Search Results

Avian studies have played a pivotal role in our appreciation of the importance of brain aromatization, the mechanics of neuroestrogen production, and the roles of neuroestrogens in organization of the vertebrate brain and the activation of diverse behaviors. Studies across bird species have also unveiled complexity in the cellular and subcellular distributions of aromatase in brain as well as the modes of neuroestrogen action. With a focus on studies of both songbirds and nonsongbirds, this chapter reviews many of the advances made toward our understanding of aromatase neurobiology derived from avian studies.

In the brain, testosterone (T) can be metabolized into estradiol via the action of the aromatase enzyme, and into 5α-dihydrotestosterone via the action of the 5α-reductase (5αR) enzyme. This chapter discusses aromatase and 5αR in reptiles, with a focus on green anole lizards. The chapter examines the role of aromatase and 5αR on reproductive behavior in this species. Next the chapter examines the whole brain activity of aromatase and 5αR, as well as the mRNA distribution of these enzymes in three brain areas critical for reproduction: the preoptic area, amygdala, and ventromedial hypothalamus. Finally the chapter discusses the expression of these enzymes in juvenile anoles. Overall, the experiments presented here highlight the importance of comparative work and lay groundwork for future research that will ascertain the role of these enzymes in anoles and the extent of their regulation by T.

The red-sided garter snake (RSGS) exhibits a dissociated reproductive pattern, mating when gonads are inactive. Although it is now recognized that sex steroid hormone plasma concentrations remain elevated throughout low temperature dormancy (LTD) and at the beginning of the breeding season, the only cue found to initiate courtship in the RSGS is a period of LTD with courtship intensity correlated to the length of dormancy. In male RSGS, aromatase immunoreactive (ARO-ir) cells were found throughout the forebrain with large immunoreactive cells concentrated in regions essential for the control of reproductive behaviors. Aromatase activity (AA) in the RSGS brain varied seasonally as well as regionally with the highest activity in the anterior hypothalamus preoptic area (AHPOA) occurring in fall before LTD. Recen data suggest a mechanism by which accumulation of estrogenic metabolites within pathways controlling courtship and mating is critical for activation of reproductive behavior on emergence from LTD.

Estrogens are ubiquitous hormones that are now known to have profound effects in the brain of both males and females across species. Available clinical and preclinical data indicate the potential for estrogens and nonfeminizing estrogens mimics to have neurotrophic, neuroprotective, and psychoprotective effects that hold promise for the treatment of brain disorders that affect men as well as women. This chapter develops the argument that sexually dimorphic responses to estrogens in the intact or diseased brain arise to a large extent from sex differences in the organization of the underlying circuitry, and it also addresses the the relative contributions of systemically and centrally generated estrogens to brain function in both normal and disrupted states. Advancement of our understanding of these factors are of prime importance if we are to realize the full translational potential of manipulating brain estrogenic activity for promoting human mental health and well-being, which current studies predict will require a sex-specific approach.

The central role of neuronal aromatase activity in masculinization of the rodent brain has been firmly established for almost 40 years, yet the myriad of mechanisms by which the principal product of aromatization, estradiol, organizes the neural substrate to predispose adult behavior continue to be elucidated. Unexpected roles for inflammatory mediators and components of the immune system in sexual differentiation elucidate novel principles of brain development. Long-standing puzzles associated with female brain development, both feminization and defeminization, are being solved by unexpectedly rapid and developmentally delayed actions of estradiol, respectively. Neurosteroidogenesis in discrete brain regions, culminating with estradiol but possibly beginning with cholesterol, hints at additional roles for aromatization in brain development outside the confounds of the classical organizational/activational hypothesis and affecting cognitive regions such as the cortex, hippocampus, and cerebellum. Collectively, it is clear that we are far from the final chapter in determining how aromatization influences brain and behavior.

Birds show a rich array of sexually differentiated behavior. Research on two species, the Japanese quail and the zebra finch, is the source of most of what is known to date about the role of hormones such as estrogens in the development of those sex differences. In both species, the gonads and brains of very young birds (embryos, nestlings) produce estrogens, and experimental manipulations of estrogens early in development have profound organizational effects on adult behavior, supporting a role for aromatase in the sexual differentiation process. Estrogens seem to be important for sexual differentiation of behavior in both Japanese quail and zebra finches, but how and where are still unclear. Newer genomic and other molecular resources and techniques can be expected to lead to significant progress in both species.

Beside their action at the genomic level, estrogens such as 17β-estradiol (E2) also activate rapid and transient cellular, physiological, and behavioral changes. Aromatase is the key limiting enzyme in the production of estrogens and the rapid modulation of this enzymatic activity could produce rapid changes in local E2 concentrations. The mechanisms that might mediate such rapid enzymatic changes are thus currently under intense scrutiny. Recent studies in our laboratory indicate that brain aromatase activity is rapidly inhibited by an increase in intracellular calcium concentration that results from potassium-induced depolarization or from the activation of glutamatergic receptors. Altogether, the phosphorylation/dephosphorylation processes affecting aromatase activity provide a new general mechanism by which the concentration of estrogens can be rapidly altered in the brain and other tissues.

The mammalian brain produces low levels of estrogens relative to the ovary and placenta, but by restricting synthesis to the site of estrogen action is able to exert powerful effects on neural development and function. The final step in estrogen production is the conversion of androgens to estrogens by cytochrome P450 aromatase. Recent evidence that hippocampus is capable of synthesizing estrogen de novo from cholesterol suggests a new paradigm for mammals in which sex steroids act independently of the gonads to regulate brain functions. In general, aromatase exhibits a dynamic and complex regulation that varies regionally, as well as with an animal’s age, sex, and physiologic status. This chapter summaries our current understanding of the distribution and regulation of aromatase in the mammalian brain and describes classic as well as novel functions for local estrogen synthesis in the brain.

