Endocrine Abstracts

Sex hormones act both as endocrine signals as well as local paracrine or autocrine factors in the nervous system. In addition to target to classical endocrine and reproductive brain areas, sex hormones and its metabolites affect learning and cognition and regulate the development and plasticity of brain regions that are not directly related to reproduction. Estrogen and progesterone exert neuroprotective effects in the central nervous system and may affect the onset and progression of several neurodegenerative and affective disorders, as well as the recovery from traumatic neurological injury. Recent studies have shown that the brain up-regulates both estradiol synthesis and estrogen receptor expression in reactive astroglia at sites of injury. Genetic or pharmacological inhibition of brain aromatase, the enzyme involved in estradiol synthesis, results in marked neuronal death after different forms of mild neurodegenerative stimuli that do not compromise neuronal survival under control conditions. This finding strongly suggest that local formation of estradiol in the CNS is neuroprotective and that the induction of aromatase and the consecutive increase in the local production of estradiol are part of the program triggered by the neural tissue to cope with neurodegenerative insults. Proteins involved in the intra-mitochondrial trafficking of cholesterol, the first step in steroidogenesis, such as the peripheral-type benzodiazepine receptor (PBR) and the steroidogenic acute regulatory protein (StAR), are also up-regulated in the brain after injury, together with the first enzyme in the steroidogenic pathway (P450scc). This suggests that brain steroidogenesis may be modified in adaptation to neurodegenerative conditions and to the brain aging process. Recent studies have shown that Ro5-4864, a PBR ligand that increases brain steroidogenesis is neuroprotective. Therefore, StAR, PBR and aromatase are attractive pharmacological targets to promote neuroprotection in the aged brain.

Supported by MEC, Spain (SAF 2005-00272) and the European Union (EWA project: LSHM-CT-2005-518245).