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Nathan Goodyear

ScienceDirect.com - Cell Metabolism - Estrogen Receptors and the Metabolic Network - 0 views

www.sciencedirect.com/...S1550413111003123

ER-alpha ER-beta estrogen receptor receptors metabolic syndrome MetS hormone hormones

shared by Nathan Goodyear on 11 Oct 12 - No Cached
  • The pro-opiomelanocortin (POMC) neurons have an anorexigenic action and, when activated, reduce food intake through the release of two peptides, α-melanocyte-stimulating hormone (α-MSH) and cocaine-and-amphetamine-regulated transcripts (CART). The neuropeptide Y (NPY) neurons, on the other hand, release NPY hormone and agouti gene-related protein (AgRP), which prevent the binding of α-MSH to MC3R and MC4R, increasing food intake
  • This suggests that the central anorexic effects of E2 may occur via ERβ
  • The main hypothalamic areas involved in food intake and satiety are the arcuate nucleus (ARC), the lateral hypothalamus (LH), the paraventricular nucleus (PVN), the ventromedial hypothalamus (VMH), and the dorsomedial hypothalamus (DMH)
  • ...22 more annotations...
  • Leptin is a potent anorexigenic and catabolic hormone secreted by adipose cells that reduces food intake and increases energy expenditure
  • E2 not only modulates leptin receptor mRNA in the ARC and VMH, but also increases hypothalamic sensitivity to leptin, altering peripheral fat distribution
  • ghrelin. It acts on growth hormone secretagogue receptors (GHSR1a) located in the ARC and is a potent stimulator of food intake
  • It thus appears that of the two ERs, ERα plays a predominant role in the CNS regulation of lipid and carbohydrate homeostasis.
  • Both ERs have been identified in the ARC
  • Stimulation of MCH neurons increases food intake and fat accumulation while its inhibition leads to decreased food intake and reduced fat accumulation.
  • Both ERs have been identified in the LH
  • both ERs have been identified in this nucleus
  • The PVN is the region of the hypothalamus with the highest expression of ERβ and is reported to be weakly ERα positive
  • The VMH is ERα regulated
  • Skeletal muscle is responsible for 75% of the insulin-induced glucose uptake in the body
  • GLUT4 is highly expressed in muscle and represents a rate-limiting step in the insulin-induced glucose uptake
  • data suggest that in the physiological range, E2 is beneficial for insulin sensitivity, whereas hypo- or hyperestrogenism is related to insulin resistance
  • In aging female rats, E2 treatment improves glucose homeostasis mainly through its ability to increase muscle GLUT4 content on the cell membrane
  • It is evident that ERα and ERβ have distinct actions and that much more research is needed to clearly identify the function of each receptor in muscle.
  • E2 prevents accumulation of visceral fat, increases central sensitivity to leptin, increases the expression of insulin receptors in adipocytes, and decreases the lipogenic activity of lipoprotein lipase in adipose tissue
  • In rats, ovariectomy increases body weight, intra-abdominal fat, fasting glucose and insulin levels, and insulin resistance followed by decreased phosphorylation of AMPK and its substrate acetyl-CoA carboxylase in adipose tissue
  • decreased adiponectin, PPARγ coactivator-1α (PGC-1α), and uncoupling protein 2 (UCP2) and increased resistin
  • Men with aromatase deficiency have truncal obesity, elevated blood lipids, and severe insulin resistance
  • Although not all studies are in agreement, polymorphisms of ERα in humans have been associated with risk factors for CVDs
  • Human subcutaneous and visceral adipose tissues express both ERα and ERβ, whereas only ERα mRNA has been identified in brown adipose tissue
  • suggesting that ERα is the main regulator of GLUT4 expression in adipose tissue
  • Nathan Goodyear on 11 Oct 12
     
    very nice article that looks at the balance of ER-alpha/ER-beta and their role in metabolic syndrome.  This article discusses the balance of  these receptors are tissue dependent in their effect.  I like their conclusion: "...but these mechanisms will never be completely understood if they are not considered in the context of a whole system.
Nathan Goodyear

Communication between genomic and non-genomic signaling events coordinate steroid hormo... - 0 views

