Brain estrogen signaling effects acute modulation of acoustic communication behaviors: A working hypothesis

Although estrogens are widely considered circulating “sex steroid hormones” typically associated with female reproduction, recent evidence suggests that estrogens can act as local modulators of brain circuits in both males and females. The functional implications of this newly characterized estrogen signaling system have begun to emerge. This essay summarizes evidence in support of the hypothesis that the rapid production of estrogens in brain circuits can drive acute changes in both the production and perception of acoustic communication behaviors. These studies have revealed two fundamental neurobiological concepts: (1) estrogens can be locally produced in brain circuits, independent of levels in nearby circuits and in the circulation and (2) estrogens can have very rapid effects within these brain circuits to modulate social vocalizations, acoustic processing, and sensorimotor integration. This vertebrate‐wide span of research, including vocalizing fishes, amphibians, and birds, emphasizes the importance of comparative model systems in understanding principles of neurobiology.     

Tissue specific hormonal regulation of the rat angiotensinogen gene expression

Angiotensinogen is the precursor of the most potent pressor substance, angiotensin. Angiotensinogen levels are increased in some forms of human hypertension. Its levels are modulated by various factors including glucocorticoids, estrogens, and prostaglandins. We have recently reported the isolation of a human angiotensinogen cDNA clone and provided evidence for the presence of its mRNA in rat liver, brain, and heart. In this communication we report the effect of dexamethasone and estradiol on angiotensinogen mRNA levels in rat liver, brain, and heart. Our results indicate that angiotensinogen levels are increased to different extents in these three tissues as a result of glucocorticoid or estrogen administration.     

Role of androgens and the androgen receptor in remodeling of spine synapses in limbic brain areas

Accumulating evidence indicate that structural synaptic plasticity in limbic areas plays a vital role not only in normal brain functions, such as cognition and mood, but also in the development of neurological and mental disorders. We have learned from studies investigating neuronal remodeling that estrogens have an exceptional synaptogenic potential that seems to be specific to limbic areas of the adult female brain. On the other hand, structural synaptic plasticity in the adult male brain and the synaptogenic effect of androgens received relatively little attention. During the last five years, the Leranth laboratory provided conclusive evidence that the hippocampus and prefrontal cortex of adult male rodents and non-human primates retain considerable structural synaptic plasticity similar to the female, and that androgens are capable of inducing spine synapse growth in both the hippocampus and prefrontal cortex similar to estrogens. Our recent work also demonstrates that androgen-induced remodeling of spine synapses in the prefrontal cortex of adult male rats is dependent, at least to some extent, on functional androgen receptors, while being entirely independent of the androgen receptor in the hippocampus. Based on these findings and on their many beneficial effects, we believe that androgens hold a great and undeservingly neglected therapeutic potential that could be employed to reverse synaptic pathology in various neurocognitive and neuropsychiatric disorders.     

Quantitative Analysis of Long-Form Aromatase mRNA in the Male and Female Rat Brain

In vitro studies show that estrogens acutely modulate synaptic function in both sexes. These acute effects may be mediated in vivo by estrogens synthesized within the brain, which could fluctuate more rapidly than circulating estrogens. For this to be the case, brain regions that respond acutely to estrogens should be capable of synthesizing them. To investigate this question, we used quantitative real-time PCR to measure expression of mRNA for the estrogen-synthesizing enzyme, aromatase, in different brain regions of male and female rats. Importantly, because brain aromatase exists in two forms, a long form with aromatase activity and a short form with unknown function, we targeted a sequence found exclusively in long-form aromatase. With this approach, we found highest expression of aromatase mRNA in the amygdala followed closely by the bed nucleus of the stria terminalis (BNST) and preoptic area (POA); we found moderate levels of aromatase mRNA in the dorsal hippocampus and cingulate cortex; and aromatase mRNA was detectable in brainstem and cerebellum, but levels were very low. In the amygdala, gonadal/hormonal status regulated aromatase expression in both sexes; in the BNST and POA, castration of males down-regulated aromatase, whereas there was no effect of estradiol in ovariectomized females. In the dorsal hippocampus and cingulate cortex, there were no differences in aromatase levels between males and females or effects of gonadal/hormonal status. These findings demonstrate that long-form aromatase is expressed in brain regions that respond acutely to estrogens, such as the dorsal hippocampus, and that gonadal/hormonal regulation of aromatase differs among different brain regions.     