Pigs have three CYP19 genes encoding functional paralogues of aromatase cytochrome P450 expressed tissue specifically in the gonads/hypothalamus, placenta, and preimplantation blastocyst. Gene duplication is predicted to have relaxed selection pressure and allowed evolution of enzyme function. All isozymes catalyze estrogen synthesis. However, the “gonadal/hypothalamic” form (ghP450arom) is unique among mammalian aromatases in also synthesizing a nonaromatizable, biopotent testosterone metabolite, 1OH-testosterone (1OH-T) that is hypothesized to have promoted increased ovulation rate and litter size. High ghP450arom expression in porcine testis facilitates study of differential regulation in hypothalamus and gonads that is not possible in other species. These, the first such studies in pig brain, demonstrate unusual aspects of P450arom expression and regulation in the hypothalamus, offering promise of gaining better insight into roles of P450arom in reproductive function.

Aromatase catalyzes the last step in the biosynthesis of estrogens in humans as well as in other species. The regional distribution and cellular and subcellular expression of human brain aromatase have been studied using different complementary methodologies, including in vivo positron emission tomography, immunohistochemistry, polymerase chain reaction (PCR), and enzyme activity assays. The regional and cellular distribution of human brain aromatase have some unique features compared with other primate and nonprimate species, including high levels in thalamus and more ubiquitous distribution among different cell types. These differences may underlie the involvement of estrogen in a range of nonreproductive behaviors and functions unique to humans.

Brain aromatase in fish is an exciting research topic because of several unconventional features that challenge the established view based on studies in other vertebrates. First, the brain of teleost fish exhibits a high degree of aromatase activity, especially in sexually mature animals. Given the emerging roles of estrogens in neurogenesis, the unique features of the adult fish brain suggest that, in addition to classical functions on brain sexual differentiation and sexual behavior, aromatase expression in radial glial cells could be involved in the modulation of the high proliferative activity in the brain of fish.

In the 1970s Carlos Beyers and his colleagues demonstrated that androgens that cannot be aromatized to estrogen also do not mimic testosterone in some test situations. These early tests of the “aromatization” hypothesis led to three sets of predictions to test the hypothesis: (1) If estrogen metabolites of testosterone are necessary for it to facilitate sexual behavior, then androgens that are not aromatized to estradiol will not sustain male or female sexual behavior. (2) If estrogen metabolites of testosterone are necessary to facilitate sexual behavior, then antiestrogen compounds should block testosterone facilitation of sexual behavior. (3) If estrogen metabolites of testosterone are required for facilitation of sexual behavior, compounds that inhibit the aromatase enzyme should block testosterone facilitation of sexual behavior. These three predictions directed much of the research on this topic for nearly two decades and led to increasingly better controlled experiments.

About 1 of every 8 women will develop breast cancer during her lifetime, and approximately 250,000 new cancer cases are expected annually as of 2017. Of those breast cancers, approximately 60% to 75% will express estrogen receptors, suggesting that estrogens are likely to promote growth of those tumors. Because the use of inhibitors of the synthesis of estrogens is the adjuvant treatment of choice for many women, it is essential that we understand the potential adverse effects on quality of life of those treatments. This review addresses the role of estrogens locally synthesized in the brain in laboratory animals and women, the effects of estrogens on cognitive function, the effects of synthesis blockers on cognitive function, and the limitations in performing experiments that will give us strong confidence in the results and conclusions.

Most of the established reproductive risk factors for breast cancer, like age at menarche or parity, are not appropriate for public health intervention. Several lines of evidence, like the associations with birthweight and early exposure to radiation, support an important influence of early-life events on subsequent breast cancer risk. The best established modifiable risk factors for the disease include postmenopausal hormone use, moderate alcohol intake, and adult weight gain. More recently, we have come to appreciate that instead of a single disease, breast cancer is rather a heterogeneous group of subtypes with different etiologies. Yet the wealth of available epidemiologic information can be synthesized into a consistent and testable, albeit still hypothetical, causal model. With our increasing knowledge on the relation between endogenous hormones and breast cancer, and the development of selective estrogen receptor modulators, as well as aromatase inhibitors, chemoprevention will likely become more common in the future.

Research from the past decade has begun to shed light on the neural mechanisms through which the potent estrogen 17β‎-estradiol (E2) regulates the formation of memories. Consolidation is a rapid process which appears to take advantage of the ability of estrogen receptors to quickly trigger cell signaling alterations that increase gene expression, local protein synthesis, and dendritic spinogenesis. This chapter discusses recent advances in understanding how the rapid effects of E2 on the hippocampus influence memory consolidation in female and male rodents and examines new directions for exploring similar mechanisms in other interconnected brain regions.

Birds are excellent animal models in studies of cognition, neuroplasticity, neuroendocrinology, and sex differences in behavior. Experiments with diverse avian species have revealed a potent modulation of neuroanatomy and complex brain function by steroids, both during development and adulthood. This chapter describes some of the foundational and more recent developments in the estrogenic modulation of spatial memory function, as well as related studies regarding effects of the steroid on auditory discrimination and memory for song in passerines. More specifically, the chapter describes the evolution of our understanding of how locally synthesized and rapidly acting estradiol modulates higher cognitive functions in this varied and important vertebrate class, as well as the mechanisms whereby this synaptic aromatization may underlie the learning and retention of these behaviors.