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. Author manuscript; available in PMC: 2023 Aug 1.
Published in final edited form as: Med Sci Sports Exerc. 2022 Feb 8;54(8):1364–1370. doi: 10.1249/MSS.0000000000002892

Relationship Between Anterior Pituitary Volume and IGF-1 Serum Levels in Soldiers with Mild Traumatic Brain Injury History

Anna K Castellano 1, Jacob R Powell 1, Michael J Cools 1, Samuel R Walton 1, Randaline R Barnett 1, Stephen M DeLellis 2, Richard L Goldberg 3, Shawn F Kane 4, Gary E Means 5, Carlos A Zamora 6, Patrick J Depenbrock 5, Jason P Mihalik 1
PMCID: PMC9287595  NIHMSID: NIHMS1776359  PMID: 35838301

Abstract

Purpose:

A high mild traumatic brain injury (mTBI) incidence rate exists in military and sport. Hypopituitarism is a mTBI sequela; however, few studies have examined this phenomenon in those with a mTBI history. This cross-sectional study of Special Operations Forces combat Soldiers aimed to (1) relate anterior pituitary gland volumes (actual and normalized) to IGF-1 concentrations, (2) examine the effect of mTBI history on anterior pituitary gland volumes (actual and normalized) and IGF-1 concentrations, and (3) measure the odds of demonstrating lower anterior pituitary gland volumes (actual and normalized) or IGF-1 concentrations if self-reporting mTBI history.

Methods:

Anterior pituitary gland volumes were manually segmented from T1-weighted 3D brain MRIs sequences; IGF-1 serum concentrations were quantified using commercial enzyme-linked immunosorbent assays. Correlations and linear regression were used to determine the association between IGF-1 serum concentration and anterior pituitary gland volume (n=74). Independent samples t-tests were used to compare outcomes between mTBI groups and logistic regression models were fit to test the odds of demonstrating IGF-1 concentration or anterior pituitary volume less than sample median based on mTBI group (n=54).

Results:

A significant linear relationship between the subjects’ anterior pituitary gland volumes and IGF-1 concentrations (r72=0.35, p=0.002) was observed. Soldiers with mTBI history had lower IGF-1 concentrations (p<0.001), lower anterior pituitary gland volumes (p=0.037) and were at greater odds for IGF-1 serum concentrations less than the sample median (OR=5.73; 95% CI=1.77, 18.55).

Conclusions:

Anterior pituitary gland volume was associated with IGF-1 serum concentrations. Mild TBI history may be adversely associated with anterior pituitary gland volumes and IGF-1 concentrations. Longitudinal IGF-1 and anterior pituitary gland monitoring may be indicated in those who report one or more mTBI.

Keywords: ADENOHYPOPHYSIS, BLOOD BIOMARKER, CONCUSSION, GROWTH HORMONE, NEUROIMAGING, SERVICE MEMBER

INTRODUCTION

Cerebral concussions are caused when direct or indirect mechanical forces cause a functional disturbance in the brain (1, 2). Concussions are mild traumatic brain injuries (mTBI) and account for over 75% of all diagnosed traumatic brain injuries (3). As many as 19.5% of United States adolescents report having sustained at least one mTBI during their lifetime (4). The mTBI incidence rate is especially high in military and sport populations (5); however, reported rates are believed to be lower than what actually occurs due to patients not reporting or underreporting their symptoms (6). Individuals in military and sport populations sustain mTBI through blast (military) and blunt (military/sports) trauma (7). It is estimated that 10 to 20 percent of combat Veterans deployed to Afghanistan or Iraq experienced blast-related head injuries including mTBI (8–11).

