in all QOLIBRI domains after 1 year of GHRT. Mixed effects analysis showed a trend toward lower overall QoL after GHRT in severe TBI patients and most model variation existed among individuals by domain of QOLIBRI. These findings suggest that GHRT is associated with improved cognitive, emotional, and physical aspects of QoL in msTBI patients with GHD, as measured by a TBI-specific instrument. The study is limited by its single-center, observational design and lack of a control group. Further research with larger, controlled cohorts is warranted to clarify the long-term benefits of GHRT and optimize management strategies for this population. Enhanced screening and treatment of endocrine dysfunction may improve outcomes for individuals with msTBI.

Keywords

quality of life growth hormone replacement therapy traumatic brain injury growth hormone deficiency endocrine dysfunction

Introduction

Traumatic brain injury (TBI) remains a leading cause of mortality and long-term morbidity worldwide, with an estimated 64–74 million new cases occurring annually.¹ Additionally, TBI is the leading cause of death for those under 45 in the Western world.¹ TBI is often seen as an acute event; however, the brain’s high oxygen needs, limited regenerative capacity, and relatively low endogenous antioxidant synthesis lead to a more unique healing process than that of other organs.² TBI can result in chronic, lifelong consequences affecting cognition, autonomic function, sexual health, metabolic regulation, and neuroendocrine balance.²

Pituitary dysfunction is an identified sequela of TBI.³ The pituitary gland’s unique location and vascularity likely contribute to the pathogenesis of post-traumatic hypopituitarism.³ The most common pituitary hormone deficiency in TBI survivors is growth hormone deficiency (GHD).^4,5 In fact, 7–28% of patients report GHD at >12 months after injury.⁶ Growth hormone (GH) is produced by the anterior pituitary gland and plays a role in cell growth, nervous system development, appetite regulation, cognition, energy, sleep, mood, and anabolic processes such as skeletal growth.⁴ GHD is associated with neurobehavioral deficits in TBI survivors including poor verbal learning, emotional problems, decreased attention and memory, and poor mental health outcomes.^4,7 These issues may be due to lower GH levels in the hippocampus and limbic system, areas that are important for memory, emotion, and learning.⁷ Patients with GHD post-TBI are shown to have a reduced quality of life (QoL).⁷ Physical health, energy and fatigue, emotional well-being, pain, and general health are commonly affected domains.⁴

Growth hormone replacement therapy (GHRT) has demonstrated promise in improving cognitive symptoms and QoL in TBI survivors with GHD. When comparing patients with GHD secondary to TBI versus a nonfunctioning pituitary adenoma, the QoL improvement was higher in post-traumatic GHD patients.⁷ Szarka et al.⁵ conducted a systematic review assessing the effects of GHRT on cognitive function and QoL after TBI. They found that GHRT after TBI was associated with a moderate improvement in processing speed and memory, reduced depression severity, and improvement in QoL.⁵ Batson et al.⁶ conducted a scoping review of 11 studies, finding that fatigue, mood, cognition, and physical performance improved with GHRT. One study within the scoping review found that structural and functional neuroimaging changes, such as increased cortical thickness and gray matter volume, were seen after treatment.⁶ Despite favorable outcomes seen with GHRT, existing studies are limited by small sample sizes, short durations, inconsistencies in patient populations, and the use of generic rather than TBI-specific QoL measures. As a result, the long-term impact of GHRT on QoL in individuals with moderate-to-severe TBI (msTBI) and GHD remains unclear.

Therefore, the objective of this study is to determine whether GHRT is associated with improved QoL in patients with msTBI and GHD over 1 year of GHRT. We hypothesize that GHRT is associated with significant improvements as measured by a validated, TBI-specific instrument: the Quality of Life after Brain Injury (QOLIBRI) questionnaire.

Methods

Participants

A prospectively enrolled neuroendocrine database from a single Brain Injury Center was used to evaluate the effects of GHRT in 69 individuals with msTBI. Institutional Review Board (IRB) approval for this study was obtained from the appropriate committee at the institution where the work was conducted (IRB-24-1919). Three individuals were lost to follow-up after the Initial and Follow-Up 1 time periods and were excluded from analyses; therefore, the final sample size used in this study is 66 individuals. Informed consent was obtained from all participants prior to their inclusion in the study. Participants aged 18–65 years with a primary diagnosis of msTBI and GHD who consented to start GHRT were eligible. msTBI was defined by a best Glasgow Coma Scale score of 3–12 within 24 h post-injury, loss of consciousness exceeding 30 min, or post-traumatic amnesia lasting >24 h. Participants were excluded from the study if they had significant cognitive impairment that precluded the ability to provide informed consent, were pregnant, had undergone pituitary surgery within the preceding 6 weeks, or had a diagnosis of active acromegaly or pheochromocytoma. Additional exclusion criteria encompassed liver enzyme concentrations exceeding three times the upper limit of normal, serum creatinine levels >2 mg/dL, a history of active malignancy within the last 5 years, poorly controlled hypertension, severe acute illness, recent exposure to GH therapy, malnutrition, or severe fasting hyperglycemia defined as a blood glucose level >180 mg/dL.