www.ncbi.nlm.nih.gov/...PMC5864526

genomic signaling cancer hormones non-genomic signaling

shared by Nathan Goodyear on 10 Apr 21 - No Cached
  • steroid hormones typically interact with their cognate receptor in the cytoplasm for AR, glucocorticoid receptor (GR) and PR, but may also bind receptor in the nucleus as appears to often be the case for ERα and ERβ
  • This ligand binding results in a conformational change in the cytoplasmic NRs that leads to the dissociation of HSPs, translocation of the ligand-bound receptor to the nucleus
  • In the nucleus, the ligand-bound receptor dimerizes and then binds to DNA at specific HREs to regulate gene transcription
  • ...25 more annotations...
  • some steroid hormone-induced nuclear events can occur in minutes
  • the genomic effects of steroid hormones take longer, with changes in gene expression occurring on the timescale of hours
  • Classical steroid hormone signaling occurs when hormone binds nuclear receptors (NR) in the cytoplasm, setting off a chain of genomic events that results in, among other changes, dimerization and translocation to the nucleus where the ligand-bound receptor forms a complex with coregulators to modulate gene transcription through direct interactions with a hormone response element (HRE)
  • NRs have been found at the plasma membrane of cells, where they can propagate signal transduction often through kinase pathways
  • Membrane-localized ER, PR and AR have been reported to modulate the activity of MAPK/ERK, phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt), nitric oxide (NO), PKC, calcium flux and increase inositol triphosphate (IP3) levels to promote cell processes including autophagy, proliferation, apoptosis, survival, differentiation, and vasodilation
  • ERα36, a 36kDa truncated form of ERα that lacks the transcriptional activation domains of the full-length protein. Membrane-localized ERα36 can activate pathways including protein kinase C (PKC) and/or mitogen activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) to promote the progression of various cancers
  • G protein-coupled receptor 30 (GPR30), also referred to as G protein-coupled estrogen receptor (GPER), is a membrane-localized receptor that has been observed to respond to estrogen to activate rapid signaling
  • hormone-responsive G protein coupled receptor is Zip9, which androgens can activate
  • GPRC6A is another G protein-coupled membrane receptor that is responsive to androgen
  • androgen-mediated non-genomic signaling through this GPCR can modulate male fertility, hormone secretion and prostate cancer progression
  • non-NR proteins located at the cell surface can bind to steroid hormones and respond by eliciting rapid signaling events
  • Estrogens have been shown to induce rapid (i.e. seconds) calcium flux via membrane-localized ER (mER)
  • ER-calcium dynamics lead to activation of kinase pathways such as MAPK/ERK which can result in cellular effects like migration and proliferation
  • 17β-estradiol (E2) has been reported to promote angiogenesis through the activation of GPER
  • Membrane NRs may also mediate rapid signaling through crosstalk with growth factor receptors (GFR)
  • A similar crosstalk occurs between the receptor tyrosine kinase insulin-related growth factor-1 receptor (IGF-IR) and ERα. Not only does IGF-IR activate ERα, but inhibition of IGF-IR downregulates estrogen-mediated ERα activity, suggesting that IGF-IR is essential for maximal ERα signaling
    • Nathan Goodyear
      Nathan Goodyear on 10 Apr 21
       
      This is a bombshell that shatters the current right brain approach to ER. It completely shatters the concept of eat sugar, whatever you want, with cancer treatment in ER+ or hormonally responsive cancer!
  • Further, ER activates IGF-IR pathways including MAPK
  • GPER is involved in the transactivation of the EGFR independent of classical ER
  • tight interconnection between genomic and non-genomic effects of NRs.
  • non-genomic pathways can also lead to genomic effects
  • androgen-bound AR associates with the kinase Src at the plasma membrane, activating Src which then leads to a signaling cascade through MAPK/ERK
  • However, Src can also increase the expression of AR target genes by the ligand-independent transactivation of AR
  • extranuclear steroid hormone actions can potentially reprogram nuclear NR events
  • estrogen modulated the expression of several genes including endothelial nitric oxide synthase (eNOS) via rapid signaling pathways
  • epigenetic changes can then mediate genomic events in uterine tissue and breast cancer cells
Nathan Goodyear

Biological functions and clinical implications of oestrogen receptors alfa and beta in ... - 0 views

onlinelibrary.wiley.com/...full

ER estrogen receptors ER-alpha ER alpha ER-beta ER beta hormones hormone

shared by Nathan Goodyear on 21 Jan 14 - No Cached
  • ERα-positive cells respond to E2 with increased proliferation
  • ERβ was artificially introduced into these cells, E2-induced proliferation was inhibited
  • The proliferative response to E2 seems to be determined by the ratio of ERα/ERβ. The functions of ERβ in the breast are probably related to its antiproliferative as well as its prodifferentiative functions
  • ...7 more annotations...
  • The risk of developing PC seems to be related to the diet
  • In the human prostate, ERβ is expressed in the basal epithelial cells and AR in the luminal epithelium.
  • For many years, DHT was considered to be the main hormone guiding prostate development and function. However, the idea was challenged when in 2001 Mahendroo et al. showed that mice in which both forms of 5α-reductase had been inactivated, have a normal functional prostate [50]. The question was then raised as to what is the real function of DHT in the prostate. In 1989 we hypothesized that DHT is a precursor of an oestrogen, 5α-androstane-3β,17β-diol (3β-Adiol) and that physiological levels of an oestrogen could be produced in the total absence of aromatase [51]. We later demonstrated that 3β-Adiol is abundant in the prostate and is a good natural ligand for ERβ
  • The overall effect of oestrogens in the immune system is determined by a balance between ERα and ERβ signalling
  • The hypothesis of our group is that ERβ plays an important role in regulating the differentiation of pluripotent haematopoietic progenitor cells whereas ERα induces proliferation
  • In tissues and cell lines of mammary epithelium for example, it has been noticed that E2 in the presence of ERα elicits proliferation, but in the presence of ERβ it inhibits proliferation
  • ERα and ERβ have distinctive tissue distributions and to the great surprise of endocrinologists [7] many tissues previously thought to be ‘oestrogen-insensitive tissues’ were found to be ERβ positive and oestrogen sensitive. The most notable of the ERα-negative ERβ-abundant tissues were the epithelium of the rodent ventral prostate [8], the granulosa cells of the ovaries [9] and the parenchyma of the lungs
  • Nathan Goodyear on 21 Jan 14
     
