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The Biochemical Journal Nov 2019Aromatase CYP19A1 catalyzes the synthesis of estrogens in endocrine, reproductive and central nervous systems. Higher levels of 17β-estradiol (E2) are associated with...
Aromatase CYP19A1 catalyzes the synthesis of estrogens in endocrine, reproductive and central nervous systems. Higher levels of 17β-estradiol (E2) are associated with malignancies and diseases of the breast, ovary and endometrium, while low E2 levels increase the risk for osteoporosis, cardiovascular diseases and cognitive disorders. E2, the transcriptional activator of the estrogen receptors, is also known to be involved in non-genomic signaling as a neurotransmitter/neuromodulator, with recent evidence for rapid estrogen synthesis (RES) within the synaptic terminal. Although regulation of brain aromatase activity by phosphorylation/dephosphorylation has been suggested, it remains obscure in the endocrine and reproductive systems. RES and overabundance of estrogens could stimulate the genomic and non-genomic signaling pathways, and genotoxic effects of estrogen metabolites. Here, by utilizing biochemical, cellular, mass spectrometric, and structural data we unequivocally demonstrate phosphorylation of human placental aromatase and regulation of its activity. We report that human aromatase has multiple phosphorylation sites, some of which are consistently detectable. Phosphorylation of the residue Y361 at the reductase-coupling interface significantly elevates aromatase activity. Other sites include the active site residue S478 and several at the membrane interface. We present the evidence that two histidine residues are phosphorylated. Furthermore, oxidation of two proline residues near the active site may have implications in regulation. Taken together, the results demonstrate that aromatase activity is regulated by phosphorylation and possibly other post-translational modifications. Protein level regulation of aromatase activity not only represents a paradigm shift in estrogen-mediated biology, it could also explain unresolved clinical questions such as aromatase inhibitor resistance.
Topics: Amino Acid Motifs; Aromatase; Estrogens; Female; Humans; Phosphorylation; Placenta; Pregnancy
PubMed: 31652308
DOI: 10.1042/BCJ20190633 -
Scientific Reports Mar 2021Estrogen signaling is crucial for breast cancer initiation and progression. Endocrine-based therapies comprising estrogen receptor (ER) modulators and aromatase...
Estrogen signaling is crucial for breast cancer initiation and progression. Endocrine-based therapies comprising estrogen receptor (ER) modulators and aromatase inhibitors remain the mainstay of treatment. This study aimed at investigating the antitumor potential of the most potent compounds in citrus peels on breast cancer by exploring their anti-estrogenic and anti-aromatase activities. The ethanolic extract of different varieties of citrus peels along with eight isolated flavonoids were screened against estrogen-dependent breast cancer cell lines besides normal cells for evaluating their safety profile. Naringenin, naringin and quercetin demonstrated the lowest IC and were therefore selected for further assays. In silico molecular modeling against ER and aromatase was performed for the three compounds. In vivo estrogenic and anti-estrogenic assays confirmed an anti-estrogenic activity for the isolates. Moreover, naringenin, naringin and quercetin demonstrated in vitro inhibitory potential against aromatase enzyme along with anticancer potential in vivo, as evidenced by decreased tumor volumes. Reduction in aromatase levels in solid tumors was also observed in treated groups. Overall, this study suggests an antitumor potential for naringenin, naringin and quercetin isolated from citrus peels in breast cancer via possible modulation of estrogen signaling and aromatase inhibition suggesting their use in pre- and post-menopausal breast cancer patients, respectively.
