Progesterone for Neuroprotection in Pediatric Traumatic Brain Injury

Courtney L. Robertson, MD, FCCM; Emin Fidan, MD; Rachel M. Stanley, MD, MHSA; Corina Noje, MD; Hülya Bayir, MD


Pediatr Crit Care Med. 2015;16(3):236-244. 

In This Article

Progesterone in Preclinical Studies of Adult TBI

Over the last 25 years, many preclinical studies have demonstrated neuroprotection by progesterone after TBI in adult animal models.[4–13] Stein[14] began investigating progesterone after observing that female rats recovered better than male rats after TBI. In initial studies, they compared three groups of adult rats (normal male rats, normally cycling female rats in proestrus, and pseudopregnant female rats with high circulating progesterone).[15] They found that normal female rats had less brain edema at 24 hours after TBI compared with male rats and that the pseudopregnant females had remarkably little brain edema compared with the other two groups. Follow-up studies showed that exogenous treatment of male rats with progesterone reduced cerebral edema, lesion volume, and neuronal loss after TBI.[15] Similarly, Bramlett and Dietrich[16] compared male rats, normal female rats, and ovariectomized female rats showing the smallest lesion volumes in normal females compared with the other two groups. Stein's group[17] also showed that the therapeutic window for progesterone could be up to 24 hours after TBI, when targeting cerebral edema, and that there is a u-shaped dose-response curve for improving cognitive outcomes, including memory acquisition in the Morris water maze.[18] In addition, they described potentially detrimental symptoms of abrupt progesterone withdrawal that may warrant tapering.[19] Other investigators have confirmed the neuroprotective properties of progesterone using a variety of TBI models in adult animals. We performed a PubMed search of all original preclinical research studies of progesterone use in adult TBI published between 1992 and 2013. The 46 identified studies (96–125) are summarized in Supplemental Table 1 (Supplemental Digital Content 1, In addition, a recent preclinical systematic review summarized the key aspects of progesterone treatment for neuroprotection after TBI and cerebral ischemia in adult animals, looking at effects on lesion volume.[20] The main finding was that progesterone was neuroprotective, but limitations in the literature were identified, including insufficient examination of dose-response relationships, therapeutic windows, and evaluation in female or aged adult animals.