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Frontiers in Endocrinology 2021Letrozole, an aromatase inhibitor that blocks estrogen synthesis by inhibiting the final step of the estrogen biosynthetic pathway, has been used in the applications of... (Review)
Review
Letrozole, an aromatase inhibitor that blocks estrogen synthesis by inhibiting the final step of the estrogen biosynthetic pathway, has been used in the applications of a wide range of infertility settings. It has been more than 20 years since the initial clinical trial of letrozole for ovulation induction. In light of the accumulating clinical and basic evidence, the efficacy and safety of letrozole have been identified. This mini review focuses on our current knowledge of the applications and mechanisms of letrozole for female infertility and various questions are put forward about how letrozole could be more effectively used.
Topics: Aromatase Inhibitors; Female; Humans; Infertility, Female; Letrozole; Treatment Outcome
PubMed: 34220713
DOI: 10.3389/fendo.2021.676133 -
Frontiers in Endocrinology 2021Aromatase inhibitors (AIs) are a key component in the chemoprevention and treatment of hormone receptor-positive (HR+) breast cancer. While the addition of AI therapy... (Review)
Review
Aromatase inhibitors (AIs) are a key component in the chemoprevention and treatment of hormone receptor-positive (HR+) breast cancer. While the addition of AI therapy has improved cancer-related outcomes in the management of HR+ breast cancer, AIs are associated with musculoskeletal adverse effects known as the aromatase inhibitor-associated musculoskeletal syndrome (AIMSS) that limit its tolerability and use. AIMSS is mainly comprised of AI-associated bone loss and arthralgias that affect up to half of women on AI therapy and detrimentally impact patient quality of life and treatment adherence. The pathophysiology of AIMSS is not fully understood though has been proposed to be related to estrogen deprivation within the musculoskeletal and nervous systems. This review aims to characterize the prevalence, risk factors, and clinical features of AIMSS, and explore the syndrome's underlying mechanisms and management strategies.
Topics: Aromatase Inhibitors; Arthralgia; Body Mass Index; Bone Density; Breast Neoplasms; Chemoprevention; Female; Humans; Musculoskeletal Diseases; Receptors, Estrogen; Risk Factors
PubMed: 34385978
DOI: 10.3389/fendo.2021.713700 -
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 -
Journal of Experimental & Clinical... Apr 2023Lipid metabolic reprogramming in colon cancer shows a potential impact on tumor immune microenvironment and is associated with response to immunotherapy. Therefore,...
BACKGROUND
Lipid metabolic reprogramming in colon cancer shows a potential impact on tumor immune microenvironment and is associated with response to immunotherapy. Therefore, this study aimed to develop a lipid metabolism-related prognostic risk score (LMrisk) to provide new biomarkers and combination therapy strategies for colon cancer immunotherapy.
METHODS
Differentially expressed lipid metabolism-related genes (LMGs) including cytochrome P450 (CYP) 19A1 were screened to construct LMrisk in TCGA colon cancer cohort. The LMrisk was then validated in three GEO datasets. The differences of immune cell infiltration and immunotherapy response between LMrisk subgroups were investigated via bioinformatic analysis. These results were comfirmed by in vitro coculture of colon cancer cells with peripheral blood mononuclear cells, human colon cancer tissue microarray analysis, multiplex immunofluorescence staining and mouse xenograft models of colon cancer.
RESULTS
Six LMGs including CYP19A1, ALOXE3, FABP4, LRP2, SLCO1A2 and PPARGC1A were selected to establish the LMrisk. The LMrisk was positively correlated with the abundance of macrophages, carcinoma-associated fibroblasts (CAFs), endothelial cells and the levels of biomarkers for immunotherapeutic response including programmed cell death ligand 1 (PD-L1) expression, tumor mutation burden and microsatellite instability, but negatively correlated with CD8 T cell infiltration levels. CYP19A1 protein expression was an independent prognostic factor, and positively correlated with PD-L1 expression in human colon cancer tissues. Multiplex immunofluorescence analyses revealed that CYP19A1 protein expression was negatively correlated with CD8 T cell infiltration, but positively correlated with the levels of tumor-associated macrophages, CAFs and endothelial cells. Importantly, CYP19A1 inhibition downregulated PD-L1, IL-6 and TGF-β levels through GPR30-AKT signaling, thereby enhancing CD8 T cell-mediated antitumor immune response in vitro co-culture studies. CYP19A1 inhibition by letrozole or siRNA strengthened the anti-tumor immune response of CD8 T cells, induced normalization of tumor blood vessels, and enhanced the efficacy of anti-PD-1 therapy in orthotopic and subcutaneous mouse colon cancer models.