Topics: Animals; Aromatase; Aromatase Inhibitors; Breast Neoplasms; Citrus; Estrogen Receptor Modulators; Female; Humans; Mice; Plant Extracts; Xenograft Model Antitumor Assays
PubMed: 33782546
DOI: 10.1038/s41598-021-86599-z -
Reproductive Biology and Endocrinology... Apr 2003The ability of the testis to convert irreversibly androgens into estrogens is related to the presence of a microsomal enzymatic complex named aromatase, which is... (Review)
Review
The ability of the testis to convert irreversibly androgens into estrogens is related to the presence of a microsomal enzymatic complex named aromatase, which is composed of a specific glycoprotein, the cytochrome P450 aromatase (P450arom) and an ubiquitous reductase. The aromatase gene is unique in humans and contained 18 exons, 9 of them being translated. In the rat testis we have immunolocalized the P450arom not only in Leydig cells but also in germ cells and especially in elongated spermatids. Related to the stage of germ cell maturation, we have shown that the level of P450arom mRNA transcripts decreases, it is much more abundant in pachytene spermatocytes and round spermatids than in mature germ cells whereas the aromatase activity is 2-4 fold greater in spermatozoa when compared to the younger germ cells. Using a highly specific quantitative competitive RT-PCR method we have evidenced that several factors direct the expression of the aromatase gene in Leydig cells, Sertoli cells, pachytene spermatocytes and round spermatids, and it is obvious that promoter PII is the main one but other promoters could be concerned. In the bank-vole testis we have observed a positive correlation between a fully developed spermatogenesis and a strong immunoreactivity for both P450arom and estrogen receptor beta not only in Sertoli cells but also in pachytene spermatocytes and round spermatids. Our recent data obtained from ejaculated human spermatozoa demonstrate the presence of aromatase both in terms of mRNA and protein, and in addition, we suggest that aromatase could be involved in the acquisition of sperm motility. Indeed in men the congenital aromatase deficiency is associated with severe bone maturation problems and sterility. Together with the widespread distribution of estrogen receptors in testicular cells these data clearly show that estrogens play a physiological role in the regulation of spermatogenesis in mammals.
Topics: Animals; Aromatase; Arvicolinae; Estrogens; Fertility; Humans; Leydig Cells; Male; Mice; Mice, Knockout; Rats; Receptors, Estrogen; Seminiferous Tubules; Sertoli Cells; Species Specificity; Sperm Motility; Spermatogenesis; Spermatozoa; Testis
PubMed: 12747806
DOI: 10.1186/1477-7827-1-35 -
Nutrients Oct 2022Polycystic ovary syndrome (PCOS) has been linked to aberrant folliculogenesis and abnormalities in the aromatase enzyme (Cyp19a1) and the steroidogenic enzyme,...
Polycystic ovary syndrome (PCOS) has been linked to aberrant folliculogenesis and abnormalities in the aromatase enzyme (Cyp19a1) and the steroidogenic enzyme, 17-alpha-hydroxylase (Cyp17a1) expression. It has been demonstrated that Kelulut honey (KH) improves both female and male reproductive system anomalies in animal studies. Here, we examined the effects of isolated and combined KH, metformin, and clomiphene in improving folliculogenesis, aromatase, and steroidogenic enzyme profiles and ovarian histomorphology in letrozole-induced PCOS rats. Letrozole (1 mg/kg/day) was administered to female Sprague-Dawley (SD) rats for 21 days to induce PCOS. PCOS rats were subsequently divided into six experimental groups: untreated, treatment with metformin (500 mg/kg/day), clomiphene (2 mg/kg/day), KH (1 g/kg/day), combined KH (1 g/kg/day) and metformin (500 mg/kg/day), and combined KH (1 g/kg/day) and clomiphene (2 mg/kg/day). All treatments were given orally for 35 days. We found that KH was comparable with clomiphene and metformin in improving the expression of Cyp17a1 and Cyp19a1, apart from enhancing folliculogenesis both histologically and through the expression of folliculogenesis-related genes. Besides, the combination of KH with clomiphene was the most effective treatment in improving the ovarian histomorphology of PCOS rats. The effectiveness of KH in restoring altered folliculogenesis, steroidogenic, and aromatase enzyme profiles in PCOS warrants a future clinical trial to validate its therapeutic effect clinically.