The pituitary gland is suspended at the base of the brain, making its vasculature vulnerable to injury when athletes and Soldiers experience forces sufficient to cause mTBI (1). Symptoms (e.g., affective, somatic, sleep), neurocognitive difficulties, and balance impairments are commonly observed in Soldiers following mTBI. Acute hypopituitarism—the deficient production of one or several hormones by the pituitary gland—is present in 15 to 45 percent of all sport-related TBI cases (mild to severe), with pituitary dysfunction prevalent in 16.9% of mTBI cases (12). Traumatic brain injury is associated with an increased prevalence of hypopituitarism and pituitary dysfunction in military personnel, with emerging scientific literature in combat Soldiers expanding upon these clinical findings by identifying neuroimaging, blood, and neurophysiological biomarkers (13, 14). While short-term deficiencies following mTBI may improve, long-term research addressing chronic neuroendocrine insufficiency is lacking. Despite many studies investigating hypopituitarism in sport and military settings, the relationship between mTBI, pituitary volumetric changes, and hypopituitarism is currently unknown (7, 15–20). Establishing a fundamental link between mTBI and neuroendocrine dysfunction will provide the necessary evidence to support future work in this area.

Hypopituitarism is often diagnosed by detecting significant hormone imbalances in the body from blood samples (7, 21). Growth hormone deficiency is a prevalent pituitary hormone deficiency in those diagnosed with hypopituitarism (1). Other hormone deficiencies resulting from hypopituitarism may involve adrenocorticotropic hormones, cortisol, insulin-like growth factor-1 (IGF-1), and other gonadotropic hormones such as testosterone and luteinizing hormones (7, 12, 16–20, 22–38). In a military sample, 42% of Service members exposed to blast mTBI displayed abnormal pituitary hormone concentrations, most commonly growth hormone, IGF-1 deficiency, and pituitary-gonadal axis deficiencies (19). The data provided by these aforementioned studies support a preliminary rationale to screen combat Soldiers for hypopituitarism and may support conducting hormone testing when Service members return from deployment. Growth hormone stimulation testing is currently the gold standard to definitively diagnose growth hormone deficiency; however, this stimulation testing is resource intensive and may pose unnecessary patient risk. Recent studies have used serum IGF-1 rather than stimulation-based markers as a more accessible and practical assessment method to screen for hypopituitarism such as growth hormone deficiency (20). In a sports model, the relationship between the pituitary gland volume and peripheral IGF-1 serum concentrations in adults and retired boxers with mTBI history was examined (39). The adults and retired boxers, including growth hormone deficient boxers, had significantly lower pituitary volumes than young and growth hormone normal boxers. Although these data relate to boxers, they provide a rationale for relating peripherally measured IGF-1 concentrations to pituitary gland volumes in other underexplored populations exposed to occupational blast and blunt trauma. No studies have examined this in a Service member population where mTBI risk is uniquely extended to blast exposure.

Long-term care for combat Soldiers who have experienced mTBI during their careers may benefit from understanding the relationship between mTBI and neuroendocrine abnormalities. Thus, our primary purpose was to determine the relationship between anterior pituitary volume (actual and normalized) and IGF-1 peripheral serum concentrations in Special Operations Forces (SOF) combat Soldiers. Secondly, we aimed to determine whether differences in anterior pituitary gland volume (actual and normalized) and IGF-1 concentrations existed between combat Soldiers with and without previous mTBI. Finally, we sought to measure the odds of demonstrating anterior pituitary gland volumes, normalized anterior pituitary gland volumes, or IGF-1 concentrations less than the sample median if a combat Soldier self-reported mTBI history. We hypothesized that 1) anterior pituitary gland volumes and normalized anterior pituitary gland volumes would be positively correlated to IGF-1 concentrations, 2) combat Soldiers reporting previous mTBI history would demonstrate lower anterior pituitary gland volumes, lower normalized anterior pituitary gland volumes, and lower IGF-1 concentrations than those reporting no prior mTBI, and 3) the odds of having anterior pituitary gland volumes, normalized anterior pituitary gland volumes, and IGF-1 concentrations less than the sample median would be greater for combat Soldiers self-reporting a prior mTBI history.

