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Clinical Medicine Insights.... 2019The source of polycystic ovarian syndrome (PCOS) is much debated and is likely to be multifactorial. There is an apparent familial inheritance with first-degree... (Review)
Review
The source of polycystic ovarian syndrome (PCOS) is much debated and is likely to be multifactorial. There is an apparent familial inheritance with first-degree relatives of sufferers more likely to be affected. Twin studies have suggested a genetic cause but candidate genes are yet to be verified. Genes affecting insulin resistance, steroid hormone production, and inflammatory cytokine responses have all been implicated. Current thinking supports the theory that exposure to environmental factors in utero predisposes a female foetus to hyperandrogenism, insulin resistance, and polycystic ovaries in adult life. Which environmental factors have an impact on the foetus and the mechanisms of exposure are still to be confirmed. Animal studies have shown a clear correlation between hyperexposure of the foetus to androgens in utero and future development of a PCOS pattern of symptoms. Placental aromatases should neutralise androgens from the maternal circulation and prevent them reaching the foetal circulation. Our hypothesis is that the high maternal anti-Mullerian hormone (AMH) levels in PCOS block the placental aromatase and allow passage of testosterone through the placenta. This maternal testosterone acts on the foetal ovaries and 'programmes' them to recruit more preantral follicles and so produce higher AMH levels when they become functional at around 36 weeks of gestation. The high AMH concentrations in PCOS also seem to increase luteinizing hormone release and inhibit follicle stimulating hormone action on aromatase, so adding to the hyperandrogenic environment of adult PCOS.
PubMed: 31516315
DOI: 10.1177/1179558119871467 -
Animals : An Open Access Journal From... Jun 2021Estrogens are important physiological regulators of testicular activity in vertebrates. Estrogen levels depend on the activity of P450 aromatase, the enzyme responsible... (Review)
Review
Estrogens are important physiological regulators of testicular activity in vertebrates. Estrogen levels depend on the activity of P450 aromatase, the enzyme responsible for the irreversible conversion of testosterone into 17β-estradiol. Therefore, P450 aromatase is the key player in the aromatase-estrogen system. The present review offers a comparative overview of P450 aromatase activity in male gonads of amphibians, reptiles, and birds, with a particular emphasis on the functions of the aromatase-estrogen system in these organisms during their developmental and adult stages. The aromatase-estrogen system appears to be crucial for the sex differentiation of gonads in vertebrates. Administration of aromatase inhibitors prior to sexual differentiation of gonads results in the development of males rather than females. In adults, both aromatase and estrogen receptors are expressed in somatic cells, Leydig and Sertoli cells, as well as germ cells, with certain differences among different species. In seasonal breeding species, the aromatase-estrogen system serves as an "on/off" switch for spermatogenesis. In some amphibian and reptilian species, increased estrogen levels in post-reproductive testes are responsible for blocking spermatogenesis, whereas, in some species of birds, estrogens function synergistically with testosterone to promote spermatogenesis. Recent evidence indicates that the production of the aromatase enzyme in excessive amounts reduces the reproductive performance in avian species of commercial interest. The use of aromatase inhibitors to improve fertility has yielded suitable positive results. Therefore, it appears that the role of the aromatase-estrogen system in regulating the testicular activity differs not only among the different classes of vertebrates but also among different species within the same class.
PubMed: 34204693
DOI: 10.3390/ani11061763 -
The Journal of Clinical Investigation Jan 2023Prostate cancer is highly dependent on androgens and the androgen receptor (AR). Hormonal therapies inhibit gonadal testosterone production, block extragonadal androgen...
Prostate cancer is highly dependent on androgens and the androgen receptor (AR). Hormonal therapies inhibit gonadal testosterone production, block extragonadal androgen biosynthesis, or directly antagonize AR. Resistance to medical castration occurs as castration-resistant prostate cancer (CRPC) and is driven by reactivation of the androgen-AR axis. 3β-hydroxysteroid dehydrogenase-1 (3βHSD1) serves as the rate-limiting step for potent androgen synthesis from extragonadal precursors, thereby stimulating CRPC. Genetic evidence in men demonstrates the role of 3βHSD1 in driving CRPC. In postmenopausal women, 3βHSD1 is required for synthesis of aromatase substrates and plays an essential role in breast cancer. Therefore, 3βHSD1 lies at a critical junction for the synthesis of androgens and estrogens, and this metabolic flux is regulated through germline-inherited mechanisms. We show that phosphorylation of tyrosine 344 (Y344) occurs and is required for 3βHSD1 cellular activity and generation of Δ4, 3-keto-substrates of 5α-reductase and aromatase, including in patient tissues. BMX directly interacts with 3βHSD1 and is necessary for enzyme phosphorylation and androgen biosynthesis. In vivo blockade of 3βHSD1 Y344 phosphorylation inhibits CRPC. These findings identify what we believe to be new hormonal therapy pharmacologic vulnerabilities for sex-steroid dependent cancers.
