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The Journal of Steroid Biochemistry and... Dec 2019Serotonin reuptake inhibitors (SRIs) are currently the main molecules prescribed to pregnant women that suffer from depression. Placental cells are exposed to SRIs via...
Serotonin reuptake inhibitors (SRIs) are currently the main molecules prescribed to pregnant women that suffer from depression. Placental cells are exposed to SRIs via maternal blood, and we have previously shown that SRIs alter feto-placental steroidogenesis in an in vitro co-culture model. More specifically, serotonin (5-HT) regulates the estrogen biosynthetic enzyme aromatase (cytochrome P450 19; CYP19), which is disrupted by fluoxetine and its active metabolite norfluoxetine in BeWo choriocarcinoma cells. Based on molecular simulations, the present study illustrates that the SRIs fluoxetine, norfluoxetine, paroxetine, sertraline, citalopram and venlafaxine exhibit binding affinity for the active-site pocket of CYP19, suggesting potential competitive inhibition. Using BeWo cells and primary villous trophoblast cells isolated from normal term placentas, we compared the effects of the SRIs on CYP19 activity. We observed that paroxetine and sertraline induce aromatase activity in BeWo cells, while venlafaxine, fluoxetine, paroxetine and sertraline decrease aromatase activity in primary villous trophoblast. The effects of paroxetine and sertraline in primary villous trophoblasts were observed at the lower doses tested. We also showed that 5-HT and the 5-HT receptor agonist 2,5-dimethoxy-4-iodoamphetamine (DOI) induced CYP19 activity. An increase in phosphorylation of serine and tyrosine and a decrease in threonine phosphorylation of CYP19 was also associated with DOI treatment. Our results contribute to better understanding how 5-HT and SRIs interact with CYP19 and may affect estrogen production. Moreover, this study suggests that alteration of placental 5-HT levels due to depression and/or SRI treatment during pregnancy may be associated with disruption of placental estrogen production.
Topics: Aromatase; Cells, Cultured; Citalopram; Female; Fluoxetine; Humans; Molecular Docking Simulation; Paroxetine; Placenta; Pregnancy; Serotonin; Selective Serotonin Reuptake Inhibitors; Sertraline; Trophoblasts; Venlafaxine Hydrochloride
PubMed: 31509772
DOI: 10.1016/j.jsbmb.2019.105470 -
Molecules (Basel, Switzerland) Feb 2020This work describes the utility of pyrazole-4-carbaldehyde as starting material for the synthesis of a novel potent series of 5α-reductase and aromatase inhibitors...
This work describes the utility of pyrazole-4-carbaldehyde as starting material for the synthesis of a novel potent series of 5α-reductase and aromatase inhibitors derived from 1,2,3-triazole derivative. Condensation of with active methylene and different amino pyrazoles produced the respective Schiff bases -, and . On the other hand, was reacted with ethyl cyanoacetate and thiourea in one-pot reaction to afford the pyrazolo-6- thioxopyridin-2-[3]-one (). Moreover, α-β unsaturated chalcone derivative was prepared via the reaction of compound with -methoxy acetophenone, which in turn reacted with each of ethyl cyanoacetate, malononitrile, hydrazine hydrate, and thiosemicarbazide to afford the corresponding pyridine and pyrazole derivatives , , and The structure of newly synthesized compounds was characterized by analytical and spectroscopic data (IR, MS and NMR) All new compounds were evaluated against 5α-reductase and aromatase inhibitors and the results showed that many of these compounds inhibit 5α-reductase and aromatase activity; compound was found to be the highest potency among the tested samples comparing with the reference drugs.
Topics: 5-alpha Reductase Inhibitors; Animals; Anti-Bacterial Agents; Antineoplastic Agents; Antiviral Agents; Aromatase; Aromatase Inhibitors; Cholestenone 5 alpha-Reductase; Dihydrotestosterone; Letrozole; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Testosterone; Triazoles
PubMed: 32033281
DOI: 10.3390/molecules25030672 -
Biology Direct Apr 2021Human aromatase is a member of the cytochrome P450 superfamily, involved in steroid hormones biosynthesis. In particular, it converts androgen into estrogens being...