METHODS

This cross-sectional study included a sample of 74 male combat Soldiers (age = 32.2 ± 3.5 years). A subset of 54 combat Soldiers self-reported their mTBI history. All participants provided verbal consent to participate in the study following informed consent procedures approved by our institution’s Office of Human Research Ethics. Once participants consented to participate in the study, they underwent several data collection procedures which included a biospecimen blood draw and neuroimaging protocol. We collected each participant’s data upon conclusion of their standardized training course required before assignment to actively deploying units at a time when those Soldiers will have experienced approximately three weeks of normalized sleep/wake cycles. While these data were collected at a single time point for each participant, study enrolment involved SOF combat Soldiers emerging from staggered—yet identical—standardized training courses over time.

Biospecimen collection

We collected fasted venous blood samples in a laboratory setting into serum-separation tubes (Becton-Dickinson Company, Plymouth, United Kingdom) via prominent cubital fossa veins. The serum-separation tubes were inverted several times, rested for 30 minutes, and centrifuged at 4,000 RPM for 10 minutes at 4 °C. Serum supernatants were aliquoted into 1.0 mL cryovials and frozen at −80 °C until analyses were conducted. Samples were analyzed in duplicate and averaged for our analytic purposes. Sample quantification was conducted by an independent laboratory at our institution by blinded laboratory personnel. Prior to assay completion, samples were cross-referenced to confirm the agreement between vial labeling and inventory documentation. Samples were then thawed, vortexed 10 seconds, and centrifuged at 3,000 RPM for 15 minutes. Supernatants were taken and assays were completed following the reagent kit manufacturer’s protocol (ALPCO; Catalogue# 22-IGFHU-E01). Although IGF-1 does not typically experience a diurnal effect in healthy individuals, we controlled for any potential confounding effect by collecting these blood samples immediately upon arrival at our research facility. The fasted blood samples were typically collected by 0800 local time. These procedures are consistent with previously published methods (14).

Neuroimaging protocol

Participants in this study underwent a neuroimaging protocol on a Siemens 3T Biograph. Siemens T1-weighted 3D Magnetization Prepared Rapid Gradient Echo (MPRAGE; TI = 900ms, TR = 2300ms, TE = 2.98ms, FA = 9°, 0.5 × 0.5 × 1mm3, FOV = 256mm3, 176 slices) volumes were used for structural segmentation. This neuroimaging protocol was developed in collaboration with neuroimaging physicists and all imaging data were collected in a standardized manner on a single scanner by imaging technicians working in a biomedical research imaging center. The research imaging technicians comply with heightened protocols to ensure consistency and quality research data are collected within and across research studies.

Estimated total intracranial volumes (mm3) were obtained using FreeSurfer 6.0 automated cortical reconstruction from each T1 MPRAGE (40). Unprocessed T1 MPRAGE images were imported into Medical Imaging Interaction Toolkit (MITK) Workbench software for anterior pituitary gland segmentation. The anterior pituitary gland was segmented in MITK and the volumes (also measured in mm3) were derived for each participant. Since these procedures required manual segmentation, we employed a systematic approach using a clear anatomical definition based on previously published manual segmentation techniques (41). First, we began in the sagittal plane starting with a midsagittal slice where the infundibulum could be traced to the inferior margin and used to create a superior border. The anterior pituitary gland’s inferior border was identified as the sphenoid sinus. We excluded cerebrospinal fluid (CSF), the infundibular stalk, and the bright posterior pituitary gland. Segmentation was continued in the sagittal plane out in both directions, given the ease in identifying the medial portion. Next, we continued to the coronal plane to verify if any ‘holes’ were present that required further segmentation. We then continued alternating between sagittal and coronal planes until we had fully segmented the anterior pituitary gland. All segmentations were completed by a single investigator (AKC). A random sample of 20 segmented images (~27%) were subsequently reviewed by two neurosurgeons (MJC, RRB). Any disagreements between the neurosurgeon reviewers were further adjudicated by a trained neuroradiologist (CAZ), and then fully resolved before the data were codified for our final analyses. Following this process, none of the images warranted correction.

