Glia as mediators of steroid hormone action on the nervous system: An overview.

This special issue on steroids and glia represents the intersection of two emerging themes in the neurosciences: (a) Glia actively modulate and participate in brain function throughout life, and (b) glia are sensitive to steroid hormones. This overview begins by reviewing some of the basic principles of steroid hormone action on the brain and introducing the various glia that inhabit the peripheral and central nervous system. A prominent theme among the articles that follow is that glia may be direct targets for steroid hormones since they possess steroid receptors and the promoter region of glial-specific genes such as glutamine synthetase contain hormone-responsive elements. The articles in this special issue discuss evidence that glia may mediate steroid action on the nervous system in the context of (a) steroid metabolism, which may control the hormonal microenvironment of neurons both in the normal and injured brain; (b) brain development including sexual differentiation; (c) synaptic plasticity which may underlie the cyclic release of luteinizing hormone releasing hormone in the female rodent brain; (d) neural repair and aging; and (e) brain immune function. Another theme among these articles is that glia influence neurons via specific secreted and cell-surface molecules, and that steroids affect this mode of communication by altering the level of glial production of these signaling molecules and/or the sensitivity of neurons to such signals.     

Sex steroid effects at target tissues: mechanisms of action

Our understanding of the mechanisms of sex hormone action has changed dramatically over the last 10 years. Estrogens, progestins, and androgens are the steroid hormones that modulate reproductive function. Recent data have shown that many other tissues are targets of sex hormones in addition to classical reproductive organs. This review outlines new advances in our understanding of the spectrum of steroid hormone ligands, newly recognized target tissues, structure-function relationships of steroid receptors, and, finally, their genomic and nongenomic actions. Sex-based specific effects are often related to the different steroid hormone mileu in men compared with women. Understanding the mechanisms of sex steroid action gives insight into the differences in normal physiology and disease states.     

Emerging mechanisms of the behavioral effects of steroids

Within two models of steroid-modulated behavior, sodium appetite and sexual receptivity, novel mechanisms of steroid action have emerged. These include interactions between different types of steroid receptors, plasticity of synapses, activation of unliganded steroid receptors, and rapid effects of steroids. These mechanisms highlight the diversity of steroid action in the central nervous system.     

Hormonal control of behaviour: steroid action in the brain

There have recently been significant advances in our understanding of the cellular action of steroids on brain mechanisms of behaviour. Brain cells contain steroid metabolizing enzymes whose activity is modified by environmental stimuli. Steroids have rapid effects on neurotransmitter receptors via cell membranes and modify the distribution of neuropeptide receptors in areas controlling behaviour. It has been known for some time that oestrogens have an effect on brain structure that can be related to behaviour in the sexually dimorphic avian song system. Recent work suggests that oestrogen may have a similar effect on the developing sexually dimorphic nuclei of the mammalian brain.     

Are gonadal steroid hormones involved in disorders of brain aging?

Human aging is associated with a decrease of circulating gonadal steroid hormones. Since these hormones act as trophic factors for neurones and glia, it is possible that the decrease in sex steroid levels may contribute to the increased risk of neurodegenerative disorders with advanced age. Sex steroids are neuroprotective in several animal models of central and peripheral neurodegenerative diseases, and clinical data suggest that these hormones may reduce the risk of neural pathology in aged humans. Potential therapeutic approaches for aged-associated neural disorders may emerge from studies conducted to understand the mechanisms of action of sex steroids in the nervous system of aged animals. Alterations in the endogenous capacity of the aged brain to synthesize and metabolize sex steroids, as well as possible aged-associated modifications in the signalling of sex steroid receptors in the nervous system, are important areas for future investigation.     

Biosynthesis and action of neurosteroids in the cerebellar Purkinje neuron

The brain is considered to be a target site of peripheral steroid hormones. In contrast to this classical concept, new findings over the past decade have established that the brain itself also synthesizes steroids de novo from cholesterol through mechanisms at least partly independent of peripheral steroidogenic glands. Such steroids synthesized de novo in the brain, as well as other areas of the nervous system, are called neurosteroids. To understand neurosteroid actions in the brain, we need data on the specific synthesis in particular sites of the brain at particular times. Therefore, our studies for this exciting area of brain research have focused on the biosynthesis and action of neurosteroids in the identified neurosteroidogenic cells underlying important brain functions. We have demonstrated that the Purkinje cell, a typical cerebellar neuron, is a major site for neurosteroid formation in the brain. This is the first observation of neuronal neurosteroidogenesis in the brain. Subsequently, genomic and nongenomic actions of neurosteroids have become clear by a series of our studies using an excellent Purkinje cellular model. On the basis of these findings, we summarize the advances made in our understanding of biosynthesis and action of neurosteroids in the cerebellar Purkinje cell.     