GHD was identified using the glucagon stimulation test (GST), which was administered at least 1 year after msTBI to allow for the possibility of spontaneous recovery of GH secretion. The diagnostic thresholds for adult GHD via GST were tailored based on each participant’s body mass index (BMI) and their pretest likelihood of GHD. Prior to dynamic testing, all individuals underwent a comprehensive neuroendocrine assessment, which included evaluation of thyroid-stimulating hormone, thyroxine, follicle-stimulating hormone, luteinizing hormone, sex steroids (testosterone or estrogen as appropriate), prolactin, cortisol, insulin-like growth factor 1 (IGF-1), and a complete metabolic panel. Any detected endocrine abnormalities were addressed and managed before proceeding with the GST.

Glucagon stimulation test

The GST was conducted using a standardized protocol designed to elicit GH secretion. Participants were required to fast overnight for 8–10 h, during which only water was permitted. Routine morning medications could be taken with water. Upon arrival, each participant’s weight was measured to determine the appropriate glucagon dosage. An intravenous cannula was inserted into one forearm to allow for serial blood sampling. Glucagon was administered intramuscularly, with a dose of 1.0 mg for individuals weighing 90 kg or less and 1.5 mg for those weighing >90 kg. Blood samples were collected at baseline and at 30, 60, 90, 120, 150, 180, 210, and 240 mins after glucagon administration. These samples were analyzed for serum GH and blood glucose levels. Interpretation of the results was based on BMI-specific criteria from the 2019 American Association of Clinical Endocrinologists and American College of Endocrinology guidelines. In normal-weight individuals (BMI < 25 kg/m²) and overweight individuals (BMI 25–30 kg/m²) with a high pretest probability (defined as IGF-1 < 0 SDS), a peak GH level ≤ 3.0 µg/L was considered diagnostic of adult GHD. For overweight individuals with a low pretest probability (defined as IGF-1 > 0 SDS) and for all obese individuals (BMI > 30 kg/m²), a peak GH level of 1.0 µg/L or less at any time during the test was considered indicative of GHD.^8,9 Serum GH assays were performed by Quest Diagnostics.

Glasgow outcome scale-extended

Glasgow outcome scale-extended (GOSE) assessments were carried out by a single examiner, thereby eliminating the possibility of interrater variability. These GOSE interviews were conducted face-to-face. Prior to initiating data collection, the examiner completed formal training and received a comprehensive manual that addressed protocols for handling ambiguous responses, complex scenarios, and provided standardized scoring guidelines. The GOSE questionnaire is composed of 14 items organized into 7 sections, mirroring the structure of the interview. It is designed for use with adult patients or their caregivers. The questionnaire format has demonstrated excellent test–retest reliability, with a weighted kappa of 0.98.¹⁰

QoL after brain injury

To assess QoL in participants, the QOLIBRI questionnaire was administered. This self-report instrument, designed specifically for individuals with TBI, includes 37 items grouped into 6 domains: Thinking Abilities, Emotions, Independence and Daily Function, Social Relationships, Feelings, and Physical Problems. Participants respond to each item using a Likert scale ranging from 1 (“not at all”) to 5 (“very”), reflecting either their satisfaction or the degree to which they are affected by TBI-related challenges. Each domain comprises between five and seven questions. The questionnaire was provided in paper format, and participants were given standardized instructions to complete it independently whenever possible. In cases where cognitive or physical limitations made self-completion difficult, a single trained research staff member assisted, ensuring that responses accurately reflected the participant’s own perspectives.¹¹

Study design

Age, sex, race, BMI, mechanism of injury, GOSE score at time of starting GHRT, Marshall classification of TBI, presence of diffuse axonal injury (DAI) on head imaging, skull base fractures, and hypothalamic swelling or hemorrhage were also recorded. GH therapy was initiated for each participant at a starting dose of somatropin (recombinant) 0.2 mg per day, administered via subcutaneous injection. Prior to beginning treatment, participants received standardized education sessions that covered the purpose of GH therapy, the correct technique for self-administering injections, and the importance of adhering to the prescribed dosing schedule. Instructional materials were provided in both written and verbal formats, and participants were given the opportunity to ask questions and demonstrate their understanding of the injection process. Additionally, information regarding potential side effects, signs of adverse reactions, and guidelines for safe storage and handling of the medication was thoroughly reviewed.