Neurocognitive effects of estrogens across the adult lifespan in nonhuman primates: State of knowledge and new perspectives

This article is part of a Special Issue "Estradiol and cognition".This review discusses the unique contribution of nonhuman primate research to our understanding of the neurocognitive effects of estrogens throughout the adult lifespan in females. Mounting evidence indicates that estrogens affect many aspects of hippocampal, prefrontal and cholinergic function in the primate brain and the underlying mechanisms are beginning to be elucidated. In addition, estrogens may also influence cognitive function indirectly, via the modulation of other systems that impact cognition. We will focus on the effects of estrogens on sleep and emphasize the need for primate models to better understand these complex interactions. Continued research with nonhuman primates is essential for the development of therapies that are optimal for the maintenance of women's cognitive health throughout the lifespan.     

Mitochondrial mechanisms of estrogen neuroprotection

Mitochondria have become a primary focus in our search not only for the mechanism(s) of neuronal death but also for neuroprotective drugs and therapies that can delay or prevent Alzheimer's disease and other chronic neurodegenerative conditions. This is because mitochrondria play a central role in regulating viability and death of neurons, and mitochondrial dysfunction has been shown to contribute to neuronal death seen in neurodegenerative diseases. In this article, we review the evidence for the role of mitochondria in cell death and neurodegeneration and provide evidence that estrogens have multiple effects on mitochondria that enhance or preserve mitochondrial function during pathologic circumstances such as excitotoxicity, oxidative stress, and others. As such, estrogens and novel non-hormonal analogs have come to figure prominently in our efforts to protect neurons against both acute brain injury and chronic neurodegeneration.     

The distribution and regulation of aromatase activity in the central nervous system

Our data demonstrate that androgen-dependent AA is found in areas of the brain that are essential for the neuroendocrine control of gonadotropin secretion and sexual behavior. However, until we know more about the neurons that contain AA, e.g., whether they are peptidergic or catecholaminergic, we can not speculate about the neuronal functions that depend on local estrogen formation. In fact, the association of AA with neurons and not glia has only recently been demonstrated. That estrogens and androgens synergize in the regulation of various neuroendocrine functions has been known for many years, but an explanation of the synergism at the cellular level was not available. One explanation for this synergism may lie in our recent observation that the administration of exogenous estradiol to castrated rats increases androgen-receptor concentrations in specific brain nuclei. Perhaps locally formed estrogens work in a similar fashion to regulate androgen receptors in the brain of the intact male.     

Nuclear progesterone receptors are up-regulated by estrogens in neurons and radial glial progenitors in the brain of zebrafish

In rodents, there is increasing evidence that nuclear progesterone receptors are transiently expressed in many regions of the developing brain, notably outside the hypothalamus. This suggests that progesterone and/or its metabolites could be involved in functions not related to reproduction, particularly in neurodevelopment. In this context, the adult fish brain is of particular interest, as it exhibits constant growth and high neurogenic activity that is supported by radial glia progenitors. However, although synthesis of neuroprogestagens has been documented recently in the brain of zebrafish, information on the presence of progesterone receptors is very limited. In zebrafish, a single nuclear progesterone receptor (pgr) has been cloned and characterized. Here, we demonstrate that this pgr is widely distributed in all regions of the zebrafish brain. Interestingly, we show that Pgr is strongly expressed in radial glial cells and more weakly in neurons. Finally, we present evidence, based on quantitative PCR and immunohistochemistry, that nuclear progesterone receptor mRNA and proteins are upregulated by estrogens in the brain of adult zebrafish. These data document for the first time the finding that radial glial cells are preferential targets for peripheral progestagens and/or neuroprogestagens. Given the crucial roles of radial glial cells in adult neurogenesis, the potential effects of progestagens on their activity and the fate of daughter cells require thorough investigation.     

