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Concussion Chronicles II: Hormones

Concussion Chronicles II: Hormones

Bruce Thomas, MD

As noted last month, traumatic brain injuries generates over 2.87 million emergency department visits a year and is a great cause of suffering for many people for months and sometimes years afterwards. Last month, we talked about a great option for treatment: neurofeedback.

We continue now mentioning other things that could help seed recovery starting with……..Hormones.

The hormone that has received the most attention is progesterone. Progesterone is known to be protective of the brain, to slow down brain cell death, protect glial cells and be anti-inflammatory (1). Trauma researchers know that premenopausal women with head injury have LESS of the inflammatory signals (cytokines) and less multi-organ failure and overwhelming infection (sepsis) than do age matched men (2). We know it helps in animal trials (3-6) and unlike other sex hormones, it is actually made in the brain (7). In the most famous trial, the ProTECT study (8), mortality after Traumatic Brain Injury (TBI) was cut in half for the progesterone group. Truth be told, subsequent trials did not always show such dramatic results (9), but further research has suggested that this could be because the dosing regimens were simply too low (10). TBI is a difficult thing to treat. The way I see it, progesterone should have a place at the table of brain injury treatment.

While not as famous as progesterone, estrogen has also been found to have brain protective effects (11-18). Because of its protective effect for Alzheimer’s (19), I often say, “Estrogen is brain.”

Interestingly, melatonin, the hormone famous for sleep, can help. I often acknowledge melatonin as the best antioxidant for the brain that I know of. Since oxidant stress is part of the mechanism of inflammation after brain injury, it is not surprising that it could help. Notably it’s higher right after a brain injury but lower a long time after TBI (20), as if the brain knows it needs it acutely after the trauma but later it gets depleted. Studies on melatonin for TBI have been favorable (20-21).

Finally, while not thought of by most as a hormone, Vitamin D actually is a hormone and has been speculated to be helpful in brain injuries (22).

One reason that brain injuries are so hard to treat is that there are many factors involved and it becomes an entire body problem. Sometimes for an optimal outcome, it is good to address it from all angles. Moreover, having the right hormone levels helps us do just that.

  1. Djebaili M, Guo Q, Pettus EH, Hoffman SW, Stein DG. The neurosteroids progesterone and allopregnanolone reduce cell death, gliosis, and functional deficits after traumatic brain injury in rats. J Neurotrauma. 2005;22:106–118. doi: 10.1089/neu.2005.22.106.
  2. Frink M, Pape HC, van Griensven M, Krettek C, Chaudry IH, Hildebrand F. Influence of sex and age on MODS and cytokines after multiple injuries. Shock 2007;27:151–156.
  3. Goss CW, Hoffman SW, Stein DG. Behavioral effects and anatomic correlates after brain injury: a progesterone dose-response study. Pharmacol Biochem Behav 2003;76:231–242.
  4. Djebaili M, Guo Q, Pettus EH, Hoffman SW, Stein DG. The neurosteroids progesterone and allopregnanolone reduce cell death, gliosis, and functional deficits after traumatic brain injury
    in rats. J Neurotrauma 2005;22:106 –118.
  5. Pettus EH, Wright DW, Stein DG, Hoffman SW. Progesterone treatment inhibits the
    inflammatory agents that accompany traumatic brain injury. Brain Res 2005;1049:112–119.
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  6. Stein DG. Progesterone exerts neuroprotective effects after brain injury. Brain Res Rev 2008;57:386 –397.
  7. Schumacher M, Guennoun R, Ghoumari A, et al. Novel perspectives for progesterone in hormone replacement therapy, with specialreference to the nervous system. Endocr Rev 2007;28:387–439.
  8. Wright, D, Kellerman A ProTECT: a randomized clinical trial of progesterone for acute traumatic brain injury et al Ann Emerg Med 2007 Apr;49(4):391-402, 402.e1-2.
  9. Wright DW1, Yeatts SD et al Very early administration of progesterone for acute traumatic brain injury. N Engl J Med. 2014 Dec 25;371(26):2457-66.
  10. Howard, R, Sayeed, I Suboptimal Dosing Parameters as Possible Factors in the Negative Phase III Clinical Trials of Progesterone for Traumatic Brain Injury J Neurotrauma. 2017 Jun 1; 34(11): 1915–1918
  11. Neese S.L., Clough R.W., Banz W.J., Smith D.C. Z-Bisdehydrodoisynolic acid (Z-BDDA): an estrogenic seco-steroid that enhances behavioral recovery following moderate fluid percussion brain injury in male rats. Brain Res. 2010;1362:93–101.
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  14. Zlotnik A., Leibowitz A., Gurevich B., Ohayon S., Boyko M., Klein M., Knyazer B., Shapira Y., Teichberg V.I. Effect of estrogens on blood glutamate levels in relation to neurological outcome after TBI in male rats. Intensive Care Med. 2012;38(1):137–144.
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  16. McClean J., Nuñez J.L. 17alpha-Estradiol is neuroprotective in male and female rats in a model of early brain injury. Exp. Neurol. 2008;210(1):41–50.
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  19. Simpkins J, Perez, E The Potential for Estrogens in Preventing Alzheimer’s Disease and Vascular Dementia Ther Adv Neurol Disord. 2009 Jan; 2(1): 31–49.
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  22. Milos Cekic M,. Stein D Traumatic brain injury and aging: Is a combination of progesterone and vitamin D hormone a simple solution to a complex problem? Neurotherapeutics. 2010 Jan; 7(1): 81–90.

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