Statistical Analyses

Following the procedures described above, we retained several outcomes to address our study aims: 1) anterior pituitary gland volume (mm3), 2) anterior pituitary gland volume normalized to total intracranial volume (%), and 3) IGF-1 serum concentration (ng/mL).

We evaluated the correlation between anterior pituitary volume and IGF-1 serum concentrations in SOF combat Soldiers to address our primary aim. We repeated this procedure by correlating normalized anterior pituitary gland volume with IGF-1 concentration. A subset of our sample (n=54, 73%) opted to self-report their mTBI history (n=26 no mTBI history; n=28 with mTBI history). We had originally considered adjusting for participant age in our analyses. Age did not emerge as significantly associated with any of our independent variables and, thus, did not improve the estimation of mTBI history group means. Thus, we conducted independent samples t-tests to determine if anterior pituitary volumes, normalized anterior pituitary gland volumes, and IGF-1 serum concentrations differed between mTBI history reporting groups to address our secondary aim.

Lastly, we performed a binary logistic regression to determine the odds of experiencing values less than the sample median for anterior pituitary gland volumes (<663.9 mm3), normalized anterior pituitary gland volumes (<0.04%) or IGF-1 concentrations (<386.7ng/mL) if a combat Soldier reported a mTBI history to address our study’s tertiary purpose. These median values were derived from within our study sample. All data were analyzed using SAS 9.4 and an a priori alpha level of 0.05 was adopted for our study analyses.

RESULTS

Descriptive data (mean, standard deviation, minimum, and maximum) for anterior pituitary gland volume, normalized anterior pituitary gland volume, and IGF-1 concentration across all study participants are provided in Table 1.

Table 1.

Descriptive data for anterior pituitary gland volume, normalized anterior pituitary gland volume, and insulin-like growth factor-1 (IGF-1) serum concentration (n = 74)

Variable Unit Mean Standard Deviation Minimum Maximum
Anterior pituitary gland volume mm3 662.1 133.6 396.3 967.5
Normalized anterior pituitary gland volume % 0.040 0.008 0.025 0.060
IGF-1 serum concentration ng/mL 394.0 155.3 58.8 861.8
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We observed statistically significant correlations between IGF-1 concentration and both anterior pituitary gland volume (r72=0.35, p=0.002) and normalized anterior pituitary gland volume (r72=0.34, p=0.003). We also identified that IGF-1 concentration was significantly associated with anterior pituitary gland volume (F1,72=9.87, p=0.002, R2=0.12) and normalized anterior pituitary gland volume (F1,72=9.49, p=0.003, R2=0.12). The model suggests that participants’ mean IGF-1 serum concentration would increase 0.40 ng/mL for every one-unit increase in anterior pituitary gland volume.

Participants endorsing a mTBI history reported a median of 3 previous mTBI (IQR=2.25; Range=1–10+). Combat Soldiers with mTBI history (628.0 ± 129.9 mm3) demonstrated significantly lower anterior pituitary gland volumes (t52=2.14, p=0.037) compared to combat Soldiers who did not self-report a mTBI history (700.1 ± 116.3 mm3) (Figure 1). Similiarly, combat Soldiers with mTBI history (0.038 ± 0.009 %) demonstrated significantly lower normalized anterior pituitary gland volumes (t52=2.04, p=0.047) compared to combat Soldiers who did not self-report a mTBI history (0.043 ± 0.008 %). Likewise, combat Soldiers with mTBI history (319.5 ± 117.9 ng/mL) expressed significantly lower IGF-1 concentrations (t52=4.04, p<0.001) compared to combat Soldiers who did not self-report previous mTBI (471.6 ± 157.5 ng/mL) (Figure 2).

Figure 1.

Figure 1.

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Combat Soldiers with mild traumatic brain injury (mTBI) history (n=28) demonstrate significantly lower anterior pituitary gland volumes compared to combat Soldiers who did not self-report previous mTBI (n=26).

Figure 2.