Human aromatase is a member of the cytochrome P450 superfamily, involved in steroid hormones biosynthesis. In particular, it converts androgen into estrogens being therefore responsible for the correct sex steroids balance. Due to its capacity in producing estrogens it has also been considered as a promising target for breast cancer therapy. Two single-nucleotide polymorphisms (R264C and R264H) have been shown to alter aromatase activity and they have been associated to an increased or decreased risk for estrogen-dependent pathologies. Here, the effect of these mutations on the protein dynamics is investigated by UV/FTIR and time resolved fluorescence spectroscopy. H/D exchange rates were measured by FTIR for the three proteins in the ligand-free, substrate- and inhibitor-bound forms and the data indicate that the wild-type enzyme undergoes a conformational change leading to a more compact tertiary structure upon substrate or inhibitor binding. Indeed, the H/D exchange rates are decreased when a ligand is present. In the variants, the exchange rates in the ligand-free and -bound forms are similar, indicating that a structural change is lacking, despite the single amino acid substitution is located in the peripheral shell of the protein molecule. Moreover, the fluorescence lifetimes data show that the quenching effect on tryptophan-224 observed upon ligand binding in the wild-type, is absent in both variants. Since this residue is located in the catalytic pocket, these findings suggest that substrate entrance and/or retention in the active site is partially compromised in both mutants. A contact network analysis demonstrates that the protein structure is organized in two main clusters, whose connectivity is altered by ligand binding, especially in correspondence of helix-G, where the amino acid substitutions occur. Our findings demonstrate that SNPs resulting in mutations on aromatase surface modify the protein flexibility that is required for substrate binding and catalysis. The cluster analysis provides a rationale for such effect, suggesting helix G as a possible target for aromatase inhibition.
Topics: Aromatase; Catalysis; Catalytic Domain; Humans; Polymorphism, Genetic; Protein Binding; Spectrometry, Fluorescence
PubMed: 33902660
DOI: 10.1186/s13062-021-00292-9 -
Frontiers in Endocrinology 2020Several reports in humans as well as transgenic mouse models have shown that estrogens play an important role in male reproduction and fertility. Estrogen receptor alpha... (Review)
Review
Several reports in humans as well as transgenic mouse models have shown that estrogens play an important role in male reproduction and fertility. Estrogen receptor alpha (ERα) and beta (ERβ) are expressed in different male tissues including the brain. The estradiol-binding protein GPER1 also mediates estrogen action in target tissues. In human testes a minimal ERα expression during prepuberty along with a marked pubertal up-regulation in germ cells has been reported. ERβ expression was detected mostly in spermatogonia, primary spermatocytes, and immature spermatids. In Sertoli cells ERβ expression increases with age. The aromatase enzyme (cP450arom), which converts androgens to estrogens, is widely expressed in human tissues (including gonads and hypothalamus), even during fetal life, suggesting that estrogens are also involved in human fetal physiology. Moreover, cP450arom is expressed in the early postnatal testicular Leydig cells and spermatogonia. Even though the aromatase complex is required for estrogen synthesis, its biological relevance is also related to the regulation of the balance between androgens and estrogens in different tissues. Knockout mouse models of aromatase (ArKO) and estrogen receptors (ERKOα, ERKOβ, and ERKOαβ) provide an important tool to study the effects of estrogens on the male reproductive physiology including the gonadal axis. High basal serum FSH levels were reported in adult aromatase-deficient men, suggesting that estrogens are involved in the negative regulatory gonadotropin feedback. However, normal serum gonadotropin levels were observed in an aromatase-deficient boy, suggesting a maturational pattern role of estrogen in the regulation of gonadotropin secretion. Nevertheless, the role of estrogens in primate testis development and function is controversial and poorly understood. This review addresses the role of estrogens in gonadotropin secretion and testicular physiology in male humans especially during childhood and puberty.
Topics: Animals; Estrogens; Gene Expression Regulation, Developmental; Gonadotropins; Humans; Male; Puberty; Testis
PubMed: 32158430
DOI: 10.3389/fendo.2020.00072 -
FASEB Journal : Official Publication of... May 2021Obesity is a risk factor for postmenopausal breast cancer. Obesity-related inflammation upregulates aromatase expression, the rate-limiting enzyme for estrogen...
