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.     

Steroid Hormone Actions on the Brain: When Is the Genome Involved?

It has become customary to distinguish between so-called "genomic" actions of steroid hormones involving intracellular receptors and "non-genomic" effects of steroids that involve putative cell surface receptors. Whereas there is no doubt that this distinction has considerable validity, it does not go far enough in addressing the variety of mechanisms that steroid hormones use to produce their effects on cells. This is because cell surface receptors may signal changes in gene expression, while genomic actions sometimes affect neuronal excitability, often doing so quite rapidly. Moreover, steroid hormones and neurotransmitters may operate together to produce effects, and sometimes these effects involve collaborations between groups of neurons. As illustrations. evidence is reviewed in this article that a number of steroid actions in the hippocampus involves the co-participation of excitatory amino acids. These interactions are evident for the regulation of synaptogenesis by estradiol in the CA1 pyramidal neurons or hippocampus and for the induction of dendritic atrophy of CA3 neurons by repeated stress as well as by glucocorticoid injections. In addition, neurogenesis in the adult and developing dentate gyrus is "contained" by adrenal steroids as well as by excitatory amino acids. In each of these three examples, NMDA receptors are involved. These results not only point to a high degree of interdependency between certain neurotransmitters and the actions of steroid hormones but also emphasize the degree to which structural plasticity is an important aspect of steroid hormone action in the adult as well as developing nervous system.     

Introduction to the special issue on Neuroprotection by steroids: New perspectives

This special issue of the Journal of Neurocytology focuses on the cellular and molecular mechanisms of neuroprotection by steroid hormones. Clinical and basic science studies have led to a deeper understanding of these novel and non-reproductive actions of steroids. New findings on neuroprotective effects of steroids in the peripheral and central nervous system and the discovery of new molecular targets and new signaling pathways of steroids has expanded, and at the same time complicated, the search for the mechanisms involved in the neuroprotection by these molecules. We considered that now is an ideal time to bring together the different views, experimental models and methodological approaches that constitute this emerging field.     

Neurotransmitter-controlled steroid hormone receptors in the central nervous system

Results are discussed indicating that neurotransmitters affect steroid hormone activity not only by controlling via neuroendocrine events the hypophysial-gonadal and hypophysial-adrenal axes, but also by modulating cell responsiveness to steroids in target cells. Hyper- or hypoactivity of pineal nerves result in enhancement or impairment of estradiol and testosterone effects on pineal metabolism in vivo and in vitro. Pineal cytoplasmic and nuclear estrogen and androgen receptors are modulated by norepinephrine released from nerve endings at the pinealocyte level. Neural activity affects the cycle of depletion-replenishment of pineal estrogen receptors following estradiol administration. Another site of modulation of steroid effects on the pinealocytes is the intracellular metabolism of testosterone and progesterone; nerve activity has a positive effect on testosterone aromatization and a negative effect on testosterone and progesterone 5α-reduction. NE activity on the pineal cells is mediated via β-adrenoceptors and cAMP. In the central nervous system information on the neurotransmitter modulation of steroid hormone action includes the following observations: (a) hypothalamic deafferentation depresses estrogen receptor levels in rat medial basal hypothalamus; (b) changes in noradrenergic transmission affect, via α-adrenoceptors, the estradiol-induced increase of cytosol progestin receptor concentration in guinea pig hypothalamus; (c) cAMP increases testosterone aromatization in cultured neurons from turtle brain; (d) electrical stimulation of dorsal hippocampus augments, and reserpine or 6-hydroxydopamine treatment decrease, corticoid binding in cat hypothalamus. In the adenohypophysis changes in dopaminergic input after median eminence lesions or bromocriptine treatment of rats result in opposite modifications of pituitary estrogen receptor levels. Therefore all these observations support the view that neurotransmitters can modulate the attachment of steroid hormones to their receptors in target cells.     

