same report further showed that administration of a single dose of 1,25 dihydroxyvitamin D3 (2 μg/kg) 30 minutes after hypoxia-ischemia in seven-day-old rats effectively reduced brain damage in these animals (Kajta et al., 2009). Although clearly very different from the accepted models of TBI, these data do suggest that future studies to examine the possible effectiveness of vitamin D in TBI models are warranted.
An examination of the literature on the possible role of vitamin D in improving resilience to TBI and in the treatment of TBI has identified a number of unanswered questions that reveal gaps in our current knowledge. It is not known whether chronic vitamin D supplementation alone improves resilience. There also is no clear evidence yet to show the extent to which vitamin D supplementation is effective in treating TBI, the therapeutic window for treatment after TBI, or the optimal dose. Although it appears that adequate vitamin D status is necessary to the action of effective treatments such as progesterone, it is not currently known if vitamin D supplementation that exceeds recommended doses would improve progesterone efficacy or enhance other treatments. It is, however, recommended that military personnel ensure adequate intakes to meet the RDA for vitamin D. Because the current vitamin D status of military personnel is not definitive, the committee recommends in Chapter 5 that dietary assessments be conducted across military settings. A retrospective assessment of pre- and postinjury nutrition status is likewise recommended in Chapter 5. This should include investigating serum vitamin D levels in patients during the acute phase of TBI, with a range of severity from mild/concussion to severe injuries, to explore whether preinjury vitamin D levels are associated with different outcomes.
Progesterone was not included for independent evaluation in this report because, although it is incorporated in some dietary supplements, there was no evidence that these preparations will have positive effects on TBI. Although progesterone can be taken orally in a micronized form that enhances solubility in aqueous solutions and absorption in the gastrointestinal tract (Fitzpatrick and Good, 1999), it appears that its positive effects in TBI are achieved only via intravenous administration and at therapeutic doses (Wright et al., 2005, 2007; Xiao et al., 2008). Although some phytoprogestins have been identified by their ability to bind progesterone receptors on the breast carcinoma cell line T47D (Zava et al., 1998), none of the herbal extracts that bound the receptors were agonists. They were either neutral or were progestin antagonists (examples include red clover, licorice, and nutmeg). Altogether, there is no evidence that oral administration of progesterone or phytoprogestins will provide a benefit as treatment for TBI.
RECOMMENDATION 15-1. The committee recommends more animal studies be conducted to determine if vitamin D enhances the beneficial actions of progesterone in the treatment of TBI. If this synergistic effect is confirmed in animals, then studies in humans should be conducted to evaluate the extent to which vitamin D supplementation might improve the efficacy of progesterone treatment.
RECOMMENDATION 15-2. Based on animal studies showing a requirement of vitamin D for the efficacy of progesterone therapy, future animal studies are recommended to test the efficacy of using vitamin D supplements to improve resilience to TBI. Should the data from animal studies support use of this steroid hormone, human trials should be implemented to test the efficacy of vitamin D in populations at high risk for TBI.