    Awesome article discusses the different balance of ER alpha and ER beta and the effects on tissue as it relates to proliferation versus differentiation.  This has clear implications in disease.  Physicians prescribing hormones without a knowledge and understanding of this are only causing potential harm to their clients.
Nathan Goodyear

Estrogen Receptors in Colorectal Cancer: Goalkeepers, Strikers, or Bystanders? - 0 views

cancerpreventionresearch.aacrjournals.org/...897.full

estrogen colon cancer ER beta ER-beta breast

shared by Nathan Goodyear on 19 Nov 13 - No Cached
  • one can conclude that ERβ has an overall antiproliferative effect, thereby inhibiting cancer cell proliferation and antagonizing ERα function in the breast
  • HRT with estrogen alone did not increase the risk of breast cancer in the Women's Health Initiative clinical trials program
  • colorectal normal or cancer epithelium does not coexpress ERα and ERβ
  • ...7 more annotations...
  • ERβ expression resulted in the inhibition of proliferation and G1 phase cell-cycle arrest
  • ERβ expression strongly inhibited cMyc and tumor growth in a xenograft mouse model
  • induced ERβ in CRC cells has an antiproliferative, tumor-suppressive function that is independent of ERα
  • ERs also have the ability to bind many other compounds with an estrogen-like structure, including phytoestrogens and xenoestrogens (or endocrine disruptors)
  • Phytoestrogens are a diverse class of natural compounds with structural similarity to estradiol
  • Barone et al. recently found that two ERβ-selective phytoestrogens effectively counteracted CRC tumorigenesis and surprisingly increased ERβ expression in mice with mutations of the tumor-suppressor gene adenomatous polyposis coli
  • We can conclude that estrogens are important in protecting against CRC initiation and progression, and that the protective effect most likely is mediated by ERβ
  • Nathan Goodyear on 19 Nov 13
     
    ER beta is a new potential mode of therapy in colon cancer.  ER beta stimulation has been shown to inhibit colon cancer cell growth.
Nathan Goodyear

Influence of Sex Hormones on Melanoma - 0 views

jco.ascopubs.org/...e94.short

cancer melanoma ER alpha ER-alpha ER beta ER-beta ER estrogen receptor hormones hormone

shared by Nathan Goodyear on 21 Oct 14 - No Cached
  • Men show lower skin levels of ERβ than women, in whom ERβ expression decreases with age and more rapidly after menopause as a result of loss of estradiol-positive feedback
  • lower ERβ (mRNA and protein) levels in thicker, more invasive melanomas
  • melanoma ERβ levels correlated with both the tumor microenvironment and the depth of invasion
  • ...3 more annotations...
  • Recent immunohistochemical analyses of ERβ protein level in melanoma tissues15,16 have shown that ERβ protein expression decreases with increasing Breslow thickness—the most important independent prognostic factor in melanoma.
  • As in breast cancer, we maintain that ERα and ERβ status also has to be determined in melanoma with the aim of identifying those displaying a high ERα/ERβ ratio
  • An ideal hormone therapy in melanoma should selectively block the proliferative ERα protein and promote the antiproliferative action of ERβ
  • Nathan Goodyear on 21 Oct 14
     
    Melanoma is a known estrogen sensitive cancer.  This study finds ER Beta loss correlates with thickness of lesion.  The authors propose ERalpha/ERbeta ratio be assessed.  ERbeta has been shown to decrease proliferation, promotes differentiation, and decrease inflammation in breast studies.  In contrast, ERalpha promotes proliferation, decreases differentiation, and promotes inflammation.  Here, the same effects seem to apply to melanoma. Of interesting note, men have lower skin ERbeta than women and ERbeta declines with age and menopause in women.  Essentially, the loss of the ability to differentiate, decrease proliferation and inflammation  occurs with increase estrogen stimulus--set up for estrogen promoting cancers.
Nathan Goodyear

Bisphenol A Promotes Human Prostate Stem-Progenitor Cell Self-Renewal and Increases In ... - 0 views

