Neuroprotection by Estrogen and Progesterone in Traumatic Brain Injury and Spinal Cord Injury

Abstract

In recent years there has been a growing body of clinical and laboratory evidence demonstrating the neuroprotective effects of estrogen and progesterone after traumatic brain injury (TBI) and spinal cord injury (SCI). In humans, women have been shown to have a lower incidence of morbidity and mortality after TBI compared with age-matched men. Similarly, numerous laboratory studies have demonstrated that estrogen and progesterone administration is associated with a mortality reduction, improvement in neurological outcomes, and a reduction in neuronal apoptosis after TBI and SCI. Here, we review the evidence that supports hormone-related neuroprotection and discuss possible underlying mechanisms. Estrogen and progesterone-mediated neuroprotection are thought to be related to their effects on hormone receptors, signaling systems, direct antioxidant effects, effects on astrocytes and microglia, modulation of the inflammatory response, effects on cerebral blood flow and metabolism, and effects on mediating glutamate excitotoxicity. Future laboratory research is needed to better determine the mechanisms underlying the hormones' neuroprotective effects, which will allow for more clinical studies. Furthermore, large randomized clinical control trials are needed to better assess their role in human neurodegenerative conditions.

Fig. (1)

Proposed mechanisms of neuroprotective effects of estrogen and progesterone on neurons, astrocytes, and the blood. Estrogen and progesterone exert its neuroprotective effects via complex and integrated mechanisms. Some of the mechanisms proposed include: 1) Estrogen and progesterone enter neurons by passive diffusion where they regulate gene transcription; 2) Estrogen and progesterone acts on GABA-A receptors after brain injury and increase cellular survival; 3) Estrogen and progesterone have antioxidant activity via intrinsic properties of scavenging oxygen free radicals; 4) Estrogen enhances the activity of the astroglial enzyme glutamine synthetase, which increases glutamate metabolism and cycling; 5) Estrogen may have effects on microglial proinflammatory mediators; 6) Progesterone modulates the expression of Aquaporin-4 channels after brain injury, resulting in decreased brain edema; 7) Estrogen may increase cerebral blood flow or promote angiogenesis; and 8) Estrogen and progesterone may scavenge blood glutamate and increase the brain to blood glutamate efflux. See text for more details.