IGF-1 scores tracked the response to therapy. During somatropin titration, IGF-1 levels were assessed every 4–6 weeks after each dose adjustment to guide safe and effective dosing and to prevent supratherapeutic exposure. Once the target IGF-1 level was achieved and the dose was stable, we monitored IGF-1 every 3–6 months, or sooner if there were any concerns about side effects or changes in clinical status. We consistently used the same Quest Diagnostics assay and age- and sex-adjusted reference ranges. GH replacement was deemed therapeutic with a z-score of 0 or higher. At six months and twelve months, participants were recorded as being therapeutic or non-therapeutic. Baseline and follow-up QOLIBRI scores were collected at 6- and 12-months postinitiation.

Statistical analysis

Prior to study initiation, a power analysis was performed to determine the required sample size for detecting a clinically meaningful change in QOLIBRI composite scores following GHRT in patients with msTBI and GHD. Assuming a moderate effect size (Cohen’s d = 0.5), an alpha of 0.05, and a desired power of 0.80, a minimum of 34 subjects was required. To account for an anticipated 20% dropout rate, the target enrollment was at least 43 subjects. As mentioned previously, 69 individuals were selected for the study and 3 were lost to follow-up at Follow-Up 2, resulting in a total of 66 individuals for analyses. Of these 66 individuals, there were no missing data for any variable, so we do not report strategies for handling missing data. QOLIBRI survey items were grouped into six domains: Thinking Abilities, Emotions, Independence and Daily Function, Social Relationships, Feelings, and Physical Problems. Four of the six QOLIBRI domains (Thinking Abilities, Emotions, Independence and Daily Function, and Social Relationships) measure positive improvements in reported QoL, while two of the six QOLIBRI domains (Feelings and Physical Problems) measure how much patients are bothered by these measures of QoL; thus, progressively lower values for Feelings and Physical Problems indicate improvements in QoL. These values were not reverse coded to account for mixed directions to faithfully adhere to the validated QOLIBRI instrument. All statistical findings involving the mixed directions are described clearly in the results and discussions.

Means values for QoL were calculated for each QOLIBRI survey item at three time points: initial (T₁), follow-up 1 at 6 months (T₂), and follow-up 2 at 12 months (T₃). Friedman tests were used to test the pairwise changes in QoL from T₁→T₂, T₂→T₃, and T₁→T₃, and overall Friedman tests were conducted across the study period. The significance of changes in mean values between these time points was assessed using these Friedman tests. For each survey item, the mean satisfaction scores at the three time points were also calculated. All p-values were corrected using the Bonferonni method to protect against the probability of detecting a significant value through repeated tests. Mean scores and changes over time were analyzed to identify trends. Box plots represented the distribution of survey responses across the three time points for each domain, providing insights into the variability and central tendency of participant responses.

A multivariate mixed effects model explored the relationships among demographic variables, clinical variables, and recovery outcomes, as measured by the GOSE scores. The general form of the mixed effects model with all parameters can be found in Equations 1 and 2, where Y_ijk is estimated QoL for individual i, in domain j, at time k and the fixed effects are: Time_ik controls for the time period (categorical) where T₁ is the baseline; Age_i controls for the age of the patient in years (continuous); Sex_i controls for the sex of the individual (categorical) where female sex is the baseline; TBI Severity_i controls for the severity of the TBI in each individual (categorical) where “moderate” is the baseline; DAI_i controls for diffuse axonal injury (categorical) where no DAI is the baseline; SBF_i controls for skull base fracture (categorical) where no SBF is the baseline; Hypothal Swelling_i controls for hypothalamic swelling (categorical) where no hypothalamic swelling is the baseline; and Domain_j controls for the QOLIBRI domain (categorical) where the Emotion domain is the baseline. The random effects are u_i, which represents the random intercept for each individual i and estimates overall between-patient variation; v_ij is the random intercept for each individual i in each domain j, which estimates how each patient’s QoL varies across domains, and e_ijk represents the residual error in the model. All statistical analyses were conducted using R (4.5.2). Significance was assessed on the α = 0.05 level. Table 1 reports descriptive statistics of the participants.