www.ncbi.nlm.nih.gov/...PMC3929731

BPA bisphenol A cancer prostate cancer prostate xenoestrogens

shared by Nathan Goodyear on 20 Apr 16 - No Cached
  • these findings show that estrogen stimulates human prostate epithelial stem cell self-renewal and progenitor cell amplification (prostasphere size), with the greatest effects observed at lower E2 doses.
  • Similar to E2, BPA increased prostasphere number and size with significant and maximal effects observed at 10 nM BPA
  • Taken together, these results provide strong evidence that, similar to E2, BPA increases stem cell self-renewal and progenitor amplification in normal human prostate epithelial cells
  • ...13 more annotations...
  • these findings provide further support that E2 and BPA maintain the stem-like state within the normal prostate epithelial cell population
  • Our previous findings demonstrated that normal prostate stem-progenitor cells within the prostaspheres expressed ERα and ERβ, implicating them as direct targets for E2 and BPA action
  • p-Akt and p-Erk, well established downstream targets of membrane-associated ERs
  • BPA and E2 had equimolar capacity for activation of these rapid signaling pathways in human prostaspheres, thus identifying a dynamic and robust signaling pathway initiated by low-dose BPA exposure in prostate stem-progenitor cells.
  • these findings indicate that both rapid membrane-initiated estrogen action and genomic ER signaling pathways are operative in human prostate progenitor cells.
  • these results document the fact that levels of bioactive BPA in the present study are similar to levels found in human umbilical cord blood and newborns in the general population
  • the present findings identify for the first time that in vivo exposure of the human prostate epithelium to low doses of BPA significantly increases the susceptibility of the human prostate epithelium to hormonal carcinogenesis.
  • The current study provides clear evidence that, similar to E2, normal human prostate stem and progenitor cells are direct targets for BPA action
  • Both hormones increased stem-like cell numbers in primary prostate epithelial cultures in a dose-dependent manner and augmented the number and size of 3-D cultured prostaspheres, markers of stem cell self-renewal and progenitor cell proliferation, respectively
  • signaling pathways engaged by estrogens through these separate receptors are multiple and complex, including both membrane-initiated signaling and genomic activation via ER transcriptional activity
  • Estrogen action is mediated by ERα and ERβ
  • the current results indicate that developmental exposure to BPA, at doses routinely found in humans, significantly increases the cancer risk in human prostate epithelium in response to elevated estrogen levels in an androgen-supported milieu. Because relative estrogen levels rise in aging men, we suggest that humans may be susceptible to BPA-driven prostate disease in a manner similar to that in the rodent models.
  • We propose that early-life perturbations in estrogen signaling including inappropriate exposure to BPA have the potential to amplify and modify the stem-progenitor cell populations within the human prostate gland and, in so doing, alter the normal homeostatic mechanisms that maintain a growth neutral state throughout life
  • Nathan Goodyear on 20 Apr 16
     
    Bisphenol A exposure in utero found to increase prostate cancer risk later in life.  This exposure occurred at typical life exposure levels as found in umbilical cord blood sampling,  This occurred through stem cell self-renewal and progenitor amplification
Nathan Goodyear

The Complex Role of Estrogens in Inflammation - 0 views

edrv.endojournals.org/...521.full

estrogens inflammation

shared by Nathan Goodyear on 14 Aug 12 - No Cached
  • These studies suggest inflammation-dependent up-regulation of ERβ relative to ERα.
  • up-regulation of ERβ relative to ERα under hypoxic conditions, which might lead to a preponderance of signaling through ERβ pathways
  • it seems that E2 at periovulatory to pregnancy levels inhibited proinflammatory cytokines from PBMCs
  • ...26 more annotations...
  • it is clear that E2 can stimulate antibody production by B cells, probably by inhibiting T cell suppression of B cells
  • In cycling women, the largest quantities of Ig were detected before ovulation
  • In contrast, E2 at high concentrations leads to a suppression of B-lymphocyte lineage precursors
  • E2 at periovulatory to pregnancy serum levels is able to stimulate antibody secretion under healthy conditions but also in autoimmune diseases, whereas similar serum levels of E2 lead to a suppression of bone marrow B cell lineage precursors
  • In chronic inflammatory disorders, where B cells play a decisive role, E2 would promote the disease when autoaggressive B cells are already present, whereas chronically elevated E2 would inhibit initiation of an autoimmune disease when no such B cells are available. This might be a good reason why particularly B cell-dependent diseases such as SLE, mixed connective tissue disease (Sharp syndrome), IgA nephropathy, dermatitis herpetiformis, gluten sensitive enteropathy, myasthenia gravis, and thyroiditis appear in women in the reproductive years, predominantly, in the third or fourth decades of life
  • Th17 cells are thought to be the main responsible cells for chronic inflammatory tissue destruction in autoimmune diseases
  • IFN-γ, IL-12, and TNF were allocated to Th1 reactions
  • IL-4, IL-5, and IL-10 to Th2 responses
  • antiinflammatory T regulatory cells producing TGF-β and proinflammatory T helper type 17 cells (Th17) producing IL-17
  • no direct effects of estrogens on Th17 cells or IL-17 secretion have been described until now.
  • So-called Th17 cells producing IL-17 are the main T cells responsible for chronic inflammation.
  • Because IFN-γ has been allocated a Th17-inhibiting role (Fig. 1⇑), its increase by E2 at pregnancy doses and the E2-mediated inhibition of TNF must be viewed as a favorable effect in chronic inflammation
  • in humans and mice, E2 at periovulatory to pregnancy levels stimulates IL-4, IL-10, and IFN-γ but inhibits TNF from CD4+ T cells
  • In humans and mice, E3 and E2, respectively, at pregnancy levels inhibit T cell-dependent delayed type hypersensitivity
  • increased IL-4, IL-10, and IFN-γ in the presence of low TNF support an antiaggressive immune response
  • secretion of IL-1β is increased at periovulatory/proestrus to early pregnancy levels, whereas IL-1 secretion is inhibited at high pregnancy levels
  • The dichotomous effect of E2 on IL-1β and TNF at high and low concentrations is most probably due to inhibition of NF-κB at high concentrations
  • experiments with mouse and rat macroglial and microglial cells demonstrate that E2 at proestrus to pregnancy levels exerts neuroprotective effects by increasing TGF-β and by inhibiting iNOS and NO release, and reducing expression of proinflammatory cytokines and prostaglandin E2 production.
  • E2 at periovulatory to pregnancy levels inhibits NF-κB activation, which must be viewed as an antiinflammatory signal
  • It was shown that E2 concentrations equal to or above 10−10 m are necessary to inhibit NF-κB activation
  • important proinflammatory cytokines are typically inhibited at periovulatory (proestrus) to pregnancy levels of E2, which is evident for IL-6, IL-8, and TNF
  • low E2 concentrations were demonstrated to have no or even stimulatory effects
  • This renders a woman in the postmenopausal phase to a more proinflammatory situation
  • most in vitro studies demonstrated a stimulatory effect of E2 on secretion of IL-4, IL-10, and TGF-β typically at periovulatory to pregnancy levels
  • E2 at periovulatory to pregnancy levels has an ameliorating effect on chronic inflammatory diseases as long as B cell-dependent immunity or an overshooting fibrotic tissue repair process do not play a crucial pathogenic role. However, when the B cell plays an important role, E2 might even stimulate the disease process as substantiated by flare-ups in SLE during pregnancy
    • Nathan Goodyear
      Nathan Goodyear on 15 Aug 12
       
