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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 -
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 -
Journal of Molecular Endocrinology Jul 2016Long-term exposure to excess estrogen increases the risk of breast cancer and type 1 endometrial cancer. Most of the estrogen in premenopausal women is synthesized by... (Review)
Review
Long-term exposure to excess estrogen increases the risk of breast cancer and type 1 endometrial cancer. Most of the estrogen in premenopausal women is synthesized by the ovaries, while extraovarian subcutaneous adipose tissue is the predominant tissue source of estrogen after menopause. Estrogen and its metabolites can cause hyperproliferation and neoplastic transformation of breast and endometrial cells via increased proliferation and DNA damage. Several genetically modified mouse models have been generated to help understand the physiological and pathophysiological roles of aromatase and estrogen in the normal breast and in the development of breast cancers. Aromatase, the key enzyme for estrogen production, is comprised of at least ten partially tissue-selective and alternatively used promoters. These promoters are regulated by distinct signaling pathways to control aromatase expression and estrogen formation via recruitment of various transcription factors to their cis-regulatory elements. A shift in aromatase promoter use from I.4 to I.3/II is responsible for the excess estrogen production seen in fibroblasts surrounding malignant epithelial cells in breast cancers. Targeting these distinct pathways and/or transcription factors to modify aromatase activity may lead to the development of novel therapeutic remedies that inhibit estrogen production in a tissue-specific manner.
Topics: Animals; Aromatase; Breast Neoplasms; Disease Models, Animal; Endometrial Neoplasms; Estrogens; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Organ Specificity; Promoter Regions, Genetic; Protein Binding; Signal Transduction; Transcription Factors
PubMed: 27067638
DOI: 10.1530/JME-15-0310 -
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 -
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 -
Fertility and Sterility Sep 2016
Topics: Aromatase; Aromatase Inhibitors; Humans; Inflammation; MicroRNAs; Obesity
PubMed: 27473353
DOI: 10.1016/j.fertnstert.2016.06.045 -
Fertility and Sterility Feb 2014Studies on the phenotypes of women and men with mutations disrupting estrogen biosynthesis and action have significantly advanced our knowledge of the physiologic roles... (Review)
Review
Studies on the phenotypes of women and men with mutations disrupting estrogen biosynthesis and action have significantly advanced our knowledge of the physiologic roles of estrogen in humans. Aromatase deficiency results from autosomal recessive inheritance of mutations in the CYP19A1 gene. It gives rise to ambiguous genitalia in 46,XX fetuses. At puberty, affected girls have hypergonadotropic hypogonadism, do not develop secondary sexual characteristics, and exhibit progressive virilization. The affected 46,XY men have normal male sexual differentiation and pubertal maturation. These men, however, are extremely tall and have eunucoid proportions with continued linear growth into adulthood, severely delayed epiphyseal closure, and osteoporosis due to estrogen deficiency. Although estrogen has been shown to be essential for normal sperm production and function in mice, its role in fertility is not clear in men. Thus far, one man and an unrelated woman with estrogen resistance due to mutations in the estrogen receptor α (ESR1) gene have been described. Their clinical presentations are similar to that of aromatase-deficient men and women.
Topics: 46, XX Disorders of Sex Development; Animals; Aromatase; Estrogen Receptor alpha; Female; Genes, Recessive; Gynecomastia; Humans; Infertility, Male; Male; Metabolism, Inborn Errors; Mutation
PubMed: 24485503
DOI: 10.1016/j.fertnstert.2013.12.022 -
Trends in Endocrinology and Metabolism:... Feb 2012Obesity has been associated with abnormally high expression of the enzyme aromatase in the breast, increased local estrogen production, and predisposition to breast... (Review)
Review
Obesity has been associated with abnormally high expression of the enzyme aromatase in the breast, increased local estrogen production, and predisposition to breast hyperplasia and cancer. Increased adiposity in postmenopausal women may trigger signaling pathways that induce aromatase expression. In breast adipose fibroblasts, increased TNF production may induce the distal aromatase promoter, whereas increased local PGE(2) production may induce the proximal promoter region. We review here the mechanisms that control aromatase gene expression in breast adipose tissue, and the paracrine interactions between malignant breast epithelial cells and the surrounding adipose fibroblasts. Systematic characterization of these signaling pathways will facilitate the identification of potential drug targets to selectively reduce aromatase expression and excessive estrogen production, with therapeutic benefit.
Topics: Adipose Tissue; Aromatase; Breast; Breast Neoplasms; Estrogens; Female; Fibroblasts; Humans; Obesity; Paracrine Communication; Signal Transduction
PubMed: 22169755
DOI: 10.1016/j.tem.2011.10.003 -
Philosophical Transactions of the Royal... May 2010In most mammalian species aromatase is encoded by a single gene (Cyp19), which contains 18 exons, nine of them being translated. In man, the presence of a biologically... (Review)
Review
In most mammalian species aromatase is encoded by a single gene (Cyp19), which contains 18 exons, nine of them being translated. In man, the presence of a biologically active aromatase and oestrogen receptors (ERalpha and ERbeta) has been reported in Leydig cells, and also in immature germ cells and ejaculated spermatozoa. Concerning aromatase, the amount of transcript and enzymatic activity are decreased in immotile compared with motile sperm. We have amplified aromatase mRNA by real-time polymerase chain reaction in spermatozoa from asthenospermic, teratospermic and asthenoteratospermic men and recorded, respectively, 44, 52 and 67 per cent decreases of the amount of transcripts compared with fertile donors. A high degree of correlation (r = -0.64) between the abnormal spermatozoa (especially microcephaly and acrosome malformations) and aromatase/GAPDH transcript ratio has been observed. Idiopathic infertility is a wide health problem and no treatment is currently available. In humans, even if the role of oestrogens in spermatogenesis is still a matter of debate, the observations of decreased sperm number and motility in men genetically deficient in aromatase, together with our data and those reported in the literature, may suggest a role for aromatase/oestrogens not only during the development and maintenance of spermatogenesis but also in the final maturation of spermatozoa.
Topics: Aromatase; Estrogens; Humans; Infertility, Male; Male; Spermatogenesis; Spermatozoa
PubMed: 20403870
DOI: 10.1098/rstb.2009.0113