Table 1.

Descriptive Statistics of Continuous and Categorical Variables Used in the Analysis of Changing QOL over Time

Variable	Descriptive statistics
Continuous variables	Mean	Median	Range
Age	34.9	29.5	18–65

Categorical variables	Frequency	%
Sex
Female	14	21.2
Male	52	78.8
Race
White	59	89.4
African American	3	4.5
Hispanic or Latino	2	3.0
Asian	2	3.0
Severity of TBI
Moderate	13	19.7
Severe	53	80.3
Diffuse Axonal Injury
Yes	23	34.8
No	43	65.2
Skull Base Fracture
Yes	10	15.2
No	56	84.8
Hypothalamic Swelling or Hemorrhage
Yes	8	12.1
No	58	87.9

Mean, median, and range of continuous variables are reported, while frequency and percent allocation of categorical variables are reported.

Fixed effects

Y_{ijk} = β_{0} + β_{1} {Time}_{i k} + β_{2} {Age}_{i} + β_{3} {Sex}_{i} + β_{4} {TBI Severity}_{i} + β_{5} {DAI}_{i} + β_{6} {SBF}_{i} + β_{7} {Hypothal Swelling}_{i} + β_{8} {Domain}_{j}

(1)

Random effects

u_{i} \sim N (0, σ_{u}^{2})

(2a)

v_{i j} \sim N (0, σ_{v}^{2})

(2b)

ε_{ijk} \sim N (0, σ_{ε}^{2})

(2c)

Results

The mean interval from msTBI to study enrollment was 402 (range, 366–462) days. At 6 months, 92% of participants achieved therapeutic IGF-1 levels, and by 12 months, 99% had reached and maintained therapeutic IGF-1 concentrations in accordance with age-adjusted reference ranges. The significant results of statistical comparisons between time periods for QoL using the QOLIBRI survey are reported in Table 2. Figure 1 illustrates the composite ratings of each domain, as well as Friedman test results for each test period and across the entire study period. The chi-square (χ²) result for each domain over the study period is reported. In the domain of thinking abilities, participants reported significant improvements with an increase from 24.9 to 28.1 at T₃ (χ² = 76.1, p < 0.001). All individual items within this domain improved, specifically, the ability to concentrate (χ² = 58.9, p < 0.001), memory satisfaction (χ² = 29.4, p < 0.001), and thinking speed (χ² = 33.5, p < 0.001). The emotions domain also showed improvement, with scores rising from 21.1 to 26.2 at T₃ (χ² = 98.6, p < 0.001). Significant gains were seen in satisfaction in all QOLIBRI items, but the largest improvements were observed in energy levels (χ² = 88.1, p < 0.001), self-esteem (χ² = 54.2, p < 0.001), and perspectives of the self (χ² = 58.6, p < 0.001).

FIG. 1.

Box plots display the distribution of participant scores in each of the six Quality of Life After Brain Injury (QOLIBRI) domains, Thinking Abilities, Emotions, Independence and Daily Function, Social Relationships, Feelings, and Physical Problems, at baseline (T₁), 6 months (T₂), and 12 months (T₃) after initiation of growth hormone replacement therapy (GHRT). Significant improvements were observed in all domains (p < 0.05, Friedman tests), with the greatest gains in cognitive and emotional domains (indicated by χ²). Boxes represent the interquartile range (IQR), horizontal lines indicate the median, and whiskers denote the range. Outliers are shown as individual points. Higher scores in Thinking Abilities, Emotions, Independence and Daily Function, and Social Relationships reflect greater satisfaction, while lower scores in Feelings and Physical Problems indicate fewer negative symptoms.

Table 2.

Results of Friedman Analysis of Changes in Quality of Life (QoL) between the Three Time Periods of the Study