Topics: Animals; Female; Rats; Aromatase; Clomiphene; Honey; Letrozole; Metformin; Polycystic Ovary Syndrome; Rats, Sprague-Dawley
PubMed: 36297046
DOI: 10.3390/nu14204364 -
The Journal of Steroid Biochemistry and... Nov 2011Classically, the estrogen signaling system has two core components: cytochrome P450 aromatase (CYP19), the enzyme complex that catalyzes the rate limiting step in... (Review)
Review
Classically, the estrogen signaling system has two core components: cytochrome P450 aromatase (CYP19), the enzyme complex that catalyzes the rate limiting step in estrogen biosynthesis; and estrogen receptors (ERs), ligand activated transcription factors that interact with the regulatory region of target genes to mediate the biological effects of estrogen. While the importance of estrogens for regulation of reproduction, development and physiology has been well-documented in gnathostome vertebrates, the evolutionary origins of estrogen as a hormone are still unclear. As invertebrates within the phylum Chordata, cephalochordates (e.g., the amphioxus of the genus Branchiostoma) are among the closest invertebrate relatives of the vertebrates and can provide critical insight into the evolution of vertebrate-specific molecules and pathways. To address this question, this paper briefly reviews relevant earlier studies that help to illuminate the history of the aromatase and ER genes, with a particular emphasis on insights from amphioxus and other invertebrates. We then present new analyses of amphioxus aromatase and ER sequence and function, including an in silico model of the amphioxus aromatase protein, and CYP19 gene analysis. CYP19 shares a conserved gene structure with vertebrates (9 coding exons) and moderate sequence conservation (40% amino acid identity with human CYP19). Modeling of the amphioxus aromatase substrate binding site and simulated docking of androstenedione in comparison to the human aromatase shows that the substrate binding site is conserved and predicts that androstenedione could be a substrate for amphioxus CYP19. The amphioxus ER is structurally similar to vertebrate ERs, but differs in sequence and key residues of the ligand binding domain. Consistent with results from other laboratories, amphioxus ER did not bind radiolabeled estradiol, nor did it modulate gene expression on an estrogen-responsive element (ERE) in the presence of estradiol, 4-hydroxytamoxifen, diethylstilbestrol, bisphenol A or genistein. Interestingly, it has been shown that a related gene, the amphioxus "steroid receptor" (SR), can be activated by estrogens and that amphioxus ER can repress this activation. CYP19, ER and SR are all primarily expressed in gonadal tissue, suggesting an ancient paracrine/autocrine signaling role, but it is not yet known how their expression is regulated and, if estrogen is actually synthesized in amphioxus, whether it has a role in mediating any biological effects. Functional studies are clearly needed to link emerging bioinformatics and in vitro molecular biology results with organismal physiology to develop an understanding of the evolution of estrogen signaling. This article is part of a Special Issue entitled 'Marine organisms'.
Topics: Amino Acid Sequence; Animals; Aromatase; Chordata; Cloning, Molecular; Crystallography, X-Ray; DNA, Complementary; Estrogens; Evolution, Molecular; Humans; Models, Molecular; Molecular Sequence Data; Polymerase Chain Reaction; Protein Binding; Receptors, Estrogen; Sequence Homology, Amino Acid; Signal Transduction; Transcription, Genetic
PubMed: 21514383
DOI: 10.1016/j.jsbmb.2011.03.022 -
Journal of Neuroendocrinology Feb 2023Steroid hormones are often synthesized in multiple tissues, affect several different targets, and modulate numerous physiological endpoints. The mechanisms by which this... (Review)
Review
Steroid hormones are often synthesized in multiple tissues, affect several different targets, and modulate numerous physiological endpoints. The mechanisms by which this modulation is achieved with temporal and spatial specificity remain unclear. 17β-estradiol for example, is made in several peripheral tissues and in the brain, where it affects a diverse set of behaviors. How is estradiol delivered to the right target, at the right time, and at the right concentration? In the last two decades, we have learned that aromatase (estrogen-synthase) can be induced in astrocytes following damage to the brain and is expressed at central synapses. Both mechanisms of estrogen provision confer spatial and temporal specificity on a lipophilic neurohormone with potential access to all cells and tissues. In this review, I trace the progress in our understanding of astrocytic and synaptic aromatization. I discuss the incidence, regulation, and functions of neuroestradiol provision by aromatization, first in astrocytes and then at synapses. Finally, I focus on a relatively novel hypothesis about the role of neuroestradiol in the orchestration of species-specific behaviors.
Topics: Animals; Songbirds; Brain; Estradiol; Estrogens; Synapses; Aromatase
PubMed: 35983989
DOI: 10.1111/jne.13192 -
Biology of Sex Differences Sep 2023Aromatase catalyzes the synthesis of estrogens from androgens. Knowledge on its regional expression in the brain is of relevance to the behavioral implications of these...