Gonadal and adrenal steroids regulate neurochemical and structural plasticity of the hippocampus via cellular mechanisms involving NMDA receptors

Summary 1. The hippocampus is an important brain structure for working and spatial memory in animals and humans, and it is also a vulnerable as well as plastic brain structure as far as sensitivity to epilepsy, ischemia, head trauma, stress, and aging.2. The hippocampus is also a target brain area for the actions of hormones of the steroid/thyroid hormone family, which traditionally have been thought to work by regulating gene expression. Genomic actions of steroid hormones involve intracellular receptors, whereas nongenomic effects of steroids involve putative cell surface receptors. Although this distinction is valid, it does not go far enough in addressing the variety of mechanisms that steroid hormones use to produce their effects on cells. This is because cell surface receptors may signal changes in gene expression, while genomic actions sometimes affect neuronal excitability, often doing so quite rapidly.3. Moreover, steroid hormones and neurotransmitters may operate together to produce effects, and sometimes these effects involve collaborations between groups of neurons. For example, a number of steroid actions in the hippocampus involve the coparticipation of excitatory amino acids. These interactions are evident for the regulation of synaptogenesis by estradiol in the CA1 pyramidal neurons of hippocampus and for the induction of dendritic atrophy of CA3 neurons by repeated stress as well as by glucocorticoid injections. In addition, neurogenesis in the adult and developing dentate gyrus is contained by adrenal steroids as well as by excitatory amino acids. In each of these three examples, NMDA receptors are involved.4. These results not only point to a high degree of interdependency between certain neurotransmitters and the actions of steroid hormones, but also emphasize the degree to which structural plasticity is an important aspect of steroid hormone action in the adult as well as developing nervous system.     

DHEA,PREG and Their Sulphate Derivatives on Plasma and Brain After CRH and ACTH Administration

The term neurosteroids applies to steroids that are synthesized in the nervous system, either de novo from cholesterol or from steroid hormone precursors. RIA was used to determine plasma and brain levels of the neurosteroids pregnenolone (PREG), ehydroepiandrosterone (DHEA), and their sulfate derivatives (PREG-S and DHEA-S) in male and female rats after administration of two typical stress hormones: corticotropin-releasing hormone (CRH) and adrenocorticotropin hormone (ACTH). In all cases, the parameters measured were detectable in plasma and brain. PREG, PREG-S, and DHEA increased significantly in plasma and brain after CRH and ACTH administration in males and females. Because neurosteroids play an important role in mammalian physiology, including that of humans, stress situations may alter the physiological functions regulated by these neurosteroids.     

Joint hormonal and sensory stimulation modulate neuronal number in adult canary brains

Treatment of adult female canaries with testosterone (T) causes them to produce male-typical vocalizations and results in striking growth of brain nuclei that control song behavior (Nottebohm, 1980). The song-control nucleus HVc (caudal nucleus of the ventral hyperstriatum) contains cells that concentrate testosterone or its metabolites, suggesting that steroid hormones may induce the growth of HVc directly by regulating the expression of specific genes in those HVc neurons that have steroid receptors. However, we have previously provided evidence that is inconsistent with the idea that steroids promote growth of HVc solely via a direct action on hormone receptors: testosterone treatment of deafened adult females results in very little growth of HVc, relative to T-treated hearing birds (Bottjer et al., 1986b). Thus, birds in the former group undergo very little overall growth of HVc despite high circulating levels of hormone. We show here that the slightly increased size of HVc in T-treated deaf birds is attributable to an increase in neuronal spacing; the greatly increased size of HVc in T-treated hearing birds is due to an increase in neuronal number as well as spacing. There was virtually no increase in number of HVc neurons in T-treated deafened birds relative to control groups, whereas T-treated hearing birds showed a marked increase in neuron number. The song-control nucleus RA (robust nucleus of the archistriatum), which receives direct afferent input from HVc, also increases in size in response to testosterone treatment. However, the volume of RA increases in both hearing and deafened birds; this increase is primarily due to an increase in neuronal spacing as well as a small increase in neuron number. These results demonstrate that the number of neurons in a specific vocal-control nucleus (HVc) can change dramatically in adult canaries and suggest that some synergistic action of hormonal and sensory stimulation is necessary to induce such a change.     