Survey item	Mean value			Pairwise significance			Total χ²	Total sig
Survey item	Initial	Follow-up 1	Follow-up 2	T₁→T₂	T₂→T₃	T₁→T₃	Total	Total
A. Thinking abilities	24.9	26.8	28.1	<0.001***	<0.001***	<0.001***	76.1	<0.001***
How satisfied are you with your ability to concentrate, for example when reading or keeping track of a conversation?	3.15	3.62	4.05	<0.001***	<0.001***	<0.001***	58.9	<0.001***
How satisfied are you with your ability to express yourself and understand others in a conversation?	3.83	3.97	4.02	0.095 (.)	0.93	0.073 (.)	7.4	0.025*
How satisfied are you with your ability to remember everyday things, for example where you have put things?	3.39	3.77	3.99	<0.001***	0.041*	<0.001***	29.4	<0.001***
How satisfied are you with your ability to plan and work out solutions to everyday practical problems, for example what to do when you lose your keys?	3.61	3.82	4.02	0.015*	0.015*	<0.001***	22.1	<0.001***
How satisfied are you with your ability to make decisions?	3.74	3.96	4.09	0.006**	0.09 (.)	<0.001***	21.5	<0.001***
How satisfied are you with your ability to find your way around?	3.71	3.94	4.08	0.009**	0.025*	<0.001***	23.5	<0.001***
How satisfied are you with your speed of thinking?	3.49	3.76	3.88	<0.001***	0.044*	<0.001***	33.5	<0.001***
B. Emotions	21.1	23.9	26.2	<0.001***	<0.001***	<0.001***	98.6	<0.001***
How satisfied are you with your level of energy?	2.26	2.99	3.73	<0.001***	<0.001***	<0.001***	88.1	<0.001***
How satisfied are you with your level of motivation to do things?	2.80	3.24	3.61	<0.001***	<0.001***	<0.001***	48.6	<0.001***
How satisfied are you with your self-esteem, how valuable you feel?	3.89	3.32	3.67	<0.001***	<0.001***	<0.001***	54.2	<0.001***
How satisfied are you with the way you look?	3.27	3.47	3.70	0.029*	0.002**	<0.001***	22.8	<0.001***
How satisfied are you with what you have achieved since your brain injury?	3.52	3.79	3.79	<0.001***	0.91	<0.001***	25.6	<0.001***
How satisfied are you with the way you perceive yourself?	3.00	3.42	3.71	<0.001***	<0.001***	<0.001***	48.6	<0.001***
How satisfied are you with the way you see your future?	3.38	3.67	3.97	0.0022**	<0.001***	<0.001***	38.1	<0.001***
C. Independence, daily function	30.4	30.5	30.7	0.11	<0.001***	<0.001***	28.1	<0.001***
D. Social relationships	21.8	22.4	22.9	<0.001***	<0.001***	<0.001***	41.8	<0.001***
How satisfied are you with your sex life?	3.03	3.33	3.70	0.005**	<0.001***	<0.001***	31.8	<0.001***
E. Feelings	16.2	14.4	13.9	<0.001***	<0.001***	<0.001***	81.5	<0.001***
How bothered are you by feeling anxious?	3.55	2.88	2.65	<0.001***	0.009**	<0.001***	59.7	<0.001***
How bothered are you by feeling sad or depressed?	3.61	2.86	2.62	<0.001***	0.001**	<0.001***	64.8	<0.001***
How bothered are you by feeling angry or aggressive?	3.00	2.73	2.76	<0.001***	0.89	0.004**	24.0	<0.001***
F. Physical problems	9.7	9.1	8.6	<0.001***	<0.001***	<0.001***	32.3	<0.001***
How bothered are you by effects of any other injuries you sustained at the same time as your brain injury?	1.77	1.36	1.21	<0.001***	0.044*	<0.001***	32.3	<0.001***
Overall, how bothered are you by the effects of your brain injury?	2.74	2.59	2.35	0.22	0.005**	0.003**	15.5	<0.001***

Bold are the overall main domains of Thinking, Emotions, Independence, Social relationships, Feeling, and Physical Problems.

Results of pairwise tests for changes over time (T1→T2, T2→T3, and T1→T3) are reported, as well as the total χ2 value for the duration of the study period and the total significance value (p value). Statistical results are reported for each domain of the QOLIBRI, while only the significant items within each domain are reported. Mean values across time points was also included for each QOLIBRI domain.

Significance codes: <0.001 = ***; <0.01 = **, <0.05 = *, <0.10 = (.).

The feelings domain exhibited a significant decrease in scores, from 16.2 to 13.9 (χ² = 81.5, p < 0.001). This indicates a decrease in negative feelings among participants. Significant reductions were observed in only three QOLIBRI items: feelings of anxiety (χ² = 59.7), feelings of sadness and depression (χ² = 64.8), and feelings of anger or aggression (χ² = 24.0), with all p-values < 0.001, primarily between T₁ and T₂. In the physical problems domain, scores decreased from 9.7 to 8.6, indicating overall improvement in how participants viewed their physical condition (χ² = 32.3, p < 0.001). Issues related to simultaneous injuries with the TBI event and overall feelings of being bothered by the effects of the brain injury showed significant improvement (χ² = 32.3, p < 0.001 and χ² = 15.5, p < 0.001, respectively).

