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 Metabolism and Progesterone Receptors in the Developing Brain

A complete discussion of neurosteroid production, metabolism, and receptor action is out of the scope of this review. The reader is referred to several key reviews in the field.[46–50] Briefly, progesterone is synthesized from pregnenolone by 3β-hydroxysteroid dehydrogenase, an enzyme that has been shown to be present in both neurons and glia in rat brains.[50–53] Baulieu et al[54] showed that progesterone is a true neurosteroid, by documenting the synthesis of progesterone in the brain. Progesterone is metabolized by the enzyme 5α-reductase to 5α-dihydroprogesterone and then to the neurosteroid allopregnanolone by the reversible enzyme 3α-hydroxysteroid dehydrogenase.[55] Allopregnanolone is felt to be one of the key metabolites responsible for neuroprotection after brain injury. The synthesis, concentration of, and metabolism of progesterone and allopregnanolone change throughout development and vary by brain region studied. A recent review summarizes these development- and region-specific changes in neurosteroids.[50]

In addition to developmental changes in progesterone brain concentration, there are developmental changes in progesterone receptor expression. The laboratory group of Wagner et al[49,56])had produced a large body of work evaluating the role of progesterone and progesterone receptors during normal brain development. They suggest that the influence of progesterone on the perinatal brain has been overlooked and that progesterone may play a role in the development of brain and behavior. Furthermore, the progesterone receptor is expressed throughout the forebrain during critical stages of brain maturation in the rodent and may influence neuronal migration, synaptogenesis, and cell death.[57,58] Importantly, Wagner et al[49] suggest that this could be true in human brain development, as children of women who were treated with progesterone during pregnancy for prevention of miscarriage had improved intellectual and behavioral performance in childhood.[59,60]

In summary, the endogenous brain levels of progesterone, as well as regional brain expression of progesterone receptors, are influenced throughout development by species studied, other brain hormones, and specific developmental timepoint being studied. These complex interactions need to be understood and taken into consideration when planning to use progesterone for neuroprotective therapy after pediatric TBI.