CONCLUSION
A risk model based on lipid metabolism-related genes may predict prognosis and immunotherapeutic response in colon cancer. CYP19A1-catalyzed estrogen biosynthesis promotes vascular abnormality and inhibits CD8 T cell function through the upregulation of PD-L1, IL-6 and TGF-β via GPR30-AKT signaling. CYP19A1 inhibition combined with PD-1 blockade represents a promising therapeutic strategy for colon cancer immunotherapy.
Topics: Animals; Mice; Humans; CD8-Positive T-Lymphocytes; B7-H1 Antigen; Lipid Metabolism; Leukocytes, Mononuclear; Endothelial Cells; Interleukin-6; Proto-Oncogene Proteins c-akt; Prognosis; Colonic Neoplasms; Transforming Growth Factor beta; Immunotherapy; Tumor Microenvironment; Aromatase
PubMed: 37055842
DOI: 10.1186/s13046-023-02647-8 -
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 -
Frontiers in Endocrinology 2021Skeletal maturation can be delayed by reducing the exposure to estrogens, either by halting pubertal development through administering a GnRH analogue (GnRHa), or by... (Review)
Review
Skeletal maturation can be delayed by reducing the exposure to estrogens, either by halting pubertal development through administering a GnRH analogue (GnRHa), or by blocking the conversion of androgens to estrogens through an aromatase inhibitor (AI). These agents have been investigated in children with growth disorders (off-label), either alone or in combination with recombinant human growth hormone (rhGH). GnRHa is effective in attaining a normal adult height (AH) in the treatment of children with central precocious puberty, but its effect in short children with normal timing of puberty is equivocal. If rhGH-treated children with growth hormone deficiency or those who were born small-for-gestational age are still short at pubertal onset, co-treatment with a GnRHa for 2-3 years increases AH. A similar effect was seen by adding rhGH to GnRHa treatment of children with central precocious puberty with a poor AH prediction and by adding rhGH plus GnRHa to children with congenital adrenal hyperplasia with a poor predicted adult height on conventional treatment with gluco- and mineralocorticoids. In girls with idiopathic short stature and relatively early puberty, rhGH plus GnRHa increases AH. Administration of letrozole to boys with constitutional delay of growth puberty may increase AH, and rhGH plus anastrozole may increase AH in boys with growth hormone deficiency or idiopathic short stature, but the lack of data on attained AH and potential selective loss-of-follow-up in several studies precludes firm conclusions. GnRHas appear to have a good overall safety profile, while for aromatase inhibitors conflicting data have been reported.
Topics: Adolescent; Adrenal Hyperplasia, Congenital; Aromatase Inhibitors; Body Height; Bone Development; Child; Female; Gonadotropin-Releasing Hormone; Growth Disorders; Haploinsufficiency; Human Growth Hormone; Humans; Infant, Small for Gestational Age; Male; Puberty; Puberty, Precocious; Recombinant Proteins
PubMed: 34975773
DOI: 10.3389/fendo.2021.812196 -
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 -
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 -
Androgens: Clinical Research and... 2021The aromatase cytochrome P450 (P450arom) enzyme, or estrogen synthase, which is coded by the gene, is widely expressed in a subpopulation of excitatory and inhibitory... (Review)
Review
The aromatase cytochrome P450 (P450arom) enzyme, or estrogen synthase, which is coded by the 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.
PubMed: 35024691
DOI: 10.1089/andro.2021.0007 -
Nature Communications Jul 2023Aromatase inhibitors (AIs) reduce recurrences and mortality in postmenopausal patients with oestrogen receptor positive (ER+) breast cancer (BC), but >20% of patients...
Aromatase inhibitors (AIs) reduce recurrences and mortality in postmenopausal patients with oestrogen receptor positive (ER+) breast cancer (BC), but >20% of patients will eventually relapse. Given the limited understanding of intrinsic resistance in these tumours, here we conduct a large-scale molecular analysis to identify features that impact on the response of ER + HER2- BC to AI. We compare the 15% of poorest responders (PRs, n = 177) as measured by proportional Ki67 changes after 2 weeks of neoadjuvant AI to good responders (GRs, n = 190) selected from the top 50% responders in the POETIC trial and matched for baseline Ki67 categories. In this work, low ESR1 levels are associated with poor response, high proliferation, high expression of growth factor pathways and non-luminal subtypes. PRs having high ESR1 expression have similar proportions of luminal subtypes to GRs but lower plasma estradiol levels, lower expression of estrogen response genes, higher levels of tumor infiltrating lymphocytes and immune markers, and more TP53 mutations.
Topics: Humans; Female; Aromatase Inhibitors; Breast Neoplasms; Ki-67 Antigen; Postmenopause; Receptors, Estrogen; Neoplasm Recurrence, Local; Receptor, ErbB-2
PubMed: 37419892
DOI: 10.1038/s41467-023-39613-z