In contrast, although there were observed improvements in the independence and daily function domain, these improvements were the lowest of all QOLIBRI domains (30.4 at T₁ to 30.7 T₃, χ² = 28.1, p < 0.001). The social relationships domain also saw a mild increase in scores from 21.8 at T₁ to 22.9 at T₃ (p < 0.001). One specific item within the social relationships domain, satisfaction with sex life, showed the greatest improvement (χ² = 31.8, p < 0.001).

The multivariate mixed effects model predicting QoL are reported in Table 3, and show that the overall composite QoL scores significantly increased from the initial assessment to T₃ (p < 0.001). Neither age nor sex were related to changes in QoL while controlling for all other covariates. Participants with severe TBI reported marginally significantly poorer QoL than those with moderate TBI (β = −1.54, p = 0.078). Interestingly, participants with diffuse axonal injury reported a trend toward higher QoL (β = 1.31, p = 0.068), whereas those with hypothalamic swelling or hemorrhage and skull base fracture reported no differences in QoL over the study period. The results of the random effects show that while individuals vary relatively little person to person (σ² = 3.12, SD = 1.77), the largest amount of variation in the model is in how individuals score within each QOLIBRI domain (σ² = 20.5, SD = 4.53). This result indicates that patients may have relatively similar composite overall QOLIBRI scores, but their individual domain values may vary significantly.

Table 3.

Results of the Multi-Level Regression Model Predicting QOL in Patients with msTBI and GHD While Controlling for Time, Age, Sex, Severity of TBI, Diffuse Axonal Injury, Skull Base Fracture, the Presence of Hypothalamic Swelling, and Domain of QOLIBRI

Fixed effects	β (SE)	95% CI	t-value	p value
Time
Initial (T1)	baseline
Follow-up 1 (T₂)	0.50 (0.13)	[0.25, 0.76]	3.87	<0.001***
Follow-up 2 (T₃)	1.06 (0.13)	[0.80, 1.31]	8.12	<0.001***
Age	0.02 (0.02)	[−0.02, 0.07]	1.03	0.31
Sex
Female	baseline
Male	0.79 (0.79)	[−0.77, 2.34]	0.99	0.33
Severity of TBI
Moderate	baseline
Severe	−1.54 (0.86)	[−3.23, 0.14]	−1.8	0.078 (.)
Diffuse Axonal Injury
No	baseline
Yes	1.31 (0.70)	[−0.07, 2.68]	1.86	0.068 (.)
Skull Base Fracture
No	baseline
Yes	−0.16 (1.22)	[−2.55, 2.22]	−0.13	0.890
Hypothalamic Swelling/Hemorrhage
No	baseline
Yes	−1.61 (1.38)	[−4.31, 1.10]	−1.17	0.25
Domain
Emotion	baseline
Feelings	−8.89 (0.81)	[−10.5, −7.30]	−10.9	<0.001***
Independence	6.79 (0.81)	[5.20, 8.38]	8.39	<0.001***
Physical	−14.6 (0.81)	[−16.2, −13.0]	−18.00	<0.001***
Social	−1.35 (0.81)	[−2.94, 0.24]	−1.67	0.096 (.)
Thinking	2.89 (0.81)	[1.30, 4.48]	3.57	<0.001***

Random effects	Variance (σ²)	SD
Individual (Intercept)	3.12	1.77
Individual*Domain (Intercept)	20.5	4.53
Residual	3.35	1.83

The coefficient estimate (β), standard error, 95% confidence interval, t-Value, and significance (p-value) are reported for each variable. Random effects (individual and individual*domain) are also reported, along with the residual value. Variance and standard deviation are reported for each random effect variable.

Significance codes: <0.001 = ***; <0.01 = **, <0.05 = *, <0.10 = (.).