BACKGROUND
Aromatase catalyzes the synthesis of estrogens from androgens. Knowledge on its regional expression in the brain is of relevance to the behavioral implications of these hormones that might be linked to sex differences in mental health. The present study investigated the distribution of cells expressing the aromatase coding gene (Cyp19a1) in limbic regions of young adult rats of both sexes, and characterized the cell types expressing this gene.
METHODS
Cyp19a1 mRNA was mapped using fluorescent in situ hybridization (FISH). Co-expression with specific cell markers was assessed with double FISH; glutamatergic, gamma-aminobutyric acid (GABA)-ergic, glial, monoaminergic, as well as interneuron markers were tested. Automated quantification of the cells expressing the different genes was performed using CellProfiler. Sex differences in the number of cells expressing Cyp19a1 was tested non-parametrically, with the effect size indicated by the rank-biserial correlation. FDR correction for multiple testing was applied.
RESULTS
In the male brain, the highest percentage of Cyp19a1 cells was found in the medial amygdaloid nucleus and the bed nucleus of stria terminalis, followed by the medial preoptic area, the CA2/3 fields of the hippocampus, the cortical amygdaloid nucleus and the amygdalo-hippocampal area. A lower percentage was detected in the caudate putamen, the nucleus accumbens, and the ventromedial hypothalamus. In females, the distribution of Cyp19a1 cells was similar but at a lower percentage. In most regions, the majority of Cyp19a1 cells were GABAergic, except for in the cortical-like regions of the amygdala where most were glutamatergic. A smaller fraction of cells co-expressed Slc1a3, suggesting expression of Cyp19a1 in astrocytes; monoaminergic markers were not co-expressed. Moreover, sex differences were detected regarding the identity of Cyp19a1 cells.
CONCLUSIONS
Females show overall a lower number of cells expressing Cyp19a1 in the limbic brain. In both sexes, aromatase is expressed in a region-specific manner in GABAergic and glutamatergic neurons. These findings call for investigations of the relevance of sex-specific and region-dependent expression of Cyp19a1 in the limbic brain to sex differences in behavior and mental health.
Topics: Female; Male; Animals; Rats; Sex Characteristics; Aromatase; In Situ Hybridization, Fluorescence; Neuroglia; Brain
PubMed: 37658400
DOI: 10.1186/s13293-023-00541-8 -
The European Journal of Neuroscience Nov 2021Estrogens support major brain functions including cognition, reproduction, neuroprotection and sensory processing. Neuroestrogens are synthesized within some brain areas...
Aromatase and nonaromatase neurons in the zebra finch secondary auditory forebrain are indistinct in their song-driven gene induction and intrinsic electrophysiological properties.
Estrogens support major brain functions including cognition, reproduction, neuroprotection and sensory processing. Neuroestrogens are synthesized within some brain areas by the enzyme aromatase and can rapidly modulate local circuit functions, yet the cellular physiology and sensory-response profiles of aromatase neurons are essentially unknown. In songbirds, social and acoustic stimuli drive neuroestrogen elevations in the auditory forebrain caudomedial nidopallium (NCM). In both males and females, neuroestrogens rapidly enhance NCM auditory processing and auditory learning. Estrogen-producing neurons in NCM may therefore exhibit distinguishing profiles for sensory-activation and intrinsic electrophysiology. Here, we explored these questions using both immunocyctochemistry and electrophysiological recordings. Immunoreactivity for aromatase and the immediate early gene EGR1, a marker of activity and plasticity, were quantified in NCM of song-exposed animals versus silence-exposed controls. Using whole-cell patch clamp recordings from NCM slices, we also documented the intrinsic excitability profiles of aromatase-positive and aromatase-negative neurons. We observed that a subset of aromatase neurons were significantly activated during song playback, in both males and females, and in both hemispheres. A comparable population of non-aromatase-expressing neurons were also similarly driven by song stimulation. Membrane properties (i.e., resting membrane potential, rheobase, input resistance and multiple action potential parameters) were similarly indistinguishable between NCM aromatase and non-aromatase neurons. Together, these findings demonstrate that aromatase and non-aromatase neurons in NCM are indistinct in terms of their intrinsic electrophysiology and responses to song. Nevertheless, such similarities in response properties may belie more subtle differences in underlying conductances and/or computational roles that may be crucial to their function.
