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Physiological Reviews Jul 2017Estrogens have historically been associated with female reproduction, but work over the last two decades established that estrogens and their main nuclear receptors... (Review)
Review
Estrogens have historically been associated with female reproduction, but work over the last two decades established that estrogens and their main nuclear receptors (ESR1 and ESR2) and G protein-coupled estrogen receptor (GPER) also regulate male reproductive and nonreproductive organs. 17β-Estradiol (E2) is measureable in blood of men and males of other species, but in rete testis fluids, E2 reaches concentrations normally found only in females and in some species nanomolar concentrations of estrone sulfate are found in semen. Aromatase, which converts androgens to estrogens, is expressed in Leydig cells, seminiferous epithelium, and other male organs. Early studies showed E2 binding in numerous male tissues, and ESR1 and ESR2 each show unique distributions and actions in males. Exogenous estrogen treatment produced male reproductive pathologies in laboratory animals and men, especially during development, and studies with transgenic mice with compromised estrogen signaling demonstrated an E2 role in normal male physiology. Efferent ductules and epididymal functions are dependent on estrogen signaling through ESR1, whose loss impaired ion transport and water reabsorption, resulting in abnormal sperm. Loss of ESR1 or aromatase also produces effects on nonreproductive targets such as brain, adipose, skeletal muscle, bone, cardiovascular, and immune tissues. Expression of GPER is extensive in male tracts, suggesting a possible role for E2 signaling through this receptor in male reproduction. Recent evidence also indicates that membrane ESR1 has critical roles in male reproduction. Thus estrogens are important physiological regulators in males, and future studies may reveal additional roles for estrogen signaling in various target tissues.
Topics: Animals; Aromatase; Estrogens; Genitalia, Male; Genotype; Humans; Male; Mice, Knockout; Mutation; Phenotype; Prostate; Prostatic Diseases; Receptors, Estrogen; Reproduction; Signal Transduction
PubMed: 28539434
DOI: 10.1152/physrev.00018.2016 -
European Review For Medical and... Jan 2021D-chiro-Inositol has been widely used in clinical practice to induce ovulation in women with polycystic ovary syndrome. Only recent evidence established that this... (Review)
Review
OBJECTIVE
D-chiro-Inositol has been widely used in clinical practice to induce ovulation in women with polycystic ovary syndrome. Only recent evidence established that this molecule acts through two different mechanisms, with potentially different outcomes. On the one hand, under a metabolic perspective, D-chiro-Inositol improves insulin signaling, thus restoring physiological insulin levels in resistant subjects. On the other hand, at a cellular level, it downregulates the expression of steroidogenic enzyme aromatase, which is responsible for the conversion of androgens to estrogens.
MATERIALS AND METHODS
We reviewed current literature in different databases, searching for D-chiro-Inositol in relation with one of the following keywords: myo-inositol, PCOS, infertility, insulin resistance, aromatase, androgen and inositol, testosterone, estrogen and inositol, estradiol, hypogonadotropic hypogonadism, fat tissue, estrogens and cancer, anovulation, uterine myoma, endometriosis, endometrial hyperplasia.
RESULTS
D-Chiro-Inositol treatment may be helpful in restoring physiological hormonal levels in various clinical disorders. However, D-Chiro-Inositol intervention should be carefully designed to avoid possible undesired side effects stemming from its multiple mechanisms of action.
CONCLUSIONS
We evaluated the optimal D Chiro-Inositol administration for different pathologies, defining dosages and timing. Even though further studies are required to validate our preliminary results, this paper is primarily intended to guide researchers through some of the pathways of D-Chiro-Inositol.
Topics: Aromatase; Down-Regulation; Female; Humans; Inositol; Insulin; Insulin Resistance; Male; Polycystic Ovary Syndrome
PubMed: 33506934
DOI: 10.26355/eurrev_202101_24412 -
The Journal of Steroid Biochemistry and... May 2019Obesity is a risk factor for estrogen receptor-positive (ER+) breast cancer after menopause. The pro-proliferative effects of estrogens are well characterized and there... (Review)
Review
Obesity is a risk factor for estrogen receptor-positive (ER+) breast cancer after menopause. The pro-proliferative effects of estrogens are well characterized and there is a growing body of evidence to also suggest an important role in tumorigenesis. Importantly, obesity not only increases the risk of breast cancer, but it also increases the risk of recurrence and cancer-associated death. Aromatase is the rate-limiting enzyme in estrogen biosynthesis and its expression in breast adipose stromal cells is hypothesized to drive the growth of breast tumors and confer resistance to endocrine therapy in obese postmenopausal women. The molecular regulation of aromatase has been characterized in response to many obesity-related molecules, including inflammatory mediators and adipokines. This review is aimed at providing an overview of our current knowledge in relation to the regulation of estrogens in adipose tissue and their role in driving breast tumor development, growth and progression.
