A growing body of evidence suggests that females experience more severe symptoms and take longer to recover after mild traumatic brain injury (mTBI) such as concussions, but researchers have struggled to pinpoint why.
A new study posits a novel theory: that such gender differences may in part be due to a sharp drop in hormone levels among females injured during the two weeks prior to their periods.
Researchers at the University of Rochester found that females suffering mTBI in the two weeks before menstruation recovered more slowly and were in poorer health one month after injury than those who suffered mTBI in the two weeks after their period or who were taking birth control pills.
They difference in outcomes, they suspect, may be due to the fact that concussion leads to a sudden drop in the production of the sex hormone progesterone by the pituitary gland. If a woman suffers a concussion in the premenstrual phase of her cycle when progesterone levels are highest, the abrupt drop may, they say, produce a kind of withdrawal, which either contributes to or worsens post-concussion symptoms like headache, nausea, and dizziness.
Consistent with this "withdrawal hypothesis," women in the two week period after menstruation with lower levels of progesterone were found to be less affected by the TBI-related suppression of hormone production, as were women taking a hormonal form of birth control, which provide constant high levels of synthetic progestins.
The results "must be considered preliminary," cautioned lead author, Jeffrey J. Bazarian, MD, MPH, Department of Emergency Medicine, University of Rochester School of Medicine and Dentistry. But, if confirmed in future studies, he believes the results could have "important implications for both treatment and prognosis."
In particular, writes Bazarian in the Journal of Head Trauma Rehabilitation, if women in the premenstrual phase at the time of concussion experience worse outcomes because their progesterone levels drop sharply after injury, a form of hormone replacement therapy might help recovery. Such women, he believes, might "represent the best target for treatment with progesterone after TBI. If the withdrawal hypothesis is accurate, such a relatively simple intervention could lead to significant improvement in outcomes."
But, Bazarian told MomsTEAM, we are not there yet. Until large-scale studies can be conducted to establish the correlation between progesterone levels and concussion symptoms, and the effectiveness of treatment protocols can be tested, the only immediate implication of the study for clinicians, says Bazarian, is that they may want to consider menstrual history when evaluating a female patient after concussion.
Taking into account the stage of their cycle at the time of injury, Bazarian says, might allow clinicians to at least suggest to those injured in the two weeks before their period that "maybe they are more likely to feel poorly and take longer to recover" and to monitor them more closely, while advising females whose injury occurred in the two weeks after their period that their recovery "might go more quickly."
Tracey Covassin, PhD, ATC, an Associate Professor and Director of the Undergraduate Athletic Training Program at Michigan State University, and author of at least four studies on the effect of gender on concussion severity and outcomes, agrees that, until further research is done, "concussions should continue to managed on an individual basis." While Covassin also agreed that it would be a "good idea" to obtain information on a female athlete's last period, she cautioned that determining the true phase of the menstrual cycle based on self-report data is "not always going to be accurate, especially when asking a 16-year-old female when her last period was."
Studies suggest that progesterone may have a protective effect on the brain, with two clinical trials using progesterone to treat TBI showing improved outcomes in those receiving the hormone, although the results were not broken down by gender.
But the results of those studies have been hard to reconcile with others reporting poorer outcomes among women of childbearing age, when progesterone and estrogen levels are high.
Searching for way to reconcile these results, Bazarian and his colleagues looked to studies on changes in sex hormone levels following TBI, including a qualitative study finding that women frequently miss their periods after TBI or cease menstruating altogether, and others showing definitively that TBI suppresses the production of the sex hormones testosterone, progesterone, and estrogen.
Those studies, says Bazarian, led he and his URMC colleagues to develop what they termed a "withdrawal hypothesis": that although sex hormones and progesterone in particular, may be protective, a sudden drop in progesterone level after injury might be a key factor contributing to worse outcomes for women.
Because males have low pre-injury levels of these hormones, and are "ostensibly less affected by TBI-related suppression," this "withdrawal hypothesis," writes Bazarian, "could simultaneously explain why women generally have worse outcomes than men, and why [taking] progesterone [after TBI] may be protective."
To test their theory, Bazarian and his colleagues studied 144 women ages 18 to 60 who arrived within four hours of a head injury at five emergency departments in upstate New York and one in Pennsylvania. Participants gave blood within six hours of injury and progesterone level determined the menstrual cycle phase at the time of injury.
Based on the results, participants fell into three groups: 37 in the premenstrual/high progesterone group; 72 in the low progesterone group (progesterone is low in the two weeks directly after a period); and 35 in the birth control group based on self-reported use.
One month later, women in the premenstrual/high progesterone group were twice as likely to score in a worse third on standardized tests measuring concussion recovery in terms of the number and type of lingering symptoms, and quality of life - as defined by mobility, self-care, usual activity, pain and emotional health - compared to women in the low progesterone group.
Women in the premenstrual/high progesterone group also scored the lowest on a health rating scale that went from 0, being the worst health imaginable, to 100, being the best. Women in the birth control group had the highest scores (average 77).
"If you get hit when progesterone is high and you experience a steep drop in the hormone, this [may be] what makes you feel lousy and causes symptoms to linger," said Bazarian. "But, if you are injured when progesterone is already low, a hit to the head can't lower it any further, so there is less change in the way you feel."