Topics: Male; Humans; Androgens; Prostatic Neoplasms, Castration-Resistant; Aromatase; Receptors, Androgen; Prostatic Neoplasms; Testosterone; Protein-Tyrosine Kinases
PubMed: 36647826
DOI: 10.1172/JCI163498 -
Molecular and Cellular Endocrinology Feb 2022Testicular aromatase catalyzes the synthesis of estradiol, which contributes to regulation of porcine Sertoli cell proliferation and postpubertal maintenance of Sertoli...
Testicular aromatase catalyzes the synthesis of estradiol, which contributes to regulation of porcine Sertoli cell proliferation and postpubertal maintenance of Sertoli cell numbers. Although aromatase enzymatic activity decreases with age and is persistently reprogrammed by prepubertal treatment with the aromatase inhibitor letrozole, the molecular bases for regulation have not been identified. DNA methylation was examined as a potential regulatory mechanism using DNA from Leydig cells isolated from 16-, 40-, and 68-week-old boars and from 68- week-old littermates treated with the aromatase inhibitor, letrozole. Methylation levels of individual CpG dinucleotides located in the distal untranslated exon 1 of the relevant aromatase encoding gene, CYP19A3, were quite high in Leydig cell DNA, and increased further with maturity of boar (P < 0.05), while aromatase activity and transcript abundance decreased more than two-fold. However, reduced aromatase activity following letrozole treatment was not accompanied by altered DNA methylation. Testicular expression of miR378 was altered by prepubertal treatment with letrozole. The data provide evidence for two different epigenetic mechanisms that regulate aromatase expression and enzymatic activity in the boar testis.
Topics: Animals; Animals, Newborn; Aromatase; Aromatase Inhibitors; Cells, Cultured; Epigenesis, Genetic; Gene Expression Regulation, Developmental; Gene Expression Regulation, Enzymologic; Letrozole; Leydig Cells; Male; Sertoli Cells; Swine; Testis
PubMed: 34856344
DOI: 10.1016/j.mce.2021.111526 -
Clinical Cancer Research : An Official... Dec 2023In estrogen receptor-positive (ER+) breast cancer, single-nucleotide polymorphisms (SNP) in the aromatase gene might affect aromatase inhibitors (AI) metabolism and...
PURPOSE
In estrogen receptor-positive (ER+) breast cancer, single-nucleotide polymorphisms (SNP) in the aromatase gene might affect aromatase inhibitors (AI) metabolism and efficacy. Here, we assessed the impact of SNP on prognosis and toxicity of patients receiving adjuvant letrozole.
EXPERIMENTAL DESIGN
We enrolled 886 postmenopausal patients in the study. They were treated with letrozole for 2 to 5 years after taking tamoxifen for 2 to 6 years, continuing until they completed 5 to 10 years of therapy. Germline DNA was genotyped for SNP rs4646, rs10046, rs749292, and rs727479. Log-rank test and Cox model were used for disease-free survival (DFS) and overall survival (OS). Cumulative incidence (CI) of breast cancer metastasis was assessed through competing risk analysis, with contralateral breast cancer, second malignancies and non-breast cancer death as competing events. CI of skeletal and cardiovascular events were assessed using DFS events as competing events. Subdistribution HR (sHR) with 95% confidence intervals were calculated through Fine-Gray method.
RESULTS
No SNP was associated with DFS. Variants rs10046 [sHR 2.03, (1.04-2.94)], rs749292 [sHR 2.11, (1.12-3.94)], and rs727479 [sHR 2.62, (1.17-5.83)] were associated with breast cancer metastasis. Three groups were identified on the basis of the number of these variants (0, 1, >1). Variant-based groups were associated with breast cancer metastasis (10-year CI 2.5%, 7.6%, 10.7%, P = 0.035) and OS (10-year estimates 96.5%, 93.0%, 89.6%, P = 0.030). Co-occurrence of rs10046 and rs749292 was negatively associated with 10-year CI of skeletal events (3.2% vs. 10%, P = 0.033). A similar association emerged between rs727479 and cardiovascular events (0.3% vs. 2.1%, P = 0.026).