Hormonal Control of Gametogenesis in the Terrestrial Snail, Euhadra peliomphala

Effects of the cerebral ganglion (brain) and the optic gland on oogenesis and spermatogenesis were studied in the terrestrial snail, Euhadra peliomphula. Removal of the optic tentacles inhibited both oogenesis and spermatogenesis. These effects were abolished by the injection of the optic tentacle extract. In the tissue of the optic tentacle, only the optic gland showed the recovery action. Furthermore, in vitro the optic gland extract stimulated spermatogenesis but had no effect on oogenesis. On the contrary, the brain extract promoted oogenesis not only in vitro and but also in viva The hermaphroditic gland extract reduced the nuclear volume of the optic gland cells, but the brain extract did not. In addition, among sex steroid hormones secreted from the hermaphroditic gland, only testosterone also reduced the nuclear volume of optic gland cells. On the basis of these results, hormonal mechanisms of gametogenesis in Euhadra peliomphala are discussed.     

Oestrogen and progestins differently prevent glutamate toxicity in cortical neurons depending on prior hormonal exposure via the induction of neural nitric oxide synthase

Sex steroids are important for brain function and protection. However, growing evidence suggests that these actions might depend on the timing of exposure to steroids. We have studied the effects of steroid administration on the survival of neural cells and we have partially characterized the possible mechanisms. The effect of a 24 h pre-treatment with 17β-estradiol or 17β-estradiol plus progesterone or medroxyprogesterone acetate on the toxic action of l-glutamate was used to test the experimental hypothesis. Pre-exposure to either steroid combinations turned in enhanced cell survival. Instead, addition of sex steroids together with l-glutamate, in the absence of a pre-exposure had no protective effect. Pre-treatment with the steroid combinations resulted in increased neural NOS expression and activity and blockade of NOS abolished the cytoprotective effects of steroids. These results suggest that NOS induction might be involved in sex steroid-induced neuroprotection. Furthermore, these data supports the hypothesis that prolonged and continued exposure to oestrogen and progesterone, leading to changes in gene expression, is necessary to obtain neuroprotection induced by sex steroids.     

Responsiveness and mechanisms of action of steroid hormones in human endometrial adenocarcinoma cells

The responsiveness and action mechanisms of steroid hormones and epidermal growth factor on human endometrial carcinoma cells are analyzed by using in vitro culture system. 1) The Ishikawa cells, derived from a well differentiated endometrial adenocarcinoma and possess ER and PR, are shown to respond to estrogens by increasing a variety of parameters, viz cell proliferation, PR levels, ALP and DNA polymerase activities. 2) ER and PR of those cells are localized in the nuclei by immunocytochemical staining using the monoclonal antibodies against to ER and PR, confirming the correctness of Gorski and Greene's one step theory involving the action mechanisms of steroid hormones. 3) Progestins reduced the ER level and stimulate E2DH activities and glycogen content, which are completely abolished by anti-progestin (RU486), suggesting that PR of those cells should be functional. 4) These responses to steroid hormones of Ishikawa cells are synergistically enhanced or appeared earlier by addition of EGF. 5) The main metabolite of E2 incubated with Ishikawa cells is E2-3-sulfate instead of E1, indicate that the higher estrogenic status may be persisted in endometrial cancer tissues.     

Regulation of neuropeptide gene expression by steroid hormones

Steroid hormones modify several brain functions, at least in part by altering expression of particular genes. Of interest are those genes that are involved in cell-cell communication in the brain, for instance neuropeptide genes and genes that code for enzymes involved in synthesis of neurotransmitters. Steroid regulation of mRNA levels for several genes has been reported, including the genes coding for the neuropeptides vasopressin, corticotropin releasing factor, luteinizing hormone-releasing factor, pro-opiomelanocortin; somatostatin, preproenkephalin, and the enzyme tyrosine hydroxylase. Steroid control of releasing factor genes is consistent with classical neuroendocrine concepts of negative feedback. Steroid-induced plasticity of gene expression is sometimes in evidence, with the presence or absence of a particular steroid inducing expression of a neuropeptide gene in neurons that under other conditions do not express the gene. As a means of gaining some insight into the mechanism of action of steroid hormones, several groups have determined some of the neuropeptide profiles of neurons that contain receptors for steroid hormones. Marked heterogeneity is found, in that often only a subpopulation of phenotypically-similar neurons, even within a single brain area, contains receptors for a given steroid.     