Topics: Adipose Tissue; Aromatase; Breast; Breast Neoplasms; Disease Progression; Estrogens; Female; Humans; Menopause; Obesity; Receptors, Estrogen
PubMed: 30851382
DOI: 10.1016/j.jsbmb.2019.03.002 -
Nutrients Apr 2023Myo-inositol is a natural polyol, the most abundant among the nine possible structural isomers available in living organisms. Inositol confers some distinctive traits... (Review)
Review
Myo-inositol is a natural polyol, the most abundant among the nine possible structural isomers available in living organisms. Inositol confers some distinctive traits that allow for a striking distinction between prokaryotes and eukaryotes, the basic clusters into which organisms are partitioned. Inositol cooperates in numerous biological functions where the polyol participates or by furnishing the fundamental backbone of several related derived metabolites, mostly obtained through the sequential addition of phosphate groups (inositol phosphates, phosphoinositides, and pyrophosphates). Overall myo-inositol and its phosphate metabolites display an entangled network, which is involved in the core of the biochemical processes governing critical transitions inside cells. Noticeably, experimental data have shown that myo-inositol and its most relevant epimer D-chiro-inositol are both necessary to permit a faithful transduction of insulin and of other molecular factors. This improves the complete breakdown of glucose through the citric acid cycle, especially in glucose-greedy tissues, such as the ovary. In particular, while D-chiro-inositol promotes androgen synthesis in the theca layer and down-regulates aromatase and estrogen expression in granulosa cells, myo-inositol strengthens aromatase and FSH receptor expression. Inositol effects on glucose metabolism and steroid hormone synthesis represent an intriguing area of investigation, as recent results have demonstrated that inositol-related metabolites dramatically modulate the expression of several genes. Conversely, treatments including myo-inositol and its isomers have proven to be effective in the management and symptomatic relief of a number of diseases associated with the endocrine function of the ovary, namely polycystic ovarian syndrome.
Topics: Humans; Female; Inositol; Aromatase; Polycystic Ovary Syndrome; Inositol Phosphates; Glucose
PubMed: 37111094
DOI: 10.3390/nu15081875 -
Asian Journal of Andrology 2016Traditionally, testosterone and estrogen have been considered to be male and female sex hormones, respectively. However, estradiol, the predominant form of estrogen,... (Review)
Review
Traditionally, testosterone and estrogen have been considered to be male and female sex hormones, respectively. However, estradiol, the predominant form of estrogen, also plays a critical role in male sexual function. Estradiol in men is essential for modulating libido, erectile function, and spermatogenesis. Estrogen receptors, as well as aromatase, the enzyme that converts testosterone to estrogen, are abundant in brain, penis, and testis, organs important for sexual function. In the brain, estradiol synthesis is increased in areas related to sexual arousal. In addition, in the penis, estrogen receptors are found throughout the corpus cavernosum with high concentration around neurovascular bundles. Low testosterone and elevated estrogen increase the incidence of erectile dysfunction independently of one another. In the testes, spermatogenesis is modulated at every level by estrogen, starting with the hypothalamus-pituitary-gonadal axis, followed by the Leydig, Sertoli, and germ cells, and finishing with the ductal epithelium, epididymis, and mature sperm. Regulation of testicular cells by estradiol shows both an inhibitory and a stimulatory influence, indicating an intricate symphony of dose-dependent and temporally sensitive modulation. Our goal in this review is to elucidate the overall contribution of estradiol to male sexual function by looking at the hormone's effects on erectile function, spermatogenesis, and libido.
Topics: Aromatase; Estradiol; Germ Cells; Humans; Hypothalamo-Hypophyseal System; Leydig Cells; Libido; Male; Penile Erection; Sertoli Cells; Spermatogenesis; Testis; Testosterone
PubMed: 26908066
DOI: 10.4103/1008-682X.173932 -
The Journal of Neuroscience : the... Apr 201917β-estradiol (E2) is produced from androgens via the action of the enzyme aromatase. E2 is known to be made in neurons in the brain, but its precise functions in the...