Discussion

This study investigated whether GHRT improved the QoL in patients with msTBI and GHD. Although GHRT has been shown to improve sequelae of acquired GHD, there is limited evidence regarding its impact on QoL as measured by the QOLIBRI in individuals with msTBI.^5,6,12,13 Existing studies evaluating the effects of GHRT on QoL have limitations such as small sample sizes, short study durations, heterogeneity of patient populations, how GHD is defined via testing, and the doses used in GHRT.^5,6,12,14,15 This paucity of information on the clinical benefits of GHRT leads to an important consequence: screening for GHD in TBI survivors is not routinely performed by many practitioners which can contribute to underdiagnosis of endocrine dysfunction in this patient population.^5,7,15,16

Our findings suggest that GHRT is associated with improved QoL in msTBI patients with GHD. Specifically, we found that GHRT was associated with an overall improvement in all QOLIBRI domains. The Thinking Abilities, Emotions, Independence, and Social relationships domains showed significant improvement from baseline, with higher scores indicating an improvement in QoL. Additionally, the Feelings and Physical Problems domains demonstrated significant improvement from baseline, as evidenced by decreased scores that correspond to improvements in QoL. Specifically, improvements were seen in concentration ability, memory satisfaction, energy levels, motivation, self-esteem, perception of appearance, perception of oneself, and views of the future. These findings are consistent with an initial body of literature indicating that GHRT may improve QoL and neuropsychological outcomes in patients with GHD following msTBI. Several studies and systematic reviews have reported that GHRT leads to improvements in domains such as cognition, mood, energy, and with particular benefits noted in areas like memory, concentration, motivation, self-esteem, and future outlook.^5,6,12,13,17 Szarka et al. also identified in their systematic review that 6–12 months of GH therapy in persons with TBI and GHD resulted in moderate improvements in processing speed and memory, as well as marked enhancements in QoL, including Emotional and Cognitive domains.⁵ Similarly, Gardner et al. demonstrated that TBI patients experienced greater and sustained improvements in QoL scores after 1 year of GHRT, especially in self-confidence, compared with other etiologies of GHD.¹⁷

Participants reported reduced feelings of anxiety and depression, which interestingly had the most significant decrease between the first and second time points (0 and 6 months) with improvements seen up to the first year after GHRT. This is consistent with previous studies, which indicates that the most significant improvements in mood and QoL occur within the first 12 months of GHRT.^5,13,17 Improvements in mood have also been observed in smaller studies, with self-reported symptoms of depression improving significantly after GHRT, even when objective cognitive measures changed little.^13,18 Participants also reported a significant decrease in being bothered by the effects of other injuries sustained at the time of TBI. This is also consistent with previous studies in individuals with TBI and GHD, which have shown that GHRT improves subjective well-being and reduces the impact of injury-related symptoms.^5,6,13 In persons with msTBI and GHD, GHRT may decrease the extent to which they are affected by the consequences of other injuries sustained at the time of TBI, primarily through improvements in mood, fatigue, and overall QoL.

However, although the Independence and Daily Function domain and the Social Relationships domain displayed significant overall improvement, these improvements were minimal and did not include significant improvements for many individual QOLIBRI items. This is consistent with previous reports that GHRT does not result in significant improvements in independence or social relationships.^6,12,15,17 While other QoL domains may respond to GHRT, the evidence does not support a meaningful impact on broader functional outcomes or social reintegration. These findings highlight the importance of setting realistic expectations for GHRT and underscore the need for comprehensive rehabilitation strategies to address functional and social recovery in the msTBI population. Only one specific item within Social Relationships domain, satisfaction with sex life, demonstrated significant improvement. The results of this study contribute to the understanding of the specific QoL improvements seen with GHRT after msTBI, which may help solidify recommendations for treatment of this patient population. These results also clarify that while GHRT can improve QoL in some domains, there are some aspects of QoL that may not be impacted by GHRT.

In addition, an interesting result was that patients with DAI trended toward higher QoL following GHRT. Vieira et al. conducted a prospective cohort study evaluating functional outcomes, activities of daily living, and QoL in 95 patients with DAI.¹⁹ They found that patients with DAI can have good long-term outcomes, with all of their cohort reporting improvements in QoL in most domains, except for general health.¹⁹ Notably, these findings suggest that targeted interventions such as GHRT may further enhance QoL in those with DAI and GHD.

