Novel cellular phenotypes and subcellular sites for androgen action in the forebrain.

Historically, morphological studies of the distribution of androgen receptors in the brain led to conclusions that the major regional targets of androgen action are involved in reproduction, that the primary cellular targets are neurons, and that functional androgen receptors are exclusively nuclear, consistent with the classical view of steroid receptors as ligand-dependent transcription factors. In this review, we discuss three separate but interrelated recent studies highlighting observations made with newer methodologies while assessing the regional, cellular or subcellular distribution of androgen receptors containing cells in the forebrain. Regional studies demonstrated that the largest forebrain target for androgen action in terms of the number of androgen receptor expressing cells is the cerebral cortex, rather than the main hypothalamic and limbic centers for reproductive function. Cellular studies to determine the phenotype of androgen receptor expressing cells confirmed that most of these cells are neurons but also revealed that small subpopulations are astrocytes. The expression of androgen receptors in astrocytes is both region and age dependent. In contrast, reactive astrocytes in the lesioned adult rat brain do not express androgen receptors whereas reactive microglia do. Finally, androgen receptor immunoreactive axons were identified in the cerebral cortex of the rat and human. These observations do not overturn classical views of the cellular and subcellular locus of steroid action in the nervous system, but rather broaden our view of the potential direct impact of gonadal steroid hormones on cellular function and emphasize the regional and developmental specificity of these effects on the nervous system.

Propiedades neuroprotectoras de los esteroides sexuales y los neuroesteroides / The neuroprotective properties of sex steroids and neurosteroids

Introducción. El sistema nervioso es una diana de las hormonas esteroides y también un tejido esteroidogénico, y produce esteroides que actúan de una forma paracrina o autocrina sobre neuronas y glía. Los esteroides formados en el tejido nervioso se denominan neuroesteroides, para diferenciarlos, por su origen, de los esteroides periféricos, aunque tienen la misma estructura molecular que éstos. Desarrollo. Se analiza la capacidad de las neuronas y las células de glía de sintetizar esteroides, y se describe el papel de algunas moléculas clave en la esteroidogénesis, como la proteína de regulación aguda de esteroidogénesis, el receptor periférico de benzodiacepinas y la enzima aromatasa, que cataliza la conversión de testosterona en estradiol. También se describen los diversos mecanismos de acción de los esteroides hormonales y los neuroesteroides en el sistema nervioso. Éstos incluyen, tanto la regulación de la síntesis de proteínas por neuronas y glía, mediante acciones sobre receptores nucleares, como efectos rápidos mediados por receptores de membrana o la modulación alostérica de receptores para neurotransmisores. Se revisan las evidencias clínicas y experimentales de los efectos neuroprotectores de los esteroides sexuales y neuroesteroides y las limitaciones de la terapia hormonal sustitutiva, tras la menopausia. Conclusiones. Dada la limitación que plantea el uso sistémico de hormonas como terapia neuroprotectora, se necesitan encontrar estrategias alternativas que aprovechen las propiedades neuroprotectoras de los esteroides, tales como aumentar localmente su síntesis en el cerebro o desarrollar moléculas que activen a los receptores de esteroides en el sistema nervioso y no en los órganos periféricos (AU)

The nervous system is a target for steroid hormones as well as a steroidogenic tissue, and it produces steroids that have a paracrine or autocrine effect on neurons and glial cells. Steroids formed in nervous tissue are called neurosteroids in order to differentiate them, in terms of their origin, from the peripheral steroids, although they both share the same molecular structure. Development. We analyse the capacity of neurons and glial cells to synthesise steroids and describe the role played in steroidogenesis by certain key molecules, such as steroidogenic acute regulatory protein, peripheral benzodiazepine receptor and aromatase enzyme, which acts as a catalyst in the conversion of testosterone into estradiol. We also provide a description of the different mechanisms of action of the hormonal steroids and neurosteroids in the nervous system. These include both the regulation of protein synthesis by neurons and glial cells, by acting on nuclear receptors, and rapid effects mediated by membrane receptors or the allosteric modulation of neurotransmitter receptors. We review the clinical and experimental evidence for the neuroprotective effects of sex steroids and neurosteroids, and the limitations of hormone replacement therapy following menopause. Conclusions. Given the restraints involved in the systemic use of hormones as neuroprotective therapy, alternative strategies that take advantage of the neuroprotective properties of steroids must be sought. These could involve locally increasing their synthesis inside the brain or developing molecules that activate the steroid receptors in the nervous system and not in the peripheral organs (AU)