Figure 2.

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Combat Soldiers with mild traumatic brain injury (mTBI) history (n=28) demonstrate significantly lower insulin-like growth factor-1 (IGF-1) concentrations compared to combat Soldiers who did not self-report previous mTBI (n=26).

Mild TBI history significantly increased the likelihood that combat Soldiers would express IGF-1 serum concentrations lower than the sample median (χ2(1) = 7.05, p=0.008), such that combat Soldiers with mTBI history had 4.75 times greater odds of exhibiting IGF-1 serum concentrations lower than the sample median (95% CI=1.50, 15.00). However, mTBI history did not significantly increase the likelihood that combat Soldiers would demonstrate values lower than the sample median for anterior pituitary gland volume (χ2(1) = 2.62, p=0.105; OR=2.47; 95% CI=0.83, 7.39).

DISCUSSION

Mild TBI history has an adverse association with anterior pituitary gland size and IGF-1 production. Additionally, there was a moderate positive correlation between anterior pituitary gland volumes and IGF-1 serum concentrations. These findings support our original hypothesis that lower anterior pituitary gland volumes would be related to lower IGF-1 serum concentrations among SOF combat Soldiers. We note, however, that despite the significant regression findings we observed (R2=0.12), 88% of the variation in IGF-1 serum concentrations was not explained by anterior pituitary volume alone. Additional unmeasured factors that likely influence IGF-1 concentrations in this population include aging (42), fear-related stress (43), and occupational exposure to chemical and pollutants (44).

We observed a significant difference in both anterior pituitary gland volumes (actual and normalized) and IGF-1 serum concentrations between combat Soldiers with mTBI history compared to those with no self-reported mTBI history. These findings support our original hypothesis that combat Soldiers with a mTBI history would have lower IGF-1 serum concentrations and anterior pituitary gland volumes. Our data also innovatively establish that combat Soldiers were more likely to have IGF-1 serum concentrations drop below the sample median values if they have experienced at least one prior mTBI. The odds ratio for expressing low anterior pituitary gland volume with endorsed mTBI history was higher than those who did not report mTBI but was not statistically significant. We believe this may point to an evolving need to expand this research area with larger sample sizes.

Mild TBI introduces many implications to short- and long-term health in combat Soldiers. We studied IGF-1 as a systemic biomarker for human growth hormone. Human growth hormone essentially stimulates all human tissue growth, and IGF-1 may have a significant role in mTBI recovery independent of global hypopituitarism (45). Impaired neuroendocrine function may, therefore, adversely affect recovery from repetitive blast and blunt exposures experienced by combat Soldiers during training exercises and combat deployments. Additionally, hypoimmunity caused by functional decreases in the hypothalamic-pituitary-gonadal and abnormal pituitary-thyroid axis may increase illness following high-intensity military activities (46). Introducing blast exposures further complicates military mTBI management as Soldiers with blast-related TBI demonstrate a reportedly greater prevalence of anterior pituitary dysfunction compared to a matched non-blast TBI civilian cohort (47). Our findings should be considered within the sport population given that both populations sustain blunt biomechanical neurotrauma which affects the pituitary gland’s physiological vulnerability. It is likely Soldiers’ neuroendocrine outcomes are worse than athletes with similar exposure to mTBI given the increased exposure to blast neurotrauma and other occupational exposures that may further exacerbate neuroendocrine function. Additional research is needed to parse out the additive damages that can be attributed to blast and other occupational exposures. Given the interrelationships between blast exposure and other short- and long-term chronic comorbidities, future studies should expand our understanding of neuroimaging correlates to anterior pituitary gland volume and neuroendocrine function.