IGF-1 in the brain as a regulator of reproductive neuroendocrine function

Given the close relationship among neuroendocrine systems, it is likely that there may be common signals that coordinate the acquisition of adult reproductive function with other homeostatic processes. In this review, we focus on central nervous system insulin-like growth factor-1 (IGF-1) as a signal controlling reproductive function, with possible links to somatic growth, particularly during puberty. In vertebrates, the appropriate neurosecretion of the decapeptide gonadotropin-releasing hormone (GnRH) plays a critical role in the progression of puberty. Gonadotropin-releasing hormone is released in pulses from neuroterminals in the median eminence (ME), and each GnRH pulse triggers the production of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). These pituitary hormones in turn stimulate the synthesis and release of sex steroids by the gonads. Any factor that affects GnRH or gonadotropin pulsatility is important for puberty and reproductive function and, among these factors, the neurotrophic factor IGF-1 is a strong candidate. Although IGF-1 is most commonly studied as the tertiary peripheral hormone in the somatotropic axis via its synthesis in the liver, IGF-1 is also synthesized in the brain, within neurons and glia. In neuroendocrine brain regions, central IGF-1 plays roles in the regulation of neuroendocrine functions, including direct actions on GnRH neurons. Moreover, GnRH neurons themselves co-express IGF-1 and the IGF-1 receptor, and this expression is developmentally regulated. Here, we examine the role of IGF-1 acting in the hypothalamus as a critical link between reproductive and other neuroendocrine functions.     

Negative feedback regulation of the secretion and actions of gonadotropin-releasing hormone in males

This minireview considers the state of knowledge regarding the interactions of testicular hormones to regulate the secretion and actions of GnRH in males, with special focus on research conducted in rams and male rhesus monkeys. In these two species, LH secretion is under the negative feedback regulation of testicular steroids that act predominantly within the central nervous system to suppress GnRH secretion. The extent to which these actions of testicular steroids result from the direct actions of testosterone or its primary metabolites, estradiol or dihydrotestosterone, is unclear. Because GnRH neurons do not contain steroid receptors, the testicular steroids must influence GnRH neurons via afferent neurons, which are largely undefined. The feedback regulation of FSH is controlled by inhibin acting directly at the pituitary gland. In male rhesus monkeys, the feedback regulation of FSH secretion is accounted for totally by the physiologically relevant form of inhibin, which appears to be inhibin B. In rams, the feedback regulation of FSH secretion involves the actions of inhibin and testosterone and interactions between these hormones, but the physiologically relevant form of inhibin has not been determined. The mechanisms of action for inhibin are not known.     

Neurometamorphosis

This article introduces this special issue of the Journal of Neurobiology by reviewing several basic issues in metamorphosis as they specifically relate to the nervous system. It promotes the idea that metamorphic changes in the nervous system (neurometamorphosis) represent adaptive restructurings rather than recapitulations of evolutionary transitions. It introduces, but leaves unresolved, the question of whether neurometamorphosis is achieved primarily as a delayed phase of embryonic neurogenesis or as a special neurogenic period. It points out that respecification of old neurons and the addition of new neurons are the main contributory pathway of neural restructuring at metamorphosis, that respecification can be dramatic and seems to be preferred over the elimination and replacement of particular neurons. It also highlights the question of how much the central rewiring during metamorphosis is driven by trophic interactions with the changing body of the metamorphic animal and to what extent neurometamorphosis is driven by the direct action of metamorphic hormones on the neural elements themselves. Finally, this article introduces the question of the cellular and molecular pathways of neurometamorphosis, from the role of the nervous system in triggering the event to the receptor mediated changes in gene expression. Further details on all of these issues are to be found in the articles that make up the rest of this special issue.     

Neurometamorphosis

This article introduces this special issue of the Journal of Neurobiology by reviewing several basic issues in metamorphosis as they specifically relate to the nervous system. It promotes the idea that metamorphic changes in the nervous system (neurometamorphosis) represent adaptive restructurings rather than recapitulations of evolutionary transitions. It introduces, but leaves unresolved, the question of whether neurometamorphosis is achieved primarily as a delayed phase of embryonic neurogenesis or as a special neurogenic period. It points out that respecification of old neurons and the addition of new neurons are the main contributory pathway of neural restructuring at metamorphosis, that respecification can be dramatic and seems to be preferred over the elimination and replacement of particular neurons. It also highlights the question of how much the central rewiring during metamorphosis is driven by trophic interactions with the changing body of the metamorphic animal and to what extent neurometamorphosis is driven by the direct action of metamorphic hormones on the neural elements themselves. Finally, this article introduces the question of the cellular and molecular pathways of neurometamorphosis, from the role of the nervous system in triggering the event to the receptor mediated changes in gene expression. Further details on all of these issues are to be found in the articles that make up the rest of this special issue.     

Glial responses to steroids as markers of brain aging.