Obesity is a risk factor for postmenopausal breast cancer. Obesity-related inflammation upregulates aromatase expression, the rate-limiting enzyme for estrogen synthesis, in breast adipose tissue (BAT), increasing estrogen production and cancer risk. The regulation of aromatase gene (CYP19A1) in BAT is complex, and the mechanisms linking obesity and aromatase dysregulation are not fully understood. An obesity-associated factor that could regulate aromatase is the CC chemokine ligand (CCL) 2, a pro-inflammatory factor that also activates signaling pathways implicated in CYP19A1 transcription. By using human primary breast adipose stromal cells (ASCs) and aromatase reporter (hARO-Luc) mouse mammary adipose explants, we demonstrated that CCL2 enhances the glucocorticoid-mediated CYP19A1 transcription. The potential mechanism involves the activation of PI.4 via ERK1/2 pathway. We also showed that CCL2 contributes to the pro-inflammatory milieu and aromatase expression in obesity, evidenced by increased expression of CCL2 and CYP19A1 in mammary tissues from obese hARO-Luc mice, and subcutaneous adipose tissue from obese women. In summary, our results indicate that postmenopausal obesity may promote CCL2 production in BAT, leading to exacerbation of the menopause-related inflammatory state and further stimulation of local aromatase and estrogens. These results provide new insights into the regulation of aromatase and may aid in finding approaches to prevent breast cancer.
Topics: Animals; Aromatase; Breast; Chemokine CCL2; Female; Gene Expression Regulation, Enzymologic; Humans; Mesenchymal Stem Cells; Mice; Obesity; Transcriptional Activation
PubMed: 33913559
DOI: 10.1096/fj.201902485RRR -
Women's Health (London, England) 2023In estrogen-receptor-positive tumors, adjuvant endocrine therapy has been shown to be highly beneficial for both overall and disease-free survival. Estradiol is key in... (Review)
Review
In estrogen-receptor-positive tumors, adjuvant endocrine therapy has been shown to be highly beneficial for both overall and disease-free survival. Estradiol is key in regulating bone and mineral physiology, and several studies found a strong correlation between these therapies and the risk of fractures. Since these therapies are often given for 5 through 10 years, the timing for bisphosphonates or denosumab initiation seems essential to managing bone metabolism. However, gray zones and discrepancies between guidelines remain as to the best threshold when to start antiresorptive treatment, or whether antiresorptive treatment should be administered to every woman undergoing adjuvant endocrine therapy, independent of their risk factors for fractures. Treatment options and strategies should be discussed at the start of hormone adjuvant therapy to come to a shared decision with the patient, with the final aim of reducing the risk of future fractures as much as possible. This review will cover present guidelines and literature on antiresorptive treatment in this setting, to provide clinicians with useful clues for managing these patients.
Topics: Female; Humans; Aromatase Inhibitors; Bone Density; Bone Density Conservation Agents; Breast Neoplasms; Fractures, Bone; Receptors, Estrogen
PubMed: 36644991
DOI: 10.1177/17455057221149493 -
The Journal of Clinical Endocrinology... Jul 2022Body fat distribution is a risk factor for obesity-associated comorbidities, and adipose tissue dysfunction plays a role in this association. In humans, there is a sex...
CONTEXT
Body fat distribution is a risk factor for obesity-associated comorbidities, and adipose tissue dysfunction plays a role in this association. In humans, there is a sex difference in body fat distribution, and steroid hormones are known to regulate several cellular processes within adipose tissue.
OBJECTIVE
Our aim was to investigate if intra-adipose steroid concentration and expression or activity of steroidogenic enzymes were associated with features of adipose tissue dysfunction in individuals with severe obesity.
METHODS
Samples from 40 bariatric candidates (31 women, 9 men) were included in the study. Visceral (VAT) and subcutaneous adipose tissue (SAT) were collected during surgery. Adipose tissue morphology was measured by a combination of histological staining and semi-automated quantification. Following extraction, intra-adipose and plasma steroid concentrations were determined by liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS). Aromatase activity was estimated using product over substrate ratio, while AKR1C2 activity was measured directly by fluorogenic probe. Gene expression was measured by quantitative PCR.
RESULTS
VAT aromatase activity was positively associated with VAT adipocyte hypertrophy (P valueadj < 0.01) and negatively with plasma high-density lipoprotein (HDL)-cholesterol (P valueadj < 0.01), while SAT aromatase activity predicted dyslipidemia in women even after adjustment for waist circumference, age, and hormonal contraceptive use. We additionally compared women with high and low visceral adiposity index (VAI) and found that VAT excess is characterized by adipose tissue dysfunction, increased androgen catabolism mirrored by increased AKR1C2 activity, and higher aromatase expression and activity indices.
CONCLUSION
In women, increased androgen catabolism or aromatization is associated with visceral adiposity and adipose tissue dysfunction.