      SLE, mixed connective tissue disease (Sharp syndrome), IgA nephropathy, dermatitis herpetiformis, gluten sensitive enteropathy, myasthenia gravis, and thyroiditis
  • Short-term administration of E2 at pregnancy levels was shown to induce an inflammatory response specific to the lateral prostate of the castrated male rat
  • Nathan Goodyear on 14 Aug 12
     
    great review of the complex interaction between Estrogens and inflammation.  Reference here is in females.
Nathan Goodyear

Estrogen receptor (ER) β, a modulator of ERα in the uterus - 0 views

www.pnas.org/...5936.full

receptors ER-alpha ER-beta hormones hormone

shared by Nathan Goodyear on 16 Aug 12 - No Cached
  • induction of PR is an ERα-mediated event and repression of epithelial PR is ERβ mediated.
  • Nathan Goodyear on 16 Aug 12
     
    ER alpha and ER beta have different effects on the uterus in this mice model.  ER beta modulates ER alpha.  ER beta decreases PR, whereas ER alpha increases PR.
Nathan Goodyear

An endocrine pathway in the prostate, ERβ, AR, 5α-androstane-3β,17β-diol, and... - 0 views

www.pnas.org/...13589.full

3-beta androstanediol DHT metabolite prostate cancer ER-beta ER beta CYP7b1 cytochrome male hormone hormones men

shared by Nathan Goodyear on 27 Jan 14 - No Cached
  • Although the prostate is an androgen-dependent tissue, estrogens influence both normal functions and pathological changes in this gland
  • This dual action may be due to the existence of two estrogen receptors, ERα and ERβ
  • ERα and ERβ have similar affinities for estradiol-17β
  • ...6 more annotations...
  • In this study we have shown that regulation of the levels of 3βAdiol by CYP7B1 is a key factor in regulation of prostatic growth
  • We provide evidence that proliferating cells in the prostate epithelium have elevated levels of AR and that AR protein but not mRNA levels are regulated by ERβ and its ligand 3βAdiol in the prostate epithelium.
  • because inhibition of 5α-reductase causes accumulation of testosterone and removal of ERβ action increases the level of AR in the prostate, the overall effect of Finasteride would be to favor proliferation of the prostate epithelium
  • studies show that ERβ tends to be lost in advanced prostate cancer.
  • DHEA is converted in the body to 5-androstene-3β,17β-diol, which is also a ligand for estrogen receptors (25, 39) and a substrate for CYP7B1
  • At the peak of proliferation, the proliferating epithelial cells in the ventral prostate expressed high levels of CYP7B1 but had no detectable ERβ, whereas in nonproliferating cells the level of ERβ was high and that of CYP7B1 was low.
  • Nathan Goodyear on 27 Jan 14
     
    3-beta androstanediola, a product of 3alpha-HSD from DHT binds to ER beta and down regulates AR in prostate cancer.  This study proposes that the mechanism is via CYP7B1.  CYP7B1 inactivates 3-beta androstanediol.  Interesting, because 3-beta androstanediol is considered "inactive" when compared to 3-alpha androstanediol and its interaction with ER alpha.  
Nathan Goodyear

