Testosterone and neurobehavioral outcomes in special operations forces military with multiple mild traumatic brain injury

1 Introduction

The U.S. Armed Special Operation Forces (SOF) undergo demanding military training and deployments. SOFs commonly experience combat deployments and numerous individual direct-action missions involving physically strenuous activities such as breaching, heavy weapon use, and parachuting (Frueh et al., 2020; Garcia et al., 2022). SOFs are at high risk of developing multiple comorbidities including musculoskeletal injuries, post-traumatic stress disorder, chronic pain, chronic headache, and multiple mild traumatic brain injury (mmTBI) (Frueh et al., 2020; Garcia et al., 2022; Stannard & Fortington, 2021). Complicating management, the symptoms for these conditions often overlap significantly. The Intensive Evaluation and Treatment Program (IETP) is a VA Central Office initiative to treat this constellation of symptoms. Palo Alto VA opened an IETP in April 2021. This 3-week multidisciplinary program involves evaluations by physical medicine & rehabilitation (PM&R) physicians, nursing, physical, occupational, speech, and recreation therapies as well as neuropsychology, rehabilitation psychology, and headache psychology. Depending on clinical findings, additional subspecialists such as orthopedics, urology, podiatry, and endocrinology are consulted. The goal of the IETP program is to address the chronic issues that may be sequelae of mmTBI.

Following the Palo Alto VA IETP launch, clinicians noted several participants entering the program with an ongoing medical prescription of testosterone. Endocrine society guidelines regarding testosterone screening were updated in 2018. These guidelines recommend against routine screening for testosterone deficiency. They recommend checking testosterone levels in those with clinical suspicion of testosterone deficiency. A standard screening consists of two fasting morning testosterone levels (total testosterone plus or minus free testosterone) on different days to ensure true below-normal value of testosterone. Concomitant LH/FSH levels are recommended as well to clarify a primary or secondary hypogonadism, since this designation changes pathophysiological implications and therapeutics, particularly with fertility (Fig. 1). They recommend against testosterone supplement use in men planning near term fertility, active or concern for prostate/breast cancer, or severe untreated obstructive sleep apnea. Goal treatment testosterone levels are to be mid-normal with the accepted range of normal for males as 300 to 1,000 nanograms per deciliter (ng/dL) (Bhasin et al., 2018). These strict criteria to diagnose hypogonadism are recommended due to the risks associated with testosterone use, including increased aggression, irritability, and cardiovascular risk (Baillargeon et al., 2018; Huo et al., 2016). Testosterone also decreases spermatogenesis, due to suppression of luteinizing hormone/follicle-stimulating hormone (FSH) in the neuroendocrine pathway, which can impact fertility. Additionally, use can contribute to hair loss and erythrocytosis (Bhasin et al., 2018; Rhoden & Morgentaler, 2004).

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Fig. 1

Flowsheet for Obtaining a Diagnosis of Hypogonadism in an Adult Cisgender Male.

Pituitary dysfunction, including hypogonadism, is well documented as potential sequela of moderate to severe TBI (msTBI). It has been hypothesized that the stalk-like anatomy of the pituitary makes it more susceptible to hypermobility with impact, increasing risk for focal trauma, rotational shearing, and disruption of its vasculature. This may result in decreased production of anterior pituitary regulated hormones, including lutenizing hormone (LH) and follicle-stimulating hormone (FSH), thereby reducing testosterone production in the testes (Aimaretti & Ghigo, 2005; West & Sharp, 2014). However, the literature is less robust with mixed results regarding development of neuroendocrine dysfunction, and specifically hypogonadism, following mild TBI (mTBI) or multiple mild TBI (mmTBI). A 2022 cross sectional study of 1,520 combat current and former service members with history of mTBI and mmTBI found no significant difference in the incidence of low growth hormone, thyroid hormone, or testosterone levels (Walker et al., 2022). These findings differed from those found in a previous 2012 military study by Wilkinson et al. Of note, the 2012 study was limited by a small sample size and retrospective design (Walker et al., 2022; Wilkinson et al., 2012). Ciarlone et al. evaluated 59 concussed and 72 non-concussed military personnel in Afghanistan. At three years, there were significant differences in luteinizing hormone (LH) and total testosterone levels, but no difference in growth hormone (GH), cortisol, and prolactin levels (Ciarlone et al., 2020). Izzy et al. looked at mTBI vs msTBI vs non-brain injury controls and found higher rates of depression and sleep disorders in mTBI compared to msTBI, as well as similar increase in hazard ratio for erectile dysfunction for both mTBI and msTBI (Izzy et al., 2022).

