Sex, sex steroids, and brain injury

Abstract

Biologic sex and sex steroids are important factors in clinical and experimental stroke and traumatic brain injury (TBI). Laboratory data strongly show that progesterone treatment after TBI reduces edema, improves outcomes, and restores blood-brain barrier function. Clinical studies to date agree with these data, and there are ongoing human trials for progesterone treatment after TBI. Estrogen has accumulated an impressive reputation as a neuroprotectant when evaluated at physiologically relevant doses in laboratory studies of stroke, but translation to patients remains to be shown. The role of androgens in male stroke or TBI is understudied and important to pursue given the epidemiology of stroke and trauma in men. To date, male sex steroids remain largely evaluated at the bench rather than the bedside. This review evaluates key evidence and highlights the importance of the platform on which brain injury occurs (i.e., genetic sex and hormonal modulators).

Figure 1. Overview of Neurosteroid Synthesis

Cholesterol is converted into pregnenolone within the mitochondria and then further converted into DHEA via P450_c17 or progesterone by 3β-HSD. DHEA is converted into testosterone via the intermediate androstenedione. Progesterone can also be converted to testosterone by P450_c17. Testosterone is converted to its more potent analog DHT by 5α-R or converted into 17β-estradiol by the enzyme Aromatase. Progesterone is converted to its highly active metabolites 5α-DHP and 3α,5α-THP (ALLO) by consecutive reductions by 5α-R and then 3α-HSD. Both pregnenolone and DHEA can be interconverted to sulfated esthers by sulfotransferase and sulfatase enzymes. P450scc, mitochondrial cholesterol side-chain cleavage enzyme; P450c17, microsomal 17 hyrdoxylase; 3β-HSD, 3β-hydroxysteroid dehydrogenase; 5α-R, 5α-reductase; 5α-HSD, 5α-hyrdoxysteroid dehydrogenase; 17β-HSD, 17β-hyrdoxysteroid dehydrogenase; Aromatase, P450-aromatase; DHT, dihydrotestosterone; 3α,5α-THP, Allopregnanolone.