CONCLUSIONS
SNP of aromatase gene predict risk of metastasis and AI-related toxicity in ER+ early breast cancer, opening an opportunity for better treatment individualization.
Topics: Female; Humans; Aromatase; Aromatase Inhibitors; Biomarkers; Breast Neoplasms; Cardiovascular Diseases; Chemotherapy, Adjuvant; Letrozole; Polymorphism, Single Nucleotide; Tamoxifen
PubMed: 37888299
DOI: 10.1158/1078-0432.CCR-23-1568 -
Frontiers in Neurology 2020Estrogens such as estradiol (E2) are potent effectors of neural structure and function via peripheral and central synthesis. In the zebra finch (), neural E2 synthesis... (Review)
Review
Estrogens such as estradiol (E2) are potent effectors of neural structure and function via peripheral and central synthesis. In the zebra finch (), neural E2 synthesis is among the highest reported in homeotherms due to the abundant constitutive expression of aromatase (E-synthase) in discrete neuronal pools across the forebrain. Following penetrating or concussive trauma, E2 synthesis increases even further via the induced expression of aromatase in reactive astrocytes around the site of damage. Injury-associated astrocytic aromatization occurs in the brains of both sexes regardless of the site of injury and can remain elevated for weeks following trauma. Interestingly, penetrating injury induces astrocytic aromatase more rapidly in females compared to males, but this sex difference is not detectable 24 h posttrauma. Indeed, unilateral penetrating injury can increase E2 content 4-fold relative to the contralateral uninjured hemisphere, suggesting that glial aromatization may be a powerful source of neural E2 available to circuits. Glial aromatization is neuroprotective as inhibition of injury-induced aromatase increases neuroinflammation, gliosis, necrosis, apoptosis, and infarct size. These effects are ameliorated upon replacement with E2, suggesting that the songbird may have evolved a rapidly responsive neurosteroidogenic system to protect vulnerable brain circuits. The precise signals that induce aromatase expression in astrocytes include elements of the inflammatory cascade and underscore the sentinel role of the innate immune system as a crucial effector of trauma-associated E2 provision in the vertebrate brain. This review will describe the inductive signals of astroglial aromatase and the neuroprotective role for glial E2 synthesis in the adult songbird brains of both sexes.
PubMed: 32655477
DOI: 10.3389/fneur.2020.00497 -
Current Opinion in Endocrine and... Dec 2021Glial cells are important contributors to the hormonal milieu of the brain, particularly following damage. In birds and mammals, neural injury induces the expression of...
Glial cells are important contributors to the hormonal milieu of the brain, particularly following damage. In birds and mammals, neural injury induces the expression of aromatase in astroglia at and around the site of damage. This review describes the progression of our understanding about the incidence, regulation, and function of estrogens synthesized in glia. Following a quick discussion of the landmark studies that first demonstrated steroidogenesis in glia, I go on to describe how the inflammatory response following perturbation of the brain results in the transcription of aromatase and the resultant rise in local estradiol. I end with several unanswered questions, the answers to which may reveal the precise manner in which neurosteroids protect the brain from injury, both prior to and immediately following injury.
PubMed: 35274063
DOI: 10.1016/j.coemr.2021.100298 -
European Review For Medical and... Apr 2022Estrogens and progestogens act on female reproductive tissues in opposite ways. As they counteract each other actions, the correct balance between these two classes of...
Estrogens and progestogens act on female reproductive tissues in opposite ways. As they counteract each other actions, the correct balance between these two classes of hormones is pivotal to avoid dangerous states. Unopposed estrogens occur when progestogen levels do not balance estrogens, primarily deriving from overproduction of estrogens via aromatase enzyme. In the endometrium, unopposed estrogens induce proliferative or invasive phenomena, which represent the first step toward different diseases. These pathologies include endometrial hyperplasia, endometrial polyps, endometriosis and adenomyosis. Endometrial hyperplasia and polyps are proliferative pathologies, while endometriosis and adenomyosis are characterized by the invasion of other tissues by endometrial cells. Current pharmacological treatments include Gonadotropin-Releasing-Hormone analogs, aromatase inhibitors and progestogens, either alone or in combination with estrogens. As these drugs usually lead to burdensome undesired effects, researchers seek to find new therapeutical molecules. Recent literature highlights the positive effects of metformin, an insulin sensitizing drug that reduces the insulin proliferative stimulus on the endometrium. d-chiro-inositol is an insulin second messenger with insulin sensitizing and mimetic properties, recently described as an aromatase down-regulator. Based on current evidence, d-chiro-inositol may be useful to treat the pathologies responsive to unopposed estrogens.