Effectively assessing and treating the SOF mmTBI population poses challenges as significant overlap exists regarding the signs and symptoms of hypogonadism, side effects of testosterone use, and the symptoms associated with mTBI or mmTBI. Examples of these overlapping symptoms include sexual dysfunction, decreased strength, fatigue, depressed mood, impaired cognition, irritability, and mood swings (Buskbjerg et al., 2019; Hua et al., 2016; Huo et al., 2016; Parahiba et al., 2020; Walther et al., 2019). Neurobehavioral outcome scores provide objective assessments for several of these symptom profiles.

The authors are not aware of any prior studies examining the prevalence of testosterone use or its effects on recovery specifically in military service members with mmTBI. The current study aims to evaluate the characteristics of SOF VA IETP participants with mmTBI comparing testosterone users to non-users. Given the overlap between common side effects of testosterone use and common post-concussion symptoms, the authors hypothesize the testosterone user group will have worse neurobehavioral outcome scores.

This is a retrospective cohort study examining participants seen in the Intensive Evaluation and Treatment Program (IETP) at the Palo Alto VA Rehabilitation Service Polytrauma System of Care from its origin in March 2021 through September 2022 (N = 55).

The standard admission intake included a history of over-the-counter medications, prescriptions, and supplements. Testosterone supplementation by prescription was continued when admitted. Participants were queried for past medical history specifically including mental health conditions and sexual function. Standard laboratory testing was obtained including a complete blood count and complete metabolic panel. Testing for neuroendocrine dysfunction was performed on a case-by-case basis based on symptoms and clinical history. Medical records were reviewed to confirm prescription testosterone use, prescribed formulation, and total blood testosterone levels. Additional demographic characteristics and physical measures including Body Mass Index were extracted from the medical record.

IETP participants complete several validated questionnaires to assess pain, sleep, depression, anxiety, post-concussive symptoms, and post-traumatic stress upon admission and discharge. Higher scores indicate areas of distress, and with clinician review, appropriate clinical responses are determined. The Neurobehavioral Symptom Inventory (NSI) is a self-reported measure used to rate the severity of 22 post-concussive symptoms on a 5-point scale from “none” to “very severe” (total scores range from 0–88) (Cicerone & Kalmar, 1995). Post-traumatic stress symptoms were measured with the PCL-C, a set of 17 questions assessing how much individuals were bothered by PTSD symptoms reported on a 5-point scale (total score 17–85) (Weathers et al., 1993). The GAD-7 asks individuals 7 questions about generalized anxiety symptom severity on a 4-point scale of how much they are experiencing symptoms from “not at all” to “nearly every day” (total score 0–21) (Spitzer et al., 2006). The PHQ-9 asks individuals 9 questions regarding depression symptoms on a 4-point scale of how much they are experiencing symptoms from “not at all” to “nearly every day” (total score 0–27) (Sun et al., 2020). The Insomnia Severity Index (ISI) is a 7-item questionnaire asking individuals to rate the severity of sleep problems on a scale from 0–4 (total score 0–28) (Bastien et al., 2001). The PROMIS Pain Interference 6-item instrument asks individuals to rate on a 5-point scale the extent to which pain hinders their engagement with physical, mental, cognitive, emotional, recreational, and social activities (total score 6–30) (PROMIS, n.d.). The Pain Catastrophizing Scale (PCS) is a 13-item self-report that asks individuals about their catastrophic thinking related to pain on a 5-point scale (total score 0–52) (Sullivan et al., 1995). The neurobehavioral scores for the post-concussive symptoms, anxiety, and depression were compared for each participant before and after IETP.