Extra-nuclear signaling of ERα to the actin cytoskeleton in the central nervous system

Cell morphology is controlled by a complex and redundant array of intracellular signaling pathways devoted to the regulation of the actin cytoskeleton and of its relationship with the cell membrane and the extracellular matrix. Sex steroids are effective regulators of cell morphology and tissue organization, and recent evidence indicates that this is obtained through the regulation of the cytoskeleton. Intriguingly, many of these regulatory actions related to cell morphology are achieved through rapid, non-classical signaling of sex steroid receptors to kinase cascades, independently from nuclear alteration of gene expression or protein synthesis. The identification of the mechanistic basis for these rapid actions on cell cytoskeleton has special relevance for the characterization of the effects of sex steroids in physiological conditions, such as their role in the control of brain cell remodeling. Brain cell morphology is controlled by estrogens that regulate the development of neuron/neuron interconnections and dendritic spine density. This is thought to be critical for gender-specific differences in brain function and dysfunction. The recent advancements in the characterization of the molecular basis of the extra-nuclear signaling of estrogen helps to understand the role of estrogen in the brain, and may in the future turn out to be of relevance for clinical purposes. This review highlights the regulatory effects on the cytoskeleton and cell morphology of estrogens as well as the recent advances in the characterization of these mechanisms, providing insights and working hypotheses on possible clinical applications for the modulation of these pathways in the central nervous system.     

Glial cells more than support cells?

Glial cells are the most abundant cells in the human brain and have long been considered as passive supporting cells for neurons. In contrast to the extensive studies on various neuronal functions in the nervous system, we still have limited knowledge about glial cells. Recently a number of pioneering studies have provided convincing evidence that glia play active roles in development and function of the central nervous system. This review discusses recent advances in our understanding of the molecular mechanisms underlying glial cell differentiation. We then highlight some of the novel findings about glial function, i.e. the role of glia in synaptogenesis and the intricate relationship between astrocytes and adult neural stem cells. Finally, we summarize the emerging studies that implicate abnormalities in the formation or maintenance of glia leading to severe brain diseases, such as Alexander disease, glioblastoma and multiple sclerosis, and potential therapeutic strategies to tackle these diseases.     

Estrogen and prostate cancer: an eclipsed truth in an androgen-dominated scenario

Prostate cancer is the commonest non-skin cancer in men. Incidence and mortality rates of this tumor vary strikingly throughout the world. Although several factors have been implicated to explain this remarkable variation, lifestyle and dietary factors may play a dominant role, with sex hormones behaving as intermediaries between exogenous factors and molecular targets in development and progression of prostate cancer. Human prostate cancer is generally considered a paradigm of androgen-dependent tumor; however, estrogen role in both normal and malignant prostate appears to be equally important. The association between plasma androgens and prostate cancer remains contradictory and mostly not compatible with the androgen hypothesis. Similar evidence apply to estrogens, although the ratio of androgen to estrogen in plasma declines with age. Apart from methodological problems, a major issue is to what extent circulating hormones can be considered representative of their intraprostatic levels. Both nontumoral and malignant human prostate tissues and cells are endowed with key enzymes of steroid metabolism, including 17betahydroxysteroid dehydrogenase (17betaHSD), 5beta-reductase, 3alpha/3betaHSD, and aromatase. A divergent expression and/or activity of these enzymes may eventually lead to a differential prostate accumulation of steroid derivatives having distinct biological activities, as it occurs for hydroxylated estrogens in the human breast. Locally produced or metabolically transformed estrogens may differently affect proliferative activity of prostate cancer cells. Aberrant aromatase expression and activity has been reported in prostate tumor tissues and cells, implying that androgen aromatization to estrogens may play a role in prostate carcinogenesis or tumor progression. Interestingly, many genes encoding for steroid enzymes are polymorphic, although only a few studies have supported their relation with risk of prostate cancer. In animal model systems estrogens, combined with androgens, appear to be required for the malignant transformation of prostate epithelial cells. Although the mechanisms underlying the hormonal induction of prostate cancer in experimental animals remain uncertain, there is however evidence to support the assumption that long term administration of androgens and estrogens results in an estrogenic milieu in rat prostates and in the ensuing development of dysplasia and cancer. Both androgen and estrogen have been reported to stimulate proliferation of cultured prostate cancer cells, primarily through receptor-mediated effects. As for estrogens, the two major receptor types, ERalpha and ERbeta, are expressed in both normal and diseased human prostate, though with a different cellular localization. Since these two receptors are different in terms of ligand binding, heterodimerization, transactivation, and estrogen response element activity, it is likely that an imbalance of their expression may be critical to determine the ultimate estrogen effects on prostate cancer cells. In prostate cancer, ERbeta activation appears to limit cell proliferation directly or through ERalpha inhibition, and loss of ERbeta has been consistently associated with tumor progression. Several splicing variants of both ERalpha and ERbeta exist. Little is known about their expression and function in the human prostate, although reciprocal regulation and interaction with gene promoter both warrant further investigation. In summary, although multiple consistent evidence suggests that estrogens are critical players in human prostate cancer, their role has been only recently reconsidered, being eclipsed for years by an androgen-dominated interest.     