Topics: Animals; Aromatase; Auditory Cortex; Estradiol; Female; Finches; Male; Neurons; Prosencephalon; Vocalization, Animal
PubMed: 34535925
DOI: 10.1111/ejn.15463 -
Endocrinology Oct 2020The biologically active estrogen estradiol has important roles in adult brain physiology and sexual behavior. A single gene, Cyp19a1, encodes aromatase, the enzyme that...
The biologically active estrogen estradiol has important roles in adult brain physiology and sexual behavior. A single gene, Cyp19a1, encodes aromatase, the enzyme that catalyzes the conversion of testosterone to estradiol in the testis and brain of male mice. Estradiol formation was shown to regulate sexual activity in various species, but the relative contributions to sexual behavior of estrogen that arises in the brain versus from the gonads remained unclear. To determine the role of brain aromatase in regulating male sexual activity, we generated a brain-specific aromatase knockout (bArKO) mouse. A newly generated whole-body total aromatase knockout mouse of the same genetic background served as a positive control. Here we demonstrate that local aromatase expression and estrogen production in the brain is partially required for male sexual behavior and sex hormone homeostasis. Male bArKO mice exhibited decreased sexual activity in the presence of strikingly elevated circulating testosterone. In castrated adult bArKO mice, administration of testosterone only partially restored sexual behavior; full sexual behavior, however, was achieved only when both estradiol and testosterone were administered together. Thus, aromatase in the brain is, in part, necessary for testosterone-dependent male sexual activity. We also found that brain aromatase is required for negative feedback regulation of circulating testosterone of testicular origin. Our findings suggest testosterone activates male sexual behavior in part via conversion to estradiol in the brain. These studies provide foundational evidence that sexual behavior may be modified through inhibition or enhancement of brain aromatase enzyme activity and/or utilization of selective estrogen receptor modulators.
Topics: Animals; Aromatase; Aromatase Inhibitors; Brain; Cells, Cultured; Female; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Mouse Embryonic Stem Cells; Sex Characteristics; Sexual Behavior, Animal; Testis
PubMed: 32910181
DOI: 10.1210/endocr/bqaa137 -
Scientific Reports Nov 2018Aromatase, an enzyme that converts androgens to estrogens, has been reported to be involved in several brain functions, including synaptic plasticity, neurogenesis,...
Aromatase, an enzyme that converts androgens to estrogens, has been reported to be involved in several brain functions, including synaptic plasticity, neurogenesis, neuroprotection, and regulation of sexual and emotional behaviours in rodents, pathophysiology of Alzheimer's disease and autism spectrum disorders in humans. Aromatase has been reported to be involved in aggressive behaviours in genetically modified mice and in personality traits by genotyping studies on humans. However, no study has investigated the relationship between aromatase in living brains and personality traits including aggression. We performed a positron emission tomography (PET) study in 21 healthy subjects using C-cetrozole, which has high selectivity and affinity for aromatase. Before performing PET scans, subjects answered the Buss-Perry Aggression Questionnaire and Temperament and Character Inventory to measure their aggression and personality traits, respectively. A strong accumulation of C-cetrozole was detected in the thalamus, hypothalamus, amygdala, and medulla. Females showed associations between aromatase levels in subcortical regions, such as the amygdala and supraoptic nucleus of the hypothalamus, and personality traits such as aggression, novelty seeking, and self-transcendence. In contrast, males exhibited associations between aromatase levels in the cortices and harm avoidance, persistence, and self-transcendence. The association of aromatase levels in the thalamus with cooperativeness was common to both sexes. The present study suggests that there might exist associations between aromatase in the brain and personality traits. Some of these associations may differ between sexes, while others are likely common to both.
Topics: Adult; Aniline Compounds; Aromatase; Brain; Carbon Radioisotopes; Female; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Personality; Triazoles
PubMed: 30442903
DOI: 10.1038/s41598-018-35065-4