Analysis was conducted in SPSS v29.0. Chi-square tests were used to evaluate differences in demographics and other categorical data elements. T-test comparisons were performed between continuous data such as the blood levels of testosterone between users and non-users. Paired t-test comparisons were performed between pre- and post-IETP neurobehavioral outcome scores.

3 Results

The authors expected irritability and aggression noted anecdotally in testosterone users to translate to lower mood, worsened experiences of pain, increased anxiety, and poorer sleep. However, testosterone users were not different than non-users in neurobehavioral measures at admission and for outcomes after the program, except for one measure (Pain Interference Score). These findings indicate testosterone use may not significantly affect symptoms of chronic pain, chronic headache, insomnia, PTSD, anxiety, and depression in the SOF mmTBI population. The small sample size may contribute to the lack of significant findings. Other possible explanations of these findings include a general lack of testosterone efficacy or decreased response to exogenous testosterone in this population. It is also possible that testosterone use improved neurobehavioral outcome scores in a subpopulation with increased symptom burden, resulting in similar scores to their peers. The analyzed neurobehavioral outcome scores may not fully capture the side effects of testosterone use, for example, level of aggression and hostility were not directly assessed.

Testosterone use was reported in 11% of the SOF participants in the current study, significantly higher than the U.S. national average of 1.67% for cisgender men and 0.5% for active duty servicemembers (Baillargeon et al., 2018). However, only 2 (33%) of the 6 testosterone users in this study met current Endocrine Society guidelines for establishing a diagnosis of hypogonadism prior to initiation of testosterone (Bhasin et al., 2018). There are several possible explanations why testosterone use is high in this population despite a clear diagnosis of hypogonadism. Unique behaviors were noted in the IETP population related to testosterone levels and supplement use. Regardless of use status, several patients specifically requested a testosterone evaluation on admission and expressed a belief that as SOF personnel, their testosterone level should be higher than a civilian male. One of the possible underlying cultural influences on testosterone use is the goal to prevent exhaustion under excessive physical stress. Literature exists demonstrating testosterone use in military populations may prevent adverse physiological bodily consequences during extreme conditions often experienced during military operations. A review article by Linderman et al. examined SOF soldiers in training and studied the effects of this training on testosterone levels. They found that during training, soldiers had lower testosterone levels, decreased body mass, and decreased strength. Unfortunately, this article does not clarify details of TBI history for study participants (Linderman et al., 2016). A study by Pasiakos et al. conducted in military personnel showed that cisgender males provided testosterone were able to maintain lean body mass even when exposed to severe energy deficits (Pasiakos et al., 2019). These findings could have broad implications in the military where operators experience extreme physiological conditions. Hart et al. encourages the utility of testosterone as a protective element in reducing injury and adding to recovery (Hart & Newton, 2019). These studies may encourage military providers to have a lower threshold to provide testosterone to military personnel, while cultural beliefs may embolden soldiers to seek out providers who are likely to provide it to them.

5 Conclusion

This retrospective analysis discovered a high prevalence of testosterone use in the Palo Alto VA SOF cohort with few participants meeting the current guidelines for the diagnosis of hypogonadism. The results of the current study suggest there is no relationship between mmTBI diagnosis, testosterone use, testosterone level and neurobehavioral outcomes. Based on the current study’s findings, testosterone supplementation in the SOF mmTBI population is neither helpful nor harmful in mmTBI recovery as measured by the neurobehavioral outcomes described. Given the paucity of literature surrounding testosterone use and mmTBI in military service members, the authors suggest future larger studies evaluating the prevalence of testosterone use in military service members with mmTBI. Additionally, the authors suggest a multi-site prospective study design to further examine a measure of effect, if any, that testosterone use may have on recovery for SOFs with mmTBI.