The Androgen 5α-Dihydrotestosterone and Its Metabolite 5α-Androstan-3β, 17β-D... - 0 views

www.jneurosci.org/...1448.full

DHT 3 beta androstanediol androgens Hypothalamus HPA hormones stress

shared by Nathan Goodyear on 15 Jul 15 - No Cached
  • Sex steroid hormones are primarily responsible for sex difference in adult HPA function; androgens inhibit whereas estrogens enhance HPA axis activation after a stressor
  • the PVN contains relatively high levels of AR (Bingaman et al., 1994; Zhou et al., 1994) and ERβ (Alves et al., 1998; Hrabovszky et al., 1998; Somponpun and Sladek, 2003) but is essentially devoid of ERα
  • the nonaromatizable androgen DHT and the nonselective ER ligand E2 influence HPA reactivity by acting on neurons within or surrounding the PVN
  • ...9 more annotations...
  • inhibitory action of DHT is detectable at both the level of hormone secretion as well as PVN c-fos mRNA expression
  • the inhibition can be mimicked by the DHT metabolite 3β-diol and by the subtype selective ERβ agonist DPN
  • E2 acts to enhance HPA reactivity
  • the ability of the ER antagonist tamoxifen, but not the AR antagonist flutamide, to block the inhibitory actions of DHT, speaks to the intracellular mechanism by which this inhibitory signal might be transduced.
    • Nathan Goodyear
      Nathan Goodyear on 15 Jul 15
       
      that is because the interaction with the DHT metabolite is not with the AR, but with the ER-beta.
  • the DHT metabolite 3β-diol and the ERβ-subtype-selective agonist DPN suppressed ACTH, corticosterone, and c-fos mRNA responses to restraint stress in a manner similar to DHT
  • metabolism of DHT to 3β-diol and subsequent binding to ERβ can be inhibitory to HPA reactivity, and this is one possible mechanism for the action of DHT.
  • Our data also suggest that E2 enhances the reactivity of the HPA axis to stress by acting on or near neurons of the PVN
  • the actions of E2 appear to be through an ERα-dependent mechanism
  • these studies suggest that ERβ, within the male hypothalamus, acts to inhibit the HPA axis and that the inhibitory effects of DHT may be, at least in part, via its intracellular conversion to 3β-diol and subsequent binding to ERβ
  • Nathan Goodyear on 15 Jul 15
     
    DHT metabolites: particularly 3beta-androstanediol inhibit HPA axis through ER-beta.
Nathan Goodyear

Impact of Estrogen Receptor β on Gene Networks Regulated by Estrogen Receptor... - 0 views

endo.endojournals.org/...4831.long

estrogen receptors receptor hormone hormones ER-alpha ER-beta ER cancer breast

shared by Nathan Goodyear on 16 Oct 12 - No Cached
  • ERβ acts as a tumor-suppressive protein
  • E2 may promote cell proliferation by inhibiting TGFβ production
  • ERβ modulated ERα regulation of TGFβ
  • Nathan Goodyear on 16 Oct 12
     
    Good discussion of the different effects of ER-alpha and ER-beta in breast cancer.  ER-beta inhibits growth in contrast to ER-alpha.
Nathan Goodyear

