Aromatase in the Human Brain

[madman]

Abstract

The aromatase cytochrome P450 (P450arom) enzyme, or estrogen synthase, which is coded by the CYP19A1 gene, is widely expressed in a subpopulation of excitatory and inhibitory neurons, astrocytes, and other cell types in the human brain. Experimental studies in laboratory animals indicate a prominent role of brain aromatization of androgens to estrogens in regulating different brain functions. However, the consequences of aromatase expression in the human brain remain poorly understood. Here, we summarize the current knowledge about aromatase expression in the human brain, abundant in the thalamus, amygdala, hypothalamus, cortex, and hippocampus, and discuss its role in the regulation of sensory integration, body homeostasis, social behavior, cognition, language, and integrative functions. Since brain aromatase is affected by neurodegenerative conditions and may participate in sex-specific manifestations of autism spectrum disorders, major depressive disorder, multiple sclerosis, stroke, and Alzheimer’s disease, we discuss future avenues for research and potential clinical and therapeutic implications of the expression of aromatase in the human brain.




Introduction

Part of the actions of androgens in the body is exerted after their conversion to estrogens by the enzyme aromatase cytochrome P450 (P450arom) or estrogen synthase. The enzyme converts androst-4-ene-3,17-dione (androstenedione) and testosterone into estrone and estradiol, respectively (Fig. 1). Half a century ago, Naftolin and collaborators reported the existence of aromatase activity in samples of human brain tissue isolated from male fetuses.1,2 The implication of this finding was that aromatizable androgens can regulate human brain function not only through the androgen receptors (AR) but also by the activation of estrogen receptors (ERs) after their conversion to estrogenic metabolites. In addition, although aromatase activity in the brain probably does not affect the overall concentration of androgens, it is plausible that by decreasing the levels of androgens at very specific intracellular domains, aromatase activity may also contribute toward modulating AR signaling in the human brain.

Studies in different vertebrate species, from fish to mammals, have shown that aromatase is expressed in the developing and adult brain and the spinal cord of both males and females. Central aromatase activity participates in a variety of functions that are not restricted to the control of the neuroendocrine axis and the regulation of reproduction or sex differences, but this includes the processing of sensory information, the coordination of sensory inputs with motor outputs, the expression of affective behavior, and the modulation of learning and memory.3–10 To exert these actions, estradiol generated by brain aromatase regulates cellular signaling, gene expression, synaptic transmission, and synaptic plasticity,11–14 and it is part of the endogenous neuroprotective and anti-inflammatory response activated in neural tissue after injury.15,16

Not all of these roles of the enzyme described in animal studies have been ascertained in humans. However, human studies have significantly advanced in recent years and we have considerable new information on the anatomical and cellular distribution of the enzyme in the human central nervous system (CNS), together with new hints on its physiological implication in the neural processing of sensory integration, the modulation of social behavior and cognition, and the central control of body homeostasis. Available data also indicate that brain aromatase expression is altered with aging and under neurodegenerative conditions. Further, genetic and neuropathological findings suggest that the enzyme may participate in the manifestation of brain diseases, including major depressive disorder, autism spectrum disorders (ASDs), and neurodegenerative diseases. Here, we review the available information on the distribution and function of aromatase in the human brain, discussing future avenues for research and potential clinical and therapeutic implications.




*Aromatase Expression and Distribution in the Human Brain

*Cellular Localization

*Physiological and Pathophysiological Function of Brain Aromatase
-Thalamus: sensory integration
-Amygdala and hypothalamus: body homeostasis, social behavior, and major -depressive disorder
-Cerebral neocortex and hippocampus: cognition, language, and integrative functions

*Alterations of Brain Aromatase with Aging

*Brain Aromatase Under Pathological Conditions
-Aromatase in ASDs
-Aromatase and epilepsy
-Aromatase and stroke
-Aromatase and chronic neurodegenerative diseases
-Aromatase and sex differences in neurodegenerative diseases

*Conclusions and Perspectives




In conclusion, there are many unsolved questions and gaps in our knowledge on human brain aromatase that remain to be explored by future research. However, the limited available information that has been reviewed here suggests that the aromatization of androgens to estrogens by the human nervous tissue is involved in many more physiological and pathological processes than previously believed.

 

[madman]

FIG. 1. Aromatase cytochrome P450 (P450arom) or estrogen synthase converts androgen c19 precursors in C18 estrogens. For instance, the enzyme converts androst-4-ene-3,17-dione (androstenedione) in estrone and testosterone into estradiol.

 

[madman]

FIG. 2. Representative examples of aromatase immunoreactive cells in the human brain. (A) Panoramic view of a section of the temporal cortex. Anti-aromatase immunoreactivity is observed in all cortical layers (1–6) and in the wm, but it is particularly intense in pyramidal cells of neocortical layers 2/3 and 5. In layer 1, aromatase immunoreactive cells, most of them with astrocyte morphology, are abundant in proximity of the pial surface (arrow). Female, 63 years old. (B) Cerebellar cortex. Intense immunoreactivity is observed in Purkinje neuronal perikarya in the PC and in their dendrites in the Mol, whereas granule cells are not immunoreactive. Immunoreactivity is also observed in interneurons in the molecular layer (arrowheads) and in a few neurons in the Gr (arrow), which may correspond to Golgi neurons. Male, 49 years old. (C) Pyramidal neurons in the Pyr of the hippocampal Ammon’s horn CA1 region showing aromatase immunoreactivity in the perikaryon and in the basal and apical dendrites. Male, 65 years old. (D) Pyramidal neurons in the Pyr of the hippocampal Ammon’s horn CA3 region showing aromatase immunoreactivity in the perikaryon and dendrites. Female, 43 years old. (E) Hippocampal dentate gyrus showing aromatase immunoreactivity in granule cell neurons in the Gr and a few interneurons in the Hil. Mol, molecular layer of the dentate gyrus. Female, 35 years old. All panels are from immunoperoxidase-stained sections using hydrogen peroxide as substrate and 3,3¢-diaminobenzidine tetrahydrochloride as chromogen. In (B), the reaction was intensified by adding a small amount of nickel chloride. Gr, granular layer; Hil, hilus; Mol, molecular layer; Or, Stratum oriens; PC, Purkinje cell layer; Pyr, pyramidal layer; Rad, Stratum radiatum; Wm, white matter

 

[madman]

FIG. 3. Aromatase immunoreactivity in astrocytes. (A) Panoramic view of the cortical white matter in the temporal lobe, showing immunoreactivity in cells with the morphology of fibrous astrocytes. (B) Detail of the layer 1 of the temporal cortex showing numerous immunoreactive astrocytes (arrowheads) in the proximity of the pial surface (arrows). (C) Immunofluorescence labeling of aromatase (green), the astrocyte cell marker GFAP (red), and the colocalization signal (yellow) in a cortical astrocyte. (D) Representative example of a fibrous astrocyte immunoreactive for aromatase in the cortical white matter. (E) Representative example of a protoplasmic astrocyte immunoreactive for aromatase in the cortical gray matter. All panels are from a 23-year-old male. GFAP, glial fibrillary acidic protein.