17β-estradiol (E2) is produced from androgens via the action of the enzyme aromatase. E2 is known to be made in neurons in the brain, but its precise functions in the brain are unclear. Here, we used a forebrain-neuron-specific aromatase knock-out (FBN-ARO-KO) mouse model to deplete neuron-derived E2 in the forebrain of mice and thereby elucidate its functions. FBN-ARO-KO mice showed a 70-80% decrease in aromatase and forebrain E2 levels compared with FLOX controls. Male and female FBN-ARO-KO mice exhibited significant deficits in forebrain spine and synaptic density, as well as hippocampal-dependent spatial reference memory, recognition memory, and contextual fear memory, but had normal locomotor function and anxiety levels. Reinstating forebrain E2 levels via exogenous E2 administration was able to rescue both the molecular and behavioral defects in FBN-ARO-KO mice. Furthermore, studies using FBN-ARO-KO hippocampal slices revealed that, whereas induction of long-term potentiation (LTP) was normal, the amplitude was significantly decreased. Intriguingly, the LTP defect could be fully rescued by acute E2 treatment Mechanistic studies revealed that FBN-ARO-KO mice had compromised rapid kinase (AKT, ERK) and CREB-BDNF signaling in the hippocampus and cerebral cortex. In addition, acute E2 rescue of LTP in hippocampal FBN-ARO-KO slices could be blocked by administration of a MEK/ERK inhibitor, further suggesting a key role for rapid ERK signaling in neuronal E2 effects. In conclusion, the findings provide evidence of a critical role for neuron-derived E2 in regulating synaptic plasticity and cognitive function in the male and female brain. The steroid hormone 17β-estradiol (E2) is well known to be produced in the ovaries in females. Intriguingly, forebrain neurons also express aromatase, the E2 biosynthetic enzyme, but the precise functions of neuron-derived E2 is unclear. Using a novel forebrain-neuron-specific aromatase knock-out mouse model to deplete neuron-derived E2, the current study provides direct genetic evidence of a critical role for neuron-derived E2 in the regulation of rapid AKT-ERK and CREB-BDNF signaling in the mouse forebrain and demonstrates that neuron-derived E2 is essential for normal expression of LTP, synaptic plasticity, and cognitive function in both the male and female brain. These findings suggest that neuron-derived E2 functions as a novel neuromodulator in the forebrain to control synaptic plasticity and cognitive function.
Topics: Animals; Anxiety; Aromatase; Cognition; Dendritic Spines; Estradiol; Female; Hippocampus; Long-Term Potentiation; Male; Memory; Mice; Mice, Inbred C57BL; Mice, Knockout; Neuronal Plasticity; Neurons; Prosencephalon; Psychomotor Performance; Spatial Learning; Synapses
PubMed: 30728170
DOI: 10.1523/JNEUROSCI.1970-18.2019 -
Cell Feb 2022Sex hormones exert a profound influence on gendered behaviors. How individual sex hormone-responsive neuronal populations regulate diverse sex-typical behaviors is...
Sex hormones exert a profound influence on gendered behaviors. How individual sex hormone-responsive neuronal populations regulate diverse sex-typical behaviors is unclear. We performed orthogonal, genetically targeted sequencing of four estrogen receptor 1-expressing (Esr1) populations and identified 1,415 genes expressed differentially between sexes or estrous states. Unique subsets of these genes were distributed across all 137 transcriptomically defined Esr1 cell types, including estrous stage-specific ones, that comprise the four populations. We used differentially expressed genes labeling single Esr1 cell types as entry points to functionally characterize two such cell types, BNSTpr and VMHvl. We observed that these two cell types, but not the other Esr1 cell types in these populations, are essential for sex recognition in males and mating in females, respectively. Furthermore, VMHvl cell type projections are distinct from those of other VMHvl cell types. Together, projection and functional specialization of dimorphic cell types enables sex hormone-responsive populations to regulate diverse social behaviors.