Testosterone: a vascular hormone in health and disease - 0 views

joe.endocrinology-journals.org/...R47.full

testosterone hormone health disease hormones men male cardiovascular disease CVD

shared by Nathan Goodyear on 13 May 13 - No Cached
  • Testosterone has beneficial effects on several cardiovascular risk factors, which include cholesterol, endothelial dysfunction and inflammation
  • In clinical studies, acute and chronic testosterone administration increases coronary artery diameter and flow, improves cardiac ischaemia and symptoms in men with chronic stable angina and reduces peripheral vascular resistance in chronic heart failure.
  • testosterone is an L-calcium channel blocker and induces potassium channel activation in vascular smooth muscle cells
  • ...54 more annotations...
  • Animal studies have consistently demonstrated that testosterone is atheroprotective, whereas testosterone deficiency promotes the early stages of atherogenesis
  • there is no compelling evidence that testosterone replacement to levels within the normal healthy range contributes adversely to the pathogenesis of CVD (Carson & Rosano 2011) or prostate cancer (Morgentaler & Schulman 2009)
  • bidirectional effect between decreased testosterone concentrations and disease pathology exists as concomitant cardiovascular risk factors (including inflammation, obesity and insulin resistance) are known to reduce testosterone levels and that testosterone confers beneficial effects on these cardiovascular risk factors
  • Achieving a normal physiological testosterone concentration through the administration of testosterone replacement therapy (TRT) has been shown to improve risk factors for atherosclerosis including reducing central adiposity and insulin resistance and improving lipid profiles (in particular, lowering cholesterol), clotting and inflammatory profiles and vascular function
  • It is well known that impaired erectile function and CVD are closely related in that ED can be the first clinical manifestation of atherosclerosis often preceding a cardiovascular event by 3–5 years
  • no decrease in the response (i.e. no tachyphylaxis) of testosterone and that patient benefit persists in the long term.
  • free testosterone levels within the physiological range, has been shown to result in a marked increase in both flow- and nitroglycerin-mediated brachial artery vasodilation in men with CAD
  • Clinical studies, however, have revealed either small reductions of 2–3 mm in diastolic pressure or no significant effects when testosterone is replaced within normal physiological limits in humans
  • Endothelium-independent mechanisms of testosterone are considered to occur primarily via the inhibition of voltage-operated Ca2+ channels (VOCCs) and/or activation of K+ channels (KCs) on smooth muscle cells (SMCs)
  • Testosterone shares the same molecular binding site as nifedipine
  • Testosterone increases the expression of endothelial nitric oxide synthase (eNOS) and enhances nitric oxide (NO) production
  • Testosterone also inhibited the Ca2+ influx response to PGF2α
  • one of the major actions of testosterone is on NO and its signalling pathways
  • In addition to direct effects on NOS expression, testosterone may also affect phosphodiesterase type 5 (PDE5 (PDE5A)) gene expression, an enzyme controlling the degradation of cGMP, which acts as a vasodilatory second messenger
  • the significance of the action of testosterone on VSMC apoptosis and proliferation in atherosclerosis is difficult to delineate and may be dependent upon the stage of plaque development
  • Several human studies have shown that carotid IMT (CIMT) and aortic calcification negatively correlate with serum testosterone
  • t long-term testosterone treatment reduced CIMT in men with low testosterone levels and angina
  • neither intracellular nor membrane-associated ARs are required for the rapid vasodilator effect
  • acute responses appear to be AR independent, long-term AR-mediated effects on the vasculature have also been described, primarily in the context of vascular tone regulation via the modulation of gene transcription
  • Testosterone and DHT increased the expression of eNOS in HUVECs
  • oestrogens have been shown to activate eNOS and stimulate NO production in an ERα-dependent manner
  • Several studies, however, have demonstrated that the vasodilatory actions of testosterone are not reduced by aromatase inhibition
  • non-aromatisable DHT elicited similar vasodilation to testosterone treatment in arterial smooth muscle
  • increased endothelial NOS (eNOS) expression and phosphorylation were observed in testosterone- and DHT-treated human umbilical vein endothelial cells
  • Androgen deprivation leads to a reduction in neuronal NOS expression associated with a decrease of intracavernosal pressure in penile arteries during erection, an effect that is promptly reversed by androgen replacement therapy
  • Observational evidence suggests that several pro-inflammatory cytokines (including interleukin 1β (IL1β), IL6, tumour necrosis factor α (TNFα), and highly sensitive CRP) and serum testosterone levels are inversely associated in patients with CAD, T2DM and/or hypogonadism
  • patients with the highest IL1β concentrations had lower endogenous testosterone levels
  • TRT has been reported to significantly reduce TNFα and elevate the circulating anti-inflammatory IL10 in hypogonadal men with CVD
  • testosterone treatment to normalise levels in hypogonadal men with the MetS resulted in a significant reduction in the circulating CRP, IL1β and TNFα, with a trend towards lower IL6 compared with placebo
  • parenteral testosterone undecanoate, CRP decreased significantly in hypogonadal elderly men
  • Higher levels of serum adiponectin have been shown to lower cardiovascular risk
  • Research suggests that the expression of VCAM-1, as induced by pro-inflammatory cytokines such as TNFα or interferon γ (IFNγ (IFNG)) in endothelial cells, can be attenuated by treatment with testosterone
  • Testosterone also inhibits the production of pro-inflammatory cytokines such as IL6, IL1β and TNFα in a range of cell types including human endothelial cells
  • decreased inflammatory response to TNFα and lipopolysaccharide (LPS) in human endothelial cells when treated with DHT
  • The key to unravelling the link between testosterone and its role in atherosclerosis may lay in the understanding of testosterone signalling and the cross-talk between receptors and intracellular events that result in pro- and/or anti-inflammatory actions in athero-sensitive cells.
  • testosterone functions through the AR to modulate adhesion molecule expression
  • pre-treatment with DHT reduced the cytokine-stimulated inflammatory response
  • DHT inhibited NFκB activation
  • DHT could inhibit an LPS-induced upregulation of MCP1
  • Both NFκB and AR act at the transcriptional level and have been experimentally found to be antagonistic to each other
  • As the AR and NFκB are mutual antagonists, their interaction and influence on functions can be bidirectional, with inflammatory agents that activate NFκB interfering with normal androgen signalling as well as the AR interrupting NFκB inflammatory transcription
  • prolonged exposure of vascular cells to the inflammatory activation of NFκB associated with atherosclerosis may reduce or alter any potentially protective effects of testosterone
  • DHT and IFNγ also modulate each other's signalling through interaction at the transcriptional level, suggesting that androgens down-regulate IFN-induced genes
  • (Simoncini et al. 2000a,b). Norata et al. (2010) suggest that part of the testosterone-mediated atheroprotective effects could depend on ER activation mediated by the testosterone/DHT 3β-derivative, 3β-Adiol
  • TNFα-induced induction of ICAM-1, VCAM-1 and E-selectin as well as MCP1 and IL6 was significantly reduced by a pre-incubation with 3β-Adiol in HUVECs
  • 3β-Adiol also reduced LPS-induced gene expression of IL6, TNFα, cyclooxygenase 2 (COX2 (PTGS2)), CD40, CX3CR1, plasminogen activator inhibitor-1, MMP9, resistin, pentraxin-3 and MCP1 in the monocytic cell line U937 (Norata et al. 2010)
  • This study suggests that testosterone metabolites, other than those generated through aromatisation, could exert anti-inflammatory effects that are mediated by ER activation.
  • The authors suggest that DHT differentially effects COX2 levels under physiological and pathophysiological conditions in human coronary artery smooth muscle cells and via AR-dependent and -independent mechanisms influenced by the physiological state of the cell
  • There are, however, a number of systematic meta-analyses of clinical trials of TRT that have not demonstrated an increased risk of adverse cardiovascular events or mortality
  • The TOM trial, which was designed to investigate the effect of TRT on frailty in elderly men, was terminated prematurely as a result of an increased incidence of cardiovascular-related events after 6 months in the treatment arm
  • trials of TRT in men with either chronic stable angina or chronic cardiac failure have also found no increase in either cardiovascular events or mortality in studies up to 12 months
  • Evidence may therefore suggest that low testosterone levels and testosterone levels above the normal range have an adverse effect on CVD, whereas testosterone levels titrated to within the mid- to upper-normal range have at least a neutral effect or, taking into account the knowledge of the beneficial effects of testosterone on a series of cardiovascular risk factors, there may possibly be a cardioprotective action
  • The effect of testosterone on human vascular function is a complex issue and may be dependent upon the underlying androgen and/or disease status.
  • the majority of studies suggest that testosterone may display both acute and chronic vasodilatory effects upon various vascular beds at both physiological and supraphysiological concentrations and via endothelium-dependent and -independent mechanisms
  • Nathan Goodyear on 13 May 13
     