Soy isoflavones and cognitive function

There is growing interest in the physiological functions of soy isoflavones, especially in whether they affect cognitive function and have beneficial effects on neurodegenerative diseases. Here we review the recent evidence from clinical and experimental studies supporting a role for soy isoflavones in cognitive function. Soy isoflavones may mimic the actions and functions of estrogens on brain, and they have been shown to have positive effects on the cognitive function in females; however, studies on their effects on spatial memory have not provided consistent results in males. Although data from humans, cultures, and animal models are currently insufficient for elucidating the metabolism of soy isoflavone actions on cognitive function and the nervous system, we suggest two putative pathways; (1) an estrogen receptor-mediated pathway and (2) via the inhibition of tyrosine kinase, in particular by genistein, which is one of the soy isoflavones. Although soy isoflavones appear to have a positive effect on brain function, further research is needed to determine not only the efficacy but also the safety of soy isoflavones on the nervous system and cognitive function.     

Phosphorylation processes mediate rapid changes of brain aromatase activity

The enzyme aromatase (also called estrogen synthase) that catalyzes the transformation of testosterone (T) into estradiol plays a key limiting role in the action of T on many aspects of reproduction. The distribution and regulation of aromatase in the quail brain has been studied by radioenzyme assays on microdissected brain areas, immunocytochemistry, RT-PCR and in situ hybridization. High levels of aromatase activity (AA) characterize the sexually dimorphic, steroid-sensitive medial preoptic nucleus (POM), a critical site of T action and aromatization for the activation of male sexual behavior. The boundaries of the POM are clearly outlined by a dense population of aromatase-containing cells as visualized by both immunocytochemistry and in situ hybridization histochemistry. Aromatase synthesis in the POM is controlled by T and its metabolite estradiol, but estradiol receptors alpha (ER) are not normally co-localized with aromatase in this brain area. Estradiol receptor beta (ERβ) has been recently cloned in quail and localized in POM but we do not yet know whether ERβ occurs in aromatase cells. It is therefore not known whether estrogens regulate aromatase synthesis directly or by affecting different inputs to aromatase cells as is the case with the gonadotropin releasing hormone neurons. The presence of aromatase in presynaptic boutons suggests that locally formed estrogens may exert part of their effects by non-genomic mechanisms at the membrane level. Rapid effects of estrogens in the brain that presumably take place at the neuronal membrane level have been described in other species. If fast transduction mechanisms for estrogen are available at the membrane level, this will not necessarily result in rapid changes in brain function if the availability of the ligand does not also change rapidly. We demonstrate here that AA in hypothalamic homogenates is rapidly down-regulated by exposure to conditions that enhance protein phosphorylation (addition of Ca²⁺, Mg²⁺, ATP). This inhibition is blocked by kinase inhibitors which supports the notion that phosphorylation processes are involved. A rapid (within minutes) and reversible regulation of AA is also observed in hypothalamic explants incubated in vitro and exposed to high Ca²⁺ levels (K⁺-induced depolarization, treatment by thapsigargin, by kainate, AMPA or NMDA). The local production and availability of estrogens in the brain can therefore be rapidly changed by Ca²⁺ based on variation in neurotransmitter activity. Locally-produced estrogens are as a consequence available for non-genomic regulation of neuronal physiology in a manner more akin to the action of a neuropeptide/neurotransmitter than previously thought.     