Topics: Adenomyosis; Aromatase; Endometrial Hyperplasia; Endometriosis; Endometrium; Estrogens; Female; Humans; Inositol; Insulins; Progestins
PubMed: 35503642
DOI: 10.26355/eurrev_202204_28629 -
Reproductive Medicine and Biology Oct 2019It has been well established that endometriosis is an estrogen-dependent disease. Although the exact pathogenesis of the disease is still unclear, it is known to be... (Review)
Review
BACKGROUND
It has been well established that endometriosis is an estrogen-dependent disease. Although the exact pathogenesis of the disease is still unclear, it is known to be characterized by estrogen-dependent growth and maintenance of the ectopic endometrium and increased local estrogen production.
METHODS
The authors reviewed studies on local estrogen production and estrogen activities mediated by estrogen receptors in endometriotic tissues.
MAIN FINDINGS
Aberrant expression of several enzymes in local endometriotic lesions contributed to the production and metabolism of estrogens. Aromatase was one of the key therapeutic targets for the regulation of local estrogen formation. Our findings suggest that PGC-1a, a transcriptional coactivator-modulating steroid hormone, regulates aromatase expression and activity. Estrogen activities mediated by different types of estrogen receptors abnormally elevated in local tissues could also be involved in the development of endometriosis. The authors demonstrated that the isoflavone aglycone, a partial agonist of the estrogen receptor, suppressed the formation of endometriotic lesions.
CONCLUSIONS
Local estrogen production and estrogen activity mediated by estrogen receptors are important potential therapeutic targets for endometriosis.
PubMed: 31607790
DOI: 10.1002/rmb2.12285 -
International Journal of Molecular... Mar 2023Polycystic ovarian syndrome (PCOS) is the most common endocrinological disorder in women, in which, besides chronic anovulation/oligomenorrhea and ovarian cysts,... (Review)
Review
Polycystic ovarian syndrome (PCOS) is the most common endocrinological disorder in women, in which, besides chronic anovulation/oligomenorrhea and ovarian cysts, hyperandrogenism plays a critical role in a large fraction of subjects. Inositol isomers-myo-Inositol and D-Chiro-Inositol-have recently been pharmacologically effective in managing many PCOS symptoms while rescuing ovarian fertility. However, some disappointing clinical results prompted the reconsideration of their specific biological functions. Surprisingly, D-Chiro-Ins stimulates androgen synthesis and decreases the ovarian estrogen pathway; on the contrary, myo-Ins activates FSH response and aromatase activity, finally mitigating ovarian hyperandrogenism. However, when the two isomers are given in association-according to the physiological ratio of 40:1-patients could benefit from myo-Ins enhanced FSH and estrogen responsiveness, while taking advantage of the insulin-sensitizing effects displayed mostly by D-Chiro-Ins. We need not postulate insulin resistance to explain PCOS pathogenesis, given that insulin hypersensitivity is likely a shared feature of PCOS ovaries. Indeed, even in the presence of physiological insulin stimulation, the PCOS ovary synthesizes D-Chiro-Ins four times more than that measured in control theca cells. The increased D-Chiro-Ins within the ovary is detrimental in preserving steroidogenic control, and this failure can easily explain why treatment strategies based upon high D-Chiro-Ins have been recognized as poorly effective. Within this perspective, two factors emerge as major determinants in PCOS: hyperandrogenism and reduced aromatase expression. Therefore, PCOS could no longer be considered a disease only due to increased androgen synthesis without considering the contemporary downregulation of aromatase and FSH receptors. Furthermore, these findings suggest that inositols can be specifically effective only for those PCOS phenotypes featured by hyperandrogenism.
Topics: Humans; Female; Polycystic Ovary Syndrome; Inositol; Hyperandrogenism; Aromatase; Androgens; Insulin Resistance; Insulin; Follicle Stimulating Hormone; Estrogens
PubMed: 37047265
DOI: 10.3390/ijms24076296