Article In Brief
Concussion symptoms at the time of injury among former football players were associated with indicators of participant-reported low testosterone levels and erectile dysfunction. These findings suggest that men with a history of head injury may benefit from discussions with their physicians about testosterone deficiency and sexual dysfunction.
Former professional football players who had concussion symptoms at the time of injury tended to report low testosterone levels and erectile dysfunction (ED) years later, a study published online August 26 in JAMA Neurology revealed.
In the cross-sectional study of men who played for the NFL after 1960, investigators found an increasing association between the number of concussion symptoms and the odds of reporting low testosterone levels and ED.
Previous small studies had suggested a possible association between head trauma and low testosterone levels and sexual dysfunction “through mechanisms that likely include hypopituitarism secondary to ischemic injury and pituitary axonal tract damage,” the authors explained.
“Hormone dysfunction has been underexplored in patients with traumatic brain injuries,” Rachel Grashow, PhD, MS, the study's lead author and a research scientist with the Football Players Health Study at Harvard University, told Neurology Today.
“Interestingly, low testosterone isn't even the most common hormone insufficiency after a head injury,” added Dr. Grashow, who is a research associate at the Harvard T. H. Chan School of Public Health. “Growth hormone, thyroid hormones, and cortisol can also be affected.”
The investigators decided to inquire about ED because men are more likely to notice this particular symptom, “even though it likely lies at the end of this cascade of traumatic brain injury-related hormonal dysfunction,” she explained.
“We certainly hope that news of our results reaches clinicians treating brain-injured patients and that it motivates them to consider hormonal dysfunction as sequelae of head injury and proactively ask their patients about sexual health,” Dr. Grashow said. “Anecdotally speaking, I've heard from a number of neurologists who have said that their patients will not raise the issue of erectile or sexual dysfunction but will disclose if it is brought up by a clinician.”
She added that she also hoped the study results will lessen the stigma associated with ED and prompt men with this condition to confide in their medical providers. Although the research did not involve any direct hormone testing, Dr. Grashow said future studies may undertake such measures.
Study Design, Findings
Between January 2015 and March 2017, the researchers surveyed former professional US football players by mail and e-mail about their football-related concussion symptoms and any recommendations or prescriptions they received for medications for low testosterone levels or ED. They were also asked about medications for other conditions such as hypertension, diabetes, heart failure, and/or pain.
Nearly 26 percent (3,506) of the 13,720 male former NFL players who were contacted responded. Researchers excluded 97 of the respondents because they had declined to answer more than half of the questions about concussion symptoms.
The researchers calculated concussion symptoms based on the sum of the frequency with which participants reported 10 symptoms at the time of the football-related head injury, including loss of consciousness, disorientation, nausea, memory problems, and dizziness.
The prevalence of indicators of low testosterone levels and ED among the respondents was 18.3 percent and 22.7 percent, respectively. The odds of reporting low testosterone levels or ED indicators were elevated for prior known risk factors (such as diabetes, sleep apnea, and mood disorders) and the odds of reporting the low testosterone indicators and ED were significantly associated with concussion symptoms (p<.001).
After adjusting for demographic characteristics, football exposures, and current health factors, the researchers found a statistically significant and increasing association of concussion symptoms with the odds of reporting the low testosterone indicators (odds ratio, 2.39; p<.001) and ED (odds ratio, 1.72; p<.001).
“It may be the best study possible of retired NFL players,” said Randolph W. Evans, MD, FAAN, clinical professor of neurology at Baylor College of Medicine. But he cautioned that the low response rate of 25.6 percent “could certainly lead to selection bias.”
The findings are nonetheless consistent with previous studies linking pituitary dysfunction with sports-related concussion, Dr. Evans said. Patients with suspect symptoms should undergo pituitary screening that includes testosterone testing, with repeated evaluations periodically as pituitary function can fluctuate over time, he added.
Symptoms of hypopituitarism vary, depending on the deficiency. They may encompass muscle weakness, poor exercise capacity, lethargy, fatigue, psychiatric and cognitive symptoms, sleep disorders, decreased libido, erectile dysfunction, low bone mineral density, constipation, weight gain, decreased body hair, and loss of tolerance to cold, Dr. Evans explained.
However, most neurologists are unlikely to encounter retired NFL players who frequently sustained numerous concussions and sub-concussive injuries, Dr. Evans said, adding that more commonly, they come across non-athletes with single mild traumatic brain injuries. Dr. Evans evaluated 395 retired NFL players from May 2017 to June 2018 as part of the NFL concussion settlement.
The study's findings are still applicable to the care of patients with mild traumatic brain injuries and prolonged symptom experience, or those with a history of exposure to these repetitive injuries, said Nicole D. Reams, MD, a sports neurologist and associate director for the sports concussion program at NorthShore University Health System in the Chicago area.