昆虫中存在高等动物性激素吗？

性激素在调控高等动物附性器官的发育和成熟, 激发和维持第二性征以及增进两性细胞的结合和孕育能力等方面有不可替代的作用。性激素包括雌性激素和雄性激素, 主要存在于哺乳动物中。随着检测技术的不断进步, 越来越多的研究显示性激素并非高等动物所特有。包括一些昆虫在内的无脊椎动物中同样含有性激素, 家蚕Bombyx mori、欧洲兔虱Spilopsyllus cuniculi等昆虫被高等动物性激素或者性激素类似物处理过后能产生一定的应答, 且有研究报道昆虫中同样含有羟基固醇脱氢酶等高等动物催化合成性激素的某些酶类。本文以雌激素为例, 在全面总结高等动物雌激素在昆虫中的鉴定、代谢、生理作用等相关研究的基础上, 分析昆虫对高等动物性激素的合成、应答以及高等动物性激素在昆虫中作为昆虫“性激素”的可能性。雌激素作为高等动物的主要雌性激素, 在很多昆虫组织或个体提取物中同样存在。目前的研究已经证实家蚕等昆虫能代谢雌激素, 用雌激素处理某些昆虫后也能影响该昆虫的生理过程。雌激素对高等动物许多生理过程都具有显著的调节作用, 但主要还是作为性激素调节性别相关的生理过程。为了明确脊椎动物雌激素在昆虫中是否存在且发挥着性激素功能, 相关的研究可以主要从3个方面着手: (1) 昆虫中能否检测到高等动物雌激素类似物存在; (2) 雌激素是否也能让昆虫产生雌性相关的生理应答,从昆虫中提取的雌激素类似物能否令高等动物产生雌性特异的响应; (3)昆虫是否能够合成雌激素, 体内是否存在参与催化合成雌激素的酶类。     

Trajectories and phenotypes with estrogen exposures across the lifespan: What does Goldilocks have to do with it?

This article is part of a Special Issue “Estradiol and cognition”.Estrogens impact the organization and activation of the mammalian brain in both sexes, with sex-specific critical windows. Throughout the female lifespan estrogens activate brain substrates previously organized by estrogens, and estrogens can induce non-transient brain and behavior changes into adulthood. Therefore, from early life through the transition to reproductive senescence and beyond, estrogens are potent modulators of the brain and behavior. Organizational, reorganizational, and activational hormone events likely impact the trajectory of brain profiles during aging. A “brain profile,” or quantitative brain measurement for research purposes, is typically a snapshot in time, but in life a brain profile is anything but static — it is in flux, variable, and dynamic. Akin to this, the only thing continuous and consistent about hormone exposures across a female's lifespan is that they are noncontinuous and inconsistent, building and rebuilding on past exposures to create a present brain and behavioral landscape. Thus, hormone variation is especially rich in females, and is likely the destiny for maximal responsiveness in the female brain. The magnitude and direction of estrogenic effects on the brain and its functions depend on a myriad of factors; a “Goldilocks” phenomenon exists for estrogens, whereby if the timing, dose, and regimen for an individual are just right, markedly efficacious effects present. Data indicate that exogenously-administered estrogens can bestow beneficial cognitive effects in some circumstances, especially when initiated in a window of opportunity such as the menopause transition. Could it be that the age-related reduction in efficacy of estrogens reflects the closure of a late-in-life critical window occurring around the menopause transition? Information from classic and contemporary works studying organizational/activational estrogen actions, in combination with acknowledging the tendency for maximal responsiveness to cyclicity, will elucidate ways to extend sensitivity and efficacy into post-menopause.     

Oestrogènes et reproduction masculine

The role of estrogen on male reproductive function has become clearer in the last decade. During these years the study of the effect of testosterone, estrogen or an aromatase inhibitor in hypogonadal men provided a first evidence of the effects of estrogens in the regulation of gonadotropin secretion. At the same time, the development of a line of transgenic male mice lacking estrogen receptor α, estrogen receptor β or aromatase gene provided further evidence about the role of estrogens not only in the regulation of gonadotropin secretion, but also on the effects of estrogens on testicular function and development. A confirmation of these actions of estrogens came from the observation of naturally occurring mutations of the estrogen receptor and of the aromatase gene in human males. Based on these data it has been demonstrated that estrogens are major regulators of gonadotropin secretion acting both at pituitary and hypotalamic level. The presence in the human reproductive structures of estrogen receptor α, estrogen receptor β and the aromatase enzyme indicates the existence of receptor α, estrogen receptor β or aromatase estrogen actions at this level. Anyway, the precise role of estrogens in testicular development and function and on the regulation of human spermatogenesis has not yet been precisely clarified.