Glia mediate neuroendocrine and neuroimmune functions that are altered during the process of normal aging. The biological functions of glia are also important in synaptic remodeling and the loss of synaptic connections that occur during aging. These functions are carried out by changes in glia, including changes in shape, interactions with neurons and other glia, and gene expression. The predominant change that occurs in glia during aging is glial activation, which can progress to reactive gliosis in response to neurodegeneration. More markers are needed to distinguish normal and reactive glia. During aging, astrocytes hypertrophy and exhibit signs of metabolic activation, and astrocytic processes surround neurons. Microglia also become activated and subsets of activated microglial increase in number and may enter the phagocytic or reactive stage. Glial markers of brain aging and glial activation include glial fibrillary acidic protein (GFAP) and transforming growth factor (TGF)-beta1, which are increased in astrocytes and microglia, respectively. Steroids regulate the interactions between glia and neurons and glial gene expression, including GFAP and TGF-beta1. Therefore, changes in these parameters during aging may be due to altered steroid regulation. In general, the effects of steroids oppose the effects of aging. Recent data indicate that steroid treatment can decrease the expression of GFAP in the aged brain, yet GFAP is resistant to down-regulation by endogenous glucocorticoids. Cellular and molecular markers of glial activation are being used to determine how changes in neuroendocrine and neuroimmune regulation contribute to repair and functional recovery that may reverse synaptic loss and cognitive impairment during aging.     

Steroid effects on the gene expression of peripheral myelin proteins

The present article summarizes recent observations obtained in our laboratory which clearly indicate that sex steroids exert relevant effects on the peripheral nervous system. In particular, the following important points have emerged: (1) Steroids exert stimulatory actions on the synthesis of the proteins proper of the peripheral myelin (e.g., glycoprotein Po and peripheral myelin protein 22) in vivo and on the Schwann cells in culture; (2) in many cases the actions of hormonal steroids are not due to their native molecular forms but rather to their metabolites (e.g., dihydroprogesterone and tetrahydroprogesterone in the case of progesterone; dihydrotestosterone and 5 alpha-androstane-3 alpha,17 beta-diol in the case of testosterone); (3) the mechanism of action of the various steroidal molecules may involve both classical (progesterone and androgen receptors) and nonclassical steroid receptors (GABA(A) receptor); and finally, (4) the stimulatory action of steroid hormones on the proteins of the peripheral myelin might have clinical significance in cases in which the rebuilding of myelin is needed (e.g., aging, peripheral injury, demyelinating diseases, and diabetic neuropathy).     

The significance of steroid metabolism in human cancer

Epidemiological and clinical evidence suggests that steroid hormones are intimately involved in the natural history of many cancers, including those of the breast, endometrium and prostate. However, it has been difficult to demonstrate that progressive changes in tumour development are related to circulating levels of steroids. This may be because further metabolism of steroids occurs locally within the tumour and its adjacent host tissue. Using the breast as an example, data has been reviewed that such local metabolism may (a) markedly change the biological potency of steroid hormones and (b) be associated with the risk, presence, pathology, stage and hormone sensitivity of cancer. The implications of these findings are discussed including the need to identify factors which regulate steroid metabolism in peripheral tissue and tumours. In this way the potential to influence the microenvironment around and within tumour cells may be realized in favour of the patient.     

Steroid receptors in the brain: Topography and some functional implications

The anatomical localization of brain cells which concentrate steroid hormones or their metabolites was carried out by radioautographic procedures. Ovariectomized or adrenalectomized animals were injected with the appropriate tritiated hormones, and brain tissue was processed through procedures which minimize the removal or displacement of steroids. Target cells were characterized by the concentration and retention of radioactive hormone in their nuclei. For each mammalian steroid hormone, nuclear binding sites exist in populations of cells with a specific regional localization in the brain and in the pituitary. The distribution of estrogen target cells was remarkably similar in the brains of rodents and primates although some minor species differences existed. Heavily labeled cells were present in the preoptic region, the septum, the amygdala and the mediobasal hypothalamus. The localization of progestagen-concentrating cells in the rodent and galago brain was limited to two hypothalamic areas: the preoptic region and the mediobasal hypothalamus. Corticosterone target cells were situated in extrahypothalamic regions of the rat central nervous system such as the hippocampus, the septum, the amygdala and certain regions of the brain cortex. However, the synthetic glucocorticosteroid, dexamethasone, was mainly found in the pituitary cells and in some neurons and glial cells of the mediobasal hypothalamus. The distribution pattern of steroid-sensitive cells within the brain and the pituitary gland corresponds to sites which are involved in the neuroendocrine processes regulating reproduction, including gonadotropin secretion and sexual behavior.     

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.