Our results must also be interpreted in the context of important limitations. The single-center design of this study may limit the generalizability to the larger population. The potential for unmeasured confounding inherent to observational database studies may influence the association between GHRT and QoL. Due to the observational design, this study lacks a control group, and observed improvements may reflect natural recovery or placebo effects rather than GHRT alone and results should be interpreted within the confines of the study methodology used and as hypothesis-generating for future randomized trials. Additionally, not all participants achieved therapeutic IGF-1 levels at each time point; however, even among those who did not reach therapeutic thresholds, increases in IGF-1 levels were still observed, suggesting a degree of biological response across the cohort. An additional limitation is the potential for selection bias, as patients who consented to inclusion in the neuroendocrine database and elected to initiate GHRT may have had higher motivation, greater social support, or different baseline functioning than those who declined (8%), which may limit the external validity of the observed QoL improvements. These findings may be most generalizable to individuals with msTBI who are engaged in specialty neuroendocrine care. Additionally, we did not systematically collect longitudinal objective outcome measures, such as standardized neuropsychological testing, functional performance scales, or metabolic parameters, concurrent with QOLIBRI assessments. As a result, we are unable to determine whether objective cognitive, functional, or metabolic changes paralleled the observed improvements in QoL, which limits interpretation of the underlying mechanisms by which GHRT may confer benefit in this population. Lastly, the follow-up period was limited to 12 months, meaning that longer term outcomes of GHRT remain underexplored in the context of this study. Further research should be directed at whether the improvements in QoL seen in GHRT vary with time past 12 months.

These results suggest that GHRT can improve QoL in persons with msTBI with GHD. However, it is important to note that specific ameliorations vary between QOLIBRI domains. GHRT was associated with significant improvements in thinking abilities and emotions and a significant reduction in being bothered by both negative feelings and physical problems. Despite these benefits, GHRT did not significantly impact independence in daily function or social relationships, underscoring the multifactorial nature of disability and social reintegration after TBI. This highlights the need for comprehensive, multidisciplinary rehabilitation strategies that extend beyond endocrine management to address broader functional and psychosocial outcomes.

Understanding the benefits of GHRT may enhance long-term management of persons with msTBI. Heightened screening for endocrine abnormalities and improved access to treatment can optimize care of this patient population. Further research on GHRT should be conducted and include larger sample sizes, physical and metabolic outcomes (body composition, bone mass, cardiovascular function) and evaluation of long-term effects past 1 year.

Transparency, Rigor, and Reproducibility Summary

This study was not formally preregistered, as it was a single-center, observational, quality-improvement cohort assembled from a prospectively enrolled neuroendocrine database. The analysis plan, including primary outcomes (QOLIBRI domain and composite changes from baseline to 6 and 12 months) and statistical methods (Friedman tests for within-subject changes; mixed effects models for associations with demographic/clinical variables; α = 0.05), was predefined and followed as specified. Power analysis (Cohen’s d = 0.5, α = 0.05, power = 0.80) indicated a minimum of 34 participants, with a target of 43 to account for 20% dropout; 69 individuals with msTBI were enrolled. GOSE assessments were performed by a single trained examiner; QOLIBRI was self-administered or staff-assisted, and data analysis was conducted without formal blinding but with prespecified, objective scoring and coded identifiers. Data were collected using standard clinical protocols (GST, IGF-1 assays, GOSE, QOLIBRI) and analyzed in R (4.5.2); all instruments and procedures are widely available, and protocol details are provided to facilitate replication. Validated instruments (QOLIBRI, GOSE) and established diagnostic criteria were used, with multivariable adjustment for relevant covariates. Nonparametric repeated-measures analyses were conducted using Friedman tests to evaluate within-subject changes in QOLIBRI domain and composite scores across baseline, 6 months, and 12 months. To further examine the influence of demographic and clinical variables on QoL outcomes over time, multivariate mixed-effects modeling was performed, incorporating fixed effects for time and relevant covariates, with random effects specified at the individual level and for individual-by-domain interactions. Standard model diagnostics were conducted to assess assumptions and model fit. Missing data were handled using complete case analysis. Effect sizes and corresponding confidence intervals are reported where appropriate. Multiple comparisons were addressed by emphasizing domain-level outcomes as primary analyses, with item-level findings considered exploratory. Internal replication was achieved across two follow-up timepoints; external validation is pending and encouraged. Deidentified data and analytic code will be made available upon request or public posting after publication, and the authors do not intend to pursue Open Access publication.

Authors’ Contributions

M.M. and J.L.W. conceived the study and designed the study protocol. M.M. and J.L.W. supervised the conduct of the study and data collection. M.M., J.LW., and T.P.v.D. provided statistical advice on study design and analyzed the data. B.S., M.N., R.B., V.M., T.P.v.D., M.M., and J.L.W. drafted the article, and all authors contributed substantially to its revision. J.L.W. takes responsibility for the article as a whole.

Footnotes

Author Disclosure Statement

The authors of this article have no conflicts of interest to disclose.

Funding Information

No funding was received for this article.

Abbreviations Used

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