The 13th J. A. F. Stevenson memorial lecture. Sexual differentiation of the brain: possible mechanisms and implications

The mammalian brain appears to be inherently feminine and the action of testicular hormones during development is necessary for the differentiation of the masculine brain both in terms of functional potential and actual structure. Experimental evidence for this statement is reviewed in this discussion. Recent discoveries of marked structural sex differences in the central nervous system, such as the sexually dimorphic nucleus of the preoptic area in the rat, offer model systems to investigate potential mechanisms by which gonadal hormones permanently modify neuronal differentiation. Although effects of these steroids on neurogenesis and neuronal migration and specification have not been conclusively eliminated, it is currently believed, but not proven, that the principle mechanism of steroid action is to maintain neuronal survival during a period of neuronal death. The structural models of the sexual differentiation of the central nervous system also provide the opportunity to identify sex differences in neurochemical distribution. Two examples in the rat brain are presented: the distribution of serotonin-immunoreactive fibers in the medial preoptic nucleus and of tyrosine hydroxylase-immunoreactive fibers and cells in the anteroventral periventricular nucleus. It is likely that sexual dimorphisms will be found to be characteristic of many neural and neurochemical systems. The final section of this review raises the possibility that the brain of the adult may, in response to steroid action, be morphologically plastic, and considers briefly the likelihood that the brain of the human species is also influenced during development by the hormonal environment.     

Steroid modulation of astrocytes in the neonatal brain: implications for adult reproductive function

There is a growing appreciation for the importance of astrocytes, a type of nonneuronal glial cell, to overall brain functioning. The ability of astrocytes to respond to gonadal steroid hormones with changes in morphology has been well documented in the adult brain. It is also apparent that astrocytes of the developing brain are permanently differentiated by the neonatal hormonal milieu, in particular by estradiol, resulting in sexually dimorphic cell morphology, synaptic patterning, and density in males and females. The mechanisms of hormonally mediated astrocyte differentiation are likely to be region specific. In the arcuate nucleus of the hypothalamus, neuron-to-astrocyte signaling appears to play a critical role in estradiol-induced astrocyte differentiation during the first few days of life. Gamma aminobutyric acid (GABA) is an amino acid neurotransmitter that is synthesized and released exclusively by neurons. The levels of GABA are increased in the arcuate nucleus of neonatal males versus females. Preventing the increase in males or mimicking GABA action in females modulates astrocytes accordingly. Speculation about and evidence in support of the functional significance of this dimorphism to adult reproductive functioning is the topic of this review.     

Roles of steroid sulfatase in brain and other tissues

Steroid sulfatase (EC 3.1.6.2) is an important enzyme involved in steroid hormone metabolism. It catalyzes the hydrolysis of steroid sulfates into their unconjugated forms. This action rapidly changes their physiological and biochemical properties, especially in brain and neural tissue. As a result, any imbalance in steroid sulfatase activity may remarkably influence physiological levels of active steroid hormones with serious consequences. Despite that the structure of the enzyme has been completely resolved there is still not enough information about the regulation of its expression and action in various tissues. In the past few years research into the enzyme properties and regulations has been strongly driven by the discovery of its putative role in the indirect stimulation of the growth of hormone-dependent tumors of the breast and prostate.     

Rapid actions of aldosterone: lymphocytes, vascular smooth muscle and endothelial cells.

The genomic theory of steroid action has been the unquestioned dogma for the explanation of steroid effects over the past four decades. Despite early observations on rapid steroid effects being clearly incompatible with this theory, only recently has nongenomic steroid action been recognized more widely and led to a critical reappraisal of unsolved questions about this dogma. Evidence for nongenomic steroid effects come from all fields of steroid research now, and mechanisms of agonist action are studied with regard to membrane receptors and second messengers involved. A prominent example of a receptor/effector-cascade for nongenomic steroid effects has been described for rapid aldosterone effects in various cell types, including lymphocytes, cultured vascular smooth muscle, and endothelial cells involving nonclassical membrane receptors with a high affinity for aldosterone, but not for cortisol, and phosphoinositide turnover. As another important second messenger, [Ca2+]i is consistently increased by aldosterone within 1-2 min. In vascular smooth muscle cells, calcium is released from perinuclear stores, while in endothelial cells a predominant increase of subplasmalemmal calcium is seen. Effects are half maximal at physiological concentrations of free aldosterone (0.1 nmol/L), while cortisol is inactive up to 0.1 micromol/L; the classical mineralocorticoid antagonist canrenone is ineffective in blocking the action of aldosterone. The data show that intracellular signaling for nongenomic aldosterone effects also involves calcium, but pathways of cell activation may vary between different cell types. Future research will have to target the cloning of the first membrane receptor for steroids, and the evaluation of the clinical relevance of these rapid steroid effects.