    Good deep look into the testosterone and CVD link.
Nathan Goodyear

Testosterone: a metabolic hormone in health and disease - 0 views

joe.endocrinology-journals.org/...R25.full

male hormone hormones testosterone hypogonadal-obesity-adipocytokine hypothesis

shared by Nathan Goodyear on 08 May 13 - No Cached
  • E2 and the inflammatory adipocytokines tumour necrosis factor α (TNFα) and interleukin 6 (IL6) inhibit hypothalamic production of GNRH and subsequent release of LH and FSH from the pituitary
  • Leptin, an adipose-derived hormone with a well-known role in regulation of body weight and food intake, also induces LH release under normal conditions via stimulation of hypothalamic GNRH neurons
  • In human obesity, whereby adipocytes are producing elevated amounts of leptin, the hypothalamic–pituitary axis becomes leptin resistant
  • ...39 more annotations...
  • there is evidence from animal studies that leptin resistance, inflammation and oestrogens inhibit neuronal release of kisspeptin
  • Beyond hypothalamic action, leptin also directly inhibits the stimulatory action of gonadotrophins on the Leydig cells of the testis to decrease testosterone production; therefore, elevated leptin levels in obesity may further diminish androgen status
  • Prostate cancer patients with pre-existing T2DM show a further deterioration of insulin resistance and worsening of diabetic control following ADT
  • ADT for the treatment of prostatic carcinoma in some large epidemiological studies has been shown to be associated with an increased risk of developing MetS and T2DM
  • Non-diabetic men undergoing androgen ablation show increased occurrence of new-onset diabetes and demonstrate elevated insulin levels and worsening glycaemic control
  • increasing insulin resistance assessed by glucose tolerence test and hypoglycemic clamp was shown to be associated with a decrease in Leydig cell testosterone secretion in men
  • The response to testosterone replacement of insulin sensitivity is in part dependent on the androgen receptor (AR)
  • Low levels of testosterone have been associated with an atherogenic lipoprotein profile, characterised by high LDL and triglyceride levels
  • a positive correlation between serum testosterone and HDL has been reported in both healthy and diabetic men
  • up to 70% of the body's insulin sensitivity is accounted for by muscle
  • Testosterone deficiency is associated with a decrease in lean body mass
  • relative muscle mass is inversely associated with insulin resistance and pre-diabetes
  • GLUT4 and IRS1 were up-regulated in cultured adipocytes and skeletal muscle cells following testosterone treatment at low dose and short-time incubations
  • local conversion of testosterone to DHT and activation of AR may be important for glucose uptake
  • inverse correlation between testosterone levels and adverse mitochondrial function
  • orchidectomy of male Wistar rats and associated testosterone deficiency induced increased absorption of glucose from the intestine
  • (Kelley & Mandarino 2000). Frederiksen et al. (2012a) recently demonstrated that testosterone may influence components of metabolic flexibility as 6 months of transdermal testosterone treatment in aging men with low–normal bioavailable testosterone levels increased lipid oxidation and decreased glucose oxidation during the fasting state.
  • Decreased lipid oxidation coupled with diet-induced chronic FA elevation is linked to increased accumulation of myocellular lipid, in particular diacylglycerol and/or ceramide in myocytes
  • In the Chang human adult liver cell line, insulin receptor mRNA expression was significantly increased following exposure to testosterone
  • Testosterone deprivation via castration of male rats led to decreased expression of Glut4 in liver tissue, as well as adipose and muscle
  • oestrogen was found to increase the expression of insulin receptors in insulin-resistant HepG2 human liver cell line
  • FFA decrease hepatic insulin binding and extraction, increase hepatic gluconeogenesis and increase hepatic insulin resistance.
  • