- Progestogens and venous thromboembolism in menopausal women: an updated oral versus transdermal estrogen meta-analysis. [Journal Article]
- CClimacteric 2018 Mar 23; :1-5
- Postmenopausal hormone therapy (HT) is a modifiable risk factor for venous thromboembolism (VTE). While the route of estrogen administration is now well recognized as an important determinant of VTE ...
Postmenopausal hormone therapy (HT) is a modifiable risk factor for venous thromboembolism (VTE). While the route of estrogen administration is now well recognized as an important determinant of VTE risk, there is also increasing evidence that progestogens may modulate the estrogen-related VTE risk. This review updates previous meta-analyses of VTE risk in HT users, focusing on the route of estrogen administration, hormonal regimen and progestogen type. Among women using estrogen-only preparations, oral but not transdermal preparations increased VTE risk (relative risk (RR) 1.48, 95% confidence interval (CI) 1.39-1.58; RR 0.97, 95% CI 0.87-1.09, respectively). In women using opposed estrogen, results were highly heterogeneous due to important differences between the molecules of progestogen. In transdermal estrogen users, there was no change in VTE risk in women using micronized progesterone (RR 0.93, 95% CI 0.65-1.33), whereas norpregnane derivatives were associated with increased VTE risk (RR 2.42, 95% CI 1.84-3.18). Among women using opposed oral estrogen, there was higher VTE risk in women using medroxyprogesterone acetate (RR 2.77, 95% CI 2.33-3.30) than in those using other progestins. These clinical findings, together with consistent biological data, emphasize the safety advantage of transdermal estrogen combined with progesterone and support the current evidence-based recommendations on HT, especially in women at high VTE risk.
- A Major Population of Functional KLRG1-ILC2s in Female Lungs Contributes to a Sex Bias in ILC2 Numbers. [Journal Article]
- IImmunohorizons 2018; 2(2):74-86
- Humans show significant sex differences in the incidence and severity of respiratory diseases, including asthma and virus infection. Sex hormones contribute to the female sex bias in type 2 inflammat...
Humans show significant sex differences in the incidence and severity of respiratory diseases, including asthma and virus infection. Sex hormones contribute to the female sex bias in type 2 inflammation associated with respiratory diseases, consistent with recent reports that female lungs harbor greater numbers of GATA-3-dependent group 2 innate lymphoid cells (ILC2s). In this study, we determined whether sex hormone levels govern sex differences in the numbers, phenotype, and function of ILC2s in the murine lung and bone marrow (BM). Our data show that lungs of female mice harbor significantly greater ILC2 numbers in homeostasis, in part due to a major subset of ILC2s lacking killer-cell lectin like receptor G1 (KLRG1), a population largely absent in male lungs. The KLRG1-ILC2s were capable of type 2 cytokine production and increased with age after sexual maturity, suggesting that a unique functional subset exists in females. Experiments with gonadectomized mice or mice bearing either global or lymphocyte restricted estrogen receptor α (Esr1) deficiency showed that androgens rather than estrogens regulated numbers of the KLRG1-ILC2 subset and ILC2 functional capacity in the lung and BM, as well as levels of GATA-3 expression in BM ILC2s. Furthermore, the frequency of BM PLZF+ILC precursors was higher in males and increased by excess androgens, suggesting that androgens act to inhibit the transition of ILC precursors to ILC2s. Taken together, these data show that a functional subset of KLRG1-ILC2s in females contributes to the sex bias in lung ILC2s that is observed after reproductive age.
- Estradiol: A Steroid with Multiple Facets. [Journal Article]
- HMHorm Metab Res 2018 Mar 22
- Seventy-five glorious years have passed since estradiol was discovered by Edward Doisy. From discovery in the ovaries to delineation of diverse physiological effects, research on estrogens has covere...
Seventy-five glorious years have passed since estradiol was discovered by Edward Doisy. From discovery in the ovaries to delineation of diverse physiological effects, research on estrogens has covered a lot of ground. Estrogen receptors that mediate estrogenic effects, have been detected not only in reproductive organs, but also in other body organs. Estrogen receptors function either as conventional transcription factors or as rapid signal transducers. These different modes of action are opted by estrogens to elicit an array of reproductive and non-reproductive functions. It is well established that estrogens promote cell proliferation in various tissues and hence are also linked to carcinogenesis. Anti-estrogens are being used as adjunct therapies for cancers since several years. On the other hand, estrogen-based strategies are used to alleviate adverse effects of menopause. Apart from estrogens synthesized in various organs, exposure to environmental estrogens can also impact physiology. Thus, too much or too less of estrogens can tip the balance and lead to unfavorable consequences. Multiple estrogen receptors with their tissue- or cell type-specific expression eliciting dose-dependent effects make it perplexing to 'unify' estrogenic actions in diverse tissues/organs. This warrants more research on estrogen-mediated effects and their regulation in somatic and reproductive tissues. This review presents physiological and pathological aspects of estrogens thus highlighting the good, bad, and ugly facets of estrogens.
- In breast cancer subtypes steroid sulfatase (STS) is associated with less aggressive tumour characteristics. [Journal Article]
- BJBr J Cancer 2018 Mar 22
- CONCLUSIONS: Increased intratumoural metabolism of oestrogens through STS is associated with significantly lower incidence of relapse and/or distant metastasis and correspondingly improved prognosis. The enrichment of STS in the HER2 overexpressing subtype is intriguing, especially given the possible role of HER-2 over-expression in endocrine resistance.
- Immune-Specific Expression and Estrogenic Regulation of the Four Estrogen Receptor Isoforms in Female Rainbow Trout (Oncorhynchus mykiss). [Journal Article]
- IJInt J Mol Sci 2018 Mar 21; 19(4)
- Genomic actions of estrogens in vertebrates are exerted via two intracellular estrogen receptor (ER) subtypes, ERα and ERβ, which show cell- and tissue-specific expression profiles. Mammalian immune ...
Genomic actions of estrogens in vertebrates are exerted via two intracellular estrogen receptor (ER) subtypes, ERα and ERβ, which show cell- and tissue-specific expression profiles. Mammalian immune cells express ERs and are responsive to estrogens. More recently, evidence became available that ERs are also present in the immune organs and cells of teleost fish, suggesting that the immunomodulatory function of estrogens has been conserved throughout vertebrate evolution. For a better understanding of the sensitivity and the responsiveness of the fish immune system to estrogens, more insight is needed on the abundance of ERs in the fish immune system, the cellular ratios of the ER subtypes, and their autoregulation by estrogens. Consequently, the aims of the present study were (i) to determine the absolute mRNA copy numbers of the fourERisoforms in the immune organs and cells of rainbow trout,Oncorhynchus mykiss, and to compare them to the hepaticERnumbers; (ii) to analyse theERmRNA isoform ratios in the immune system; and, (iii) finally, to examine the alterations of immuneERmRNA expression levels in sexually immature trout exposed to 17β-estradiol (E2), as well as the alterations of immuneERmRNA expression levels in sexually mature trout during the reproductive cycle. All four ER isoforms were present in immune organs-head kidney, spleen-and immune cells from head kidney and blood of rainbow trout, but their mRNA levels were substantially lower than in the liver. The ER isoform ratios were tissue- and cell-specific, both within the immune system, but also between the immune system and the liver. Short-term administration of E2 to juvenile female trout altered theERmRNA levels in the liver, but the ERs of the immune organs and cells were not responsive. Changes ofERgene transcript numbers in immune organs and cells occurred during the reproductive cycle of mature female trout, but the changes in the immune ER profiles differed from those in the liver and gonads. The correlation betweenERgene transcript numbers and serum E2 concentrations was only moderate to low. In conclusion, the low mRNA numbers of nuclear ER in the trout immune system, together with their limited estrogen-responsiveness, suggest that the known estrogen actions on trout immunity may be not primarily mediated through genomic actions, but may involve other mechanisms, such as non-genomic pathways or indirect effects.
- Secretoneurin A Directly Regulates the Proteome of Goldfish Radial Glial CellsIn Vitro. [Journal Article]
- FEFront Endocrinol (Lausanne) 2018; 9:68
- Radial glial cells (RGCs) are the main macroglia in the teleost brain and have established roles in neurogenesis and neurosteroidogenesis. They are the only brain cell type expressing aromatase B (cy...
Radial glial cells (RGCs) are the main macroglia in the teleost brain and have established roles in neurogenesis and neurosteroidogenesis. They are the only brain cell type expressing aromatase B (cyp19a1b), the enzyme that synthesizes estrogens from androgen precursors. There are few studies on the regulation of RGC functions, but our previous investigations demonstrated that dopamine stimulatescyp19a1bexpression in goldfish RGCs, while secretoneurin A (SNa) inhibits the expression of this enzyme. Here, we determine the range of proteins and cellular processes responsive to SNa treatments in these steroidogenic cells. The focus here is on SNa, because this peptide is derived from selective processing of secretogranin II in magnocellular cells embedded within the RGC-rich preoptic nucleus. Primary cultures of RGCs were treated (24 h) with 10, 100, or 1,000 nM SNa. By using isobaric tagging for relative and absolute quantitation and a Hybrid Quadrupole Obritrap Mass Spectrometry system, a total of 1,363 unique proteins were identified in RGCs, and 609 proteins were significantly regulated by SNa at one or more concentrations. Proteins that showed differential expression with all three concentrations of SNa included H1 histone, glutamyl-prolyl-tRNA synthetase, Rho GDP dissociation inhibitor γ, vimentin A2, and small nuclear ribonucleoprotein-associated protein. At 10, 100, and 1,000 nM SNa, there were 5, 195, and 489 proteins that were downregulated, respectively, whereas the number of upregulated proteins were 72, 44, and 51, respectively. Subnetwork enrichment analysis of differentially regulated proteins revealed that processes such as actin organization, cytoskeleton organization and biogenesis, apoptosis, mRNA processing, RNA splicing, translation, cell growth, and proliferation are regulated by SNa based on the proteomic response. Moreover, we observed that, at the low concentration of SNa, there was an increase in the abundance of proteins involved in cell growth, proliferation, and migration, whereas higher concentration of SNa appeared to downregulate proteins involved in these processes, indicating a dose-dependent proteome response. At the highest concentration of SNa, proteins linked to the etiology of diseases of the central nervous system (brain injuries, Alzheimer disease, Parkinson's disease, cerebral infraction, brain ischemia) were also differentially regulated. These data implicate SNa in the control of cell proliferation and neurogenesis.
- Estrogen Interactions With Lipid Rafts Related to Neuroprotection. Impact of Brain Ageing and Menopause. [Review]
- FNFront Neurosci 2018; 12:128
- Estrogens (E2) exert a plethora of neuroprotective actions against aged-associated brain diseases, including Alzheimer's disease (AD). Part of these actions takes place through binding to estrogen re...
Estrogens (E2) exert a plethora of neuroprotective actions against aged-associated brain diseases, including Alzheimer's disease (AD). Part of these actions takes place through binding to estrogen receptors (ER) embedded in signalosomes, where numerous signaling proteins are clustered. Signalosomes are preferentially located in lipid rafts which are dynamic membrane microstructures characterized by a peculiar lipid composition enriched in gangliosides, saturated fatty acids, cholesterol, and sphingolipids. Rapid E2 interactions with ER-related signalosomes appear to trigger intracellular signaling ultimately leading to the activation of molecular mechanisms against AD. We have previously observed that the reduction of E2 blood levels occurring during menopause induced disruption of ER-signalosomes at frontal cortical brain areas. These molecular changes may reduce neuronal protection activities, as similar ER signalosome derangements were observed in AD brains. The molecular impairments may be associated with changes in the lipid composition of lipid rafts observed in neurons during menopause and AD. These evidences indicate that the changes in lipid raft structure during aging may be at the basis of alterations in the activity of ER and other neuroprotective proteins integrated in these membrane microstructures. Moreover, E2 is a homeostatic modulator of lipid rafts. Recent work has pointed to this relevant aspect of E2 activity to preserve brain integrity, through mechanisms affecting lipid uptake and local biosynthesis in the brain. Some evidences have demonstrated that estrogens and the docosahexaenoic acid (DHA) exert synergistic effects to stabilize brain lipid matrix. DHA is essential to enhance molecular fluidity at the plasma membrane, promoting functional macromolecular interactions in signaling platforms. In support of this, DHA detriment in neuronal lipid rafts has been associated with the most common age-associated neuropathologies, namely AD and Parkinson disease. Altogether, these findings indicate that E2 may participate in brain preservation through a dual membrane-related mechanism. On the one hand, E2 interacting with ER related signalosomes may protect against neurotoxic insults. On the other hand, E2 may exert lipostatic actions to preserve lipid balance in neuronal membrane microdomains. The different aspects of the emerging multifunctional role of estrogens in membrane-related signalosomes will be discussed in this review.
- Characterization of MCF-12A cell phenotype, response to estrogens, and growth in 3D. [Journal Article]
- CCCancer Cell Int 2018; 18:43
- CONCLUSIONS: MCF-12A cells are a heterogeneous pseudo-epithelial cell line capable of forming a variety of multicellular structures in 3D culture. We found no indication that the cells display estrogen-responsive characteristics, thus refuting previous studies which reported estrogen responsiveness. We report that MCF-12A cells are not suited for use in studies in which differential behaviors of "normal" and "cancerous" estrogen-responsive cells are to be compared.
- Neuroestrogens rapidly shape auditory circuits to support communication learning and perception: Evidence from songbirds. [Review]
- HBHorm Behav 2018 Mar 16
- Steroid hormones, such as estrogens, were once thought to be exclusively synthesized in the ovaries and enact transcriptional changes over the course of hours to days. However, estrogens are also loc...
Steroid hormones, such as estrogens, were once thought to be exclusively synthesized in the ovaries and enact transcriptional changes over the course of hours to days. However, estrogens are also locally synthesized within neural circuits, wherein they rapidly (within minutes) modulate a range of behaviors, including spatial cognition and communication. Here, we review the role of brain-derived estrogens (neuroestrogens) as modulators within sensory circuits in songbirds. We first present songbirds as an attractive model to explore how neuroestrogens in auditory cortex modulate vocal communication processing and learning. Further, we examine how estrogens may enhance vocal learning and auditory memory consolidation in sensory cortex via mechanisms similar to those found in the hippocampus of rodents and birds. Finally, we propose future directions for investigation, including: 1) the extent of developmental and hemispheric shifts in aromatase and membrane estrogen receptor expression in auditory circuits; 2) how neuroestrogens may impact inhibitory interneurons to regulate audition and critical period plasticity; and, 3) dendritic spine plasticity as a candidate mechanism mediating estrogen-dependent effects on vocal learning. Together, this perspective of estrogens as neuromodulators in the vertebrate brain has opened new avenues in understanding sensory plasticity, including how hormones can act on communication circuits to influence behaviors in other vocal learning species, such as in language acquisition and speech processing in humans.
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- Estradiol and reproduction in the South American toad Rhinella arenarum (Amphibian, Anura). [Review]
- GCGen Comp Endocrinol 2018 Mar 16
- Rhinella arenarum is a South American toad with wide geographic distribution. Testes of this toad produce high amount of androgens during the non reproductive season and shift steroid synthesis from ...
Rhinella arenarum is a South American toad with wide geographic distribution. Testes of this toad produce high amount of androgens during the non reproductive season and shift steroid synthesis from androgens to 5α-pregnanedione during the breeding. In addition, plasma estradiol (E2) in males of this species shows seasonal variations but, since testes of R. arenarum do not express aromatase, the source of plasma E2remained unknown for several years. However, the Bidder's organ (BO), a structure located at one pole of each testis, is proposed to be the main source of E2in male's toads since it expresses several steroidogenic enzymes and is able to produce E2from endogenous substrates throughout the year. In addition, there were significant correlations between plasma E2and total activity of BO aromatase, and between plasma E2and the amount of hormone produced by the BO in vitro. In the toad, apoptosis induced by in vitro treatment with E2was mostly detected in spermatocytes during the breeding and in spermatids during the post-reproductive season, suggesting that this steroid has an important role in controlling spermatogenesis. However, in vitro treatment with E2had no effect on proliferation. This evidence suggests that the mechanism of action of E2on amphibian spermatogenesis is complex and more studies are necessary to fully understand the role of estrogens regulating the balance between cellular proliferation and apoptosis. In addition, in R. arenarum in vitro studies suggested that E2has no effect on CypP450c17 protein levels or enzymatic activity, while it reduces 3β-hydroxysteroid dehydrogenase/isomerase (3β-HSD/I) activity during the post reproductive season. As well, E2regulates FSHβ mRNA expression all over the year suggesting a down regulation process carried out by this steroid. The effect on LHβ mRNA is dual, since during the reproductive season estradiol increases the expression of LHβ mRNA while in the non-reproductive season it has no effect. In conclusion, the effect of E2on gonadotropins and testicular function is complex, not clearly understood and probably varies depending on the species. The aim of the current article is to review evidence on reproductive endocrinology and on the role of estradiol regulating reproduction in amphibians, with emphasis on the South American species Rhinella arenarum.