Investigators made careful statistical considerations, accounting for health risk factors such as cardiovascular disease and sleep apnea, as well as examining the length of the athletic career and when the individual played the sport, Dr. Reams said.
Among the study's weaknesses was that it included a retrospective cohort, which requires participants to recall concussion symptoms and exposure that in many cases had occurred 20 to 30 years earlier. The researchers also did not include a control group to report on the prevalence of ED and low testosterone in the non-trauma population of similar age, sex, and other factors, she said.
Furthermore, investigators inquired about the number of times each symptom occurred after an injury. “The investigators did not elect to place a minimum number of symptoms in conjunction with one another or a duration of symptoms in which to define an injury but pooled the occurrence of any symptom into the overall concussion score for that individual,” Dr. Reams explained.
For a clinical diagnosis of concussion, a forceful impact has to cause neurologic dysfunction among a diffuse network, she said. Concussion does not typically cause a single isolated symptom—for example, concussion resulting in only nausea would be atypical—and transient neurologic symptoms lasting 30 seconds would not generally count as concussion injury. Nonetheless, she noted, the authors found similar associations with ED and low testosterone in player reports of impact causing loss of consciousness.
While evaluating patients with low libido and ED who had sustained multiple concussions and repetitive impact exposure, “it is certainly difficult to tease out clinically in some cases what the etiology of the sexual dysfunction complaints are, as many of these individuals have comorbidities as mentioned in the article: depression, sleep apnea, hypertension, and diabetes,” Dr. Reams said.
In individuals with persistent symptoms following mild traumatic brain injuries without a clear source, or individuals with a history of multiple concussion or repetitive impact exposure, Dr. Reams recommends endocrine lab screening with testosterone, thyroid stimulating hormone, morning cortisol, and IGF-1. “Investigating for endocrine dysfunction in this selected patient population can be important in ultimately reducing symptom burden,” she said.
With sexual health comprising an important part of an individual's well-being and relationships, the study “opens up a bigger conversation about quality of life and what that actually encompasses for people,” said Tiffany Greco, PhD, assistant project scientist at the University of California, Los Angeles, whose research focuses on metabolism and hormonal dysfunction following traumatic brain injury. More often, Dr. Greco said, studies tend to delve into other disorders that may arise in the aftermath of traumatic brain injuries—migraines, depression, and anxiety, to name a few.
Neurologists “should definitely be on the lookout” for hormonal deficiency and sexual dysfunction in patients who play contact sports, Dr. Greco said. The manifestation “tends to be very intricate,” as there is “a lot of interplay between the hormones,” and the disruption of another one—not testosterone—could be the culprit. To ensure accuracy, she added that testosterone testing should be done early in the morning when testosterone is at its highest, and more than one blood draw on different days may be necessary before forming any conclusions, she said.
“We should also be paying attention to reproductive hormone changes in women following traumatic brain injury,” Dr. Greco said. Questions arise over the effects of menstrual cycle timing or the use of birth control pills on the initial injury's severity. “We know that women's menstrual cycles are disrupted after injury, contributing to decreased fertility, sexual dysfunction, and quality of life as well.”
A prospective study of women with concussions sustained while playing collegiate ice hockey, soccer, and basketball is underway at the University of Rochester and the Rochester Institute of Technology in Rochester, NY. Launched in 2017 in collaboration with the National Institutes of Health (NIH), the study is measuring hormone levels in sweat, said Jeff Bazarian, MD, MPH, professor of emergency medicine and neurology at the University of Rochester.
After a concussion, a female athlete applies a sweat patch to the torso every 72 hours for two weeks. The patches are analyzed for hormones and inflammatory markers under the direction of Jessica M. Gill, PhD, RN, senior investigator in the Tissue Injury Branch of the NIH. Dr. Gill's lab initially developed the sweat patch technology to detect brain proteins, such as tau, which are released after head injury. She adapted the technology to measure hormones that may indicate concussion-related pituitary injury.
Learning about the impact of contact sports-related concussions on hormones “is an important issue,” Dr. Gill said. “It really deserves looking at more closely in bigger long-term more prospective studies.”
Prospective research could delve into whether the pituitary gland recovers during a hiatus from contact sports, and if so, how much time off athletes need. Monitoring them frequently and allowing periods of rest may help prevent the development of permanent problems, Dr. Bazarian said.
As for the retrospective study of former professional football players, he noted that the investigators “did such a good job of adjusting for other factors that also could potentially come into play.”
The findings add to previous research indicating that the pituitary gland doesn't work as well after multiple concussions, Dr. Bazarian said, adding: “There's no perfect study, but this is pretty well done.”
Dr. Grashow reported grants from the NFL Players Association during the conduct of the study. Dr. Bazarian has received honoraria for serving on the advisory boards of Abbott Pharmaceuticals and Q30 Innovation and has received salary support for a research contract with BrainScope LLC. Dr. Greco had no disclosures.