Topics: Adipose Tissue; Androgens; Aromatase; Body Fat Distribution; Body Mass Index; Female; Gonadal Steroid Hormones; Humans; Intra-Abdominal Fat; Male; Obesity, Morbid; Tandem Mass Spectrometry
PubMed: 35511873
DOI: 10.1210/clinem/dgac261 -
SAGE Open Medicine 2022Since their introduction into clinical use in the 1970s, aromatase inhibitors have been a cornerstone of therapy for estrogen-receptor positive breast cancer in... (Review)
Review
Since their introduction into clinical use in the 1970s, aromatase inhibitors have been a cornerstone of therapy for estrogen-receptor positive breast cancer in postmenopausal women. Unfortunately, this therapy leads to estrogen depletion in the body, which can lead to unpleasant side effects such as menopausal symptoms like hot flashes, insomnia, slightly increased risk of ischemic heart disease, accelerated bone loss leading to higher osteoporosis risk, and most significantly, arthralgias. The joint pain induced by aromatase inhibitor therapy is frequently cited as the leading cause of premature discontinuation; approximately 50% of patients will report new onset or worsening joint pain 1 year after therapy initiation, approximately 30% of patients discontinue therapy after 1 year, and only 50%-68% of patients remain fully compliant with therapy after 3 years. This article will describe risk factors for aromatase inhibitor-associated musculoskeletal syndrome, including genetic predispositions correlated with an increased risk of this syndrome, explain the currently understood pathophysiology, and give an overview of effective treatment options in managing this syndrome.
PubMed: 35321462
DOI: 10.1177/20503121221078722 -
In Vivo (Athens, Greece) 2022Aromatase inhibitor therapy is currently the preferred choice in postmenopausal women with estrogen receptor positive breast cancer. This article reviews the ocular side... (Review)
Review
BACKGROUND
Aromatase inhibitor therapy is currently the preferred choice in postmenopausal women with estrogen receptor positive breast cancer. This article reviews the ocular side effects of treatment with aromatase inhibitors (AIs) in patients with breast cancer.
MATERIALS AND METHODS
A comprehensive search was performed on PubMed, Web of Science and Google scholar.
RESULTS
After duplication removal, 14 clinical studies and 5 case reports, published between 2008 and 2021, were identified. Most frequently, AI treatment resulted in minor to moderate dry eye symptoms. "De novo" onset of Sjogren syndrome during AI therapy was also reported. Retinal and optic nerve side effects varied from mild, subclinical anatomic and functional impairment to severe decreased vision, secondary to hemi-central retinal artery occlusion, bilateral optic neuritis or uveitis with bilateral macular edema.
CONCLUSION
Visual disturbances encountered during AI treatment may be underestimated. Ophthalmic screening is important for early detection and appropriate treatment.
Topics: Antineoplastic Agents, Hormonal; Aromatase Inhibitors; Breast Neoplasms; Female; Humans
PubMed: 34972698
DOI: 10.21873/invivo.12674 -
Cardiovascular Journal of AfricaEpicardial adipose tissue (EAT) aromatase converts androstenedione and other adrenal androgens into oestrogens. The locally produced oestradiol (E) may have...
OBJECTIVES
Epicardial adipose tissue (EAT) aromatase converts androstenedione and other adrenal androgens into oestrogens. The locally produced oestradiol (E) may have cardiovascular protective effects. Little is known about the relationship between EAT aromatase level and coronary heart disease (CHD). Here, we compared EAT aromatase levels in CHD versus non-CHD patients and assessed the relationship between EAT aromatase levels and lesion degree in the coronary arteries.
METHODS
EAT and blood specimens were obtained from patients undergoing thoracotomy prior to cardiopulmonary bypass. Serum E levels were obtained from our hospital laboratory. EAT aromatase expression was determined by RT-qPCR and ELISA assays. All patients underwent coronary angiography and the level of coronary lesions was evaluated with the SYNTAX score.
RESULTS
Compared with non-CHD patients, CHD patients had lower EAT aromatase mRNA and protein levels. In the CHD patients, EAT aromatase and oestrogen levels negatively correlated with the severity of coronary artery disease.
CONCLUSIONS
Our data revealed that reduced EAT aromatase levels correlated with coronary atherosclerotic lesions. Reduced EAT aromatase protein levels may aggravate the severity of atherosclerosis. Future studies should investigate the mechanisms regulating aromatase expression in epicardial fat.
Topics: Adipose Tissue; Aged; Aged, 80 and over; Aromatase; Case-Control Studies; Coronary Angiography; Coronary Artery Disease; Enzyme-Linked Immunosorbent Assay; Estrogens; Female; Gene Expression Regulation; Humans; Male; Middle Aged; Pericardium; Real-Time Polymerase Chain Reaction
PubMed: 34128950
DOI: 10.5830/CVJA-2021-012