Topics: Aggression; Animals; Aromatase; Autistic Disorder; Estrogen Receptor alpha; Estrous Cycle; Female; Gene Expression Profiling; Gene Expression Regulation; HEK293 Cells; Humans; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Neurons; Sex Characteristics; Sexual Behavior, Animal; Social Behavior
PubMed: 35065713
DOI: 10.1016/j.cell.2021.12.031 -
Frontiers in Neuroendocrinology Apr 2022This review explores the role of aromatase in the brain as illuminated by a set of conserved network-level connections identified in several vertebrate taxa.... (Review)
Review
This review explores the role of aromatase in the brain as illuminated by a set of conserved network-level connections identified in several vertebrate taxa. Aromatase-expressing neurons are neurochemically heterogeneous but the brain regions in which they are found are highly-conserved across the vertebrate lineage. During development, aromatase neurons have a prominent role in sexual differentiation of the brain and resultant sex differences in behavior and human brain diseases. Drawing on literature primarily from birds and rodents, we delineate brain regions that express aromatase and that are strongly interconnected, and suggest that, in many species, aromatase expression essentially defines the Social Behavior Network. Moreover, in several cases the inputs to and outputs from this core Social Behavior Network also express aromatase. Recent advances in molecular and genetic tools for neuroscience now enable in-depth and taxonomically diverse studies of the function of aromatase at the neural circuit level.
Topics: Animals; Aromatase; Brain; Female; Male; Neurons; Sex Characteristics; Social Behavior
PubMed: 34942232
DOI: 10.1016/j.yfrne.2021.100973 -
Physiology (Bethesda, Md.) Jul 2016Aromatase (estrogen synthetase; EC 1.14.14.1) catalyzes the demethylation of androgens' carbon 19, producing phenolic 18-carbon estrogens. Aromatase is most widely known... (Review)
Review
Aromatase (estrogen synthetase; EC 1.14.14.1) catalyzes the demethylation of androgens' carbon 19, producing phenolic 18-carbon estrogens. Aromatase is most widely known for its roles in reproduction and reproductive system diseases, and as a target for inhibitor therapy in estrogen-sensitive diseases including cancer, endometriosis, and leiomyoma (141, 143). However, all tissues contain estrogen receptor-expressing cells, the majority of genes have a complete or partial estrogen response element that regulates their expression (61), and there are plentiful nonreceptor effects of estrogens (79); therefore, the effect of aromatase through the provision of estrogen is almost universal in terms of health and disease. This review will provide a brief but comprehensive overview of the enzyme, its role in steroidogenesis, the problems that arise with its functional mutations and mishaps, the roles in human physiology of aromatase and its product estrogens, its current clinical roles, and the effects of aromatase inhibitors. While much of the story is that of the consequences of the formation of its product estrogens, we also will address alternative enzymatic roles of aromatase as a demethylase or nonenzymatic actions of this versatile molecule. Although this short review is meant to be thorough, it is by no means exhaustive; rather, it is meant to reflect the cutting-edge, exciting properties and possibilities of this ancient enzyme and its products.
Topics: Animals; Aromatase; Aromatase Inhibitors; Brain; Disease; Estrogens; Female; Homeostasis; Human Development; Humans; Male
PubMed: 27252161
DOI: 10.1152/physiol.00054.2015 -
Frontiers in Neuroendocrinology Jan 2016Aromatase catalyzes the last and obligatory step in the biosynthesis of estrogens across species. In vivo visualization of aromatase can be performed using positron... (Review)
Review
Aromatase catalyzes the last and obligatory step in the biosynthesis of estrogens across species. In vivo visualization of aromatase can be performed using positron emission tomography (PET) with radiolabeled aromatase inhibitors such as [(11)C]vorozole. PET studies in rats, monkeys and healthy human subjects demonstrate widespread but heterogeneous aromatase availability in brain and body, which appears to be regulated in a species, sex and region-specific manner. Thus, aromatase availability is high in brain amygdala and in ovaries of all species examined to date, with males demonstrating higher levels than females in all comparable organs. However, the highest concentrations of aromatase in the human brain are found in specific nuclei of the thalamus while the highest levels in rats and monkeys are found in the amygdala. Regional brain aromatase availability is increased by androgens and inhibited by nicotine. Future studies may improve diagnosis and treatment in brain disorders and cancers overexpressing aromatase.
Topics: Androgens; Animals; Aromatase; Aromatase Inhibitors; Brain; Brain Diseases; Humans; Positron-Emission Tomography
PubMed: 26456904
DOI: 10.1016/j.yfrne.2015.10.001