We considered anterior pituitary gland volume normalized to total intracranial brain volume would be a variable of unique interest. Our data present synchrony between actual and normalized anterior pituitary gland volume findings. Given the small size of the anterior pituitary gland relative to other brain structures, we acknowledge that normalized volumes generate even smaller values (e.g., we report a mean of 0.04% in Table 1) that may expose analyses to spurious statistical findings that may be cause simply due to rounding artifact. As such, a methodological contribution from our study was identifying normalized anterior pituitary gland volume to be a variable that does not add much to the extant literature within the context we studied it. We initially believed normalizing the anterior pituitary gland volumes would be important to account for heterogeneous intracranial volumes derived from our sample. A strong correlation between anterior pituitary gland volume and its normalized volume (r72=0.93, p<0.0001), in addition to synchronous findings between actual and normalized anterior pituitary gland volume reported in our results, provide a compelling rationale to exclude normalized volumes in future work. Additionally, the volumes we document for the anterior pituitary gland were relatively low and the normalized volume may not be a conceptually accurate variable given the pituitary gland is neither cerebral white nor gray matter (48). While normalized structural volume is used with larger neuroanatomical structures, our data serve to temper our enthusiasm for including normalized volume in future studies in this research area.

There are several study limitations worth discussing. First, this study employed a convenience sample of SOF combat Soldiers and, therefore, our findings may not fully represent this population. Our sample was restricted to combat Soldiers with both MRI scans and IGF-1 serum concentrations. Our study was further limited by relying on SOF combat Soldiers to provide self-reported injury information to accurately discern mTBI history. This is an approach commonly employed in the mTBI literature, but we acknowledge this approach may introduce recall bias. Notwithstanding, mTBI nondisclosure is pervasive in both military and civilian populations. Nondisclosure factors in both populations includes fear of missing game/practice time (49), service career repercussions (50), or simply not knowing it was a concussion (49). These nondisclosures would ultimately lead to inaccurate medical records rendering medical diagnosis as an equally limited gold standard in this context. This limitation is not restricted to our study but more broadly to our entire field. Bias during anterior pituitary gland volume segmentation was also possible. We attempted to limit measurement error in our dataset by having only one study team member analyze and segment the anterior pituitary glands. We did not have access to an automated anterior pituitary gland segmentation algorithm when we performed our study, but we agree establishing a freely available, reliable algorithm would permit the scientific community to pursue this research area with increased parity and consistency. To mitigate any possible segmentation errors, we additionally engaged two board certified neurosurgeons and a neuroradiologist to verify data segmentation accuracy. Notwithstanding these study limitations, the literature suggests mTBI is the leading cause of hypopituitarism (16, 18).

CONCLUSIONS

Our findings suggest that mTBI is associated with worse anterior pituitary gland health and that combat Soldiers with mTBI history are more likely to have lower IGF-1 serum concentrations and lower anterior pituitary gland volumes than those reporting no mTBI history. The SOF combat Soldiers’ IGF-1 serum concentrations should be interpreted with context to this homogenous population. In fact, only one subject fell below the established reference range for their age (51) despite associations with mTBI and pituitary gland volume. This suggests elevated values may represent the norm for SOF combat Soldiers. Thus, the long-term effects between the anterior pituitary gland and IGF-1—in addition to other neuroendocrine markers—should be studied prior to, during, and following recovery from mTBI in this population. Understanding the profound clinical implications associated with decreased IGF-1 serum concentrations and anterior pituitary gland volumes in Soldiers may inform effective treatments to improve their short- and long-term health and well-being.

ACKNOWLEDGMENTS

The project described was supported by the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health, through Grant Award Number UL1TR002489. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Data used in this project were also funded in part with contract grant support from the United States Army Special Operations Command (USASOC) to the University of North Carolina at Chapel Hill (Chapel Hill, NC, USA). This work is also supported by the US Army Medical Research and Development Command under Contract No. W81XWH-20-C-0022. The views, opinions and/or findings contained in this report are those of the authors and should not be construed as an official Department of the Army position, policy or decision unless so designated by other documentation. Co-authors Depenbrock and Means were employed by USASOC for the study period.

Footnotes

CONFLICT OF INTEREST

The authors declare no conflict of interest. The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. The results of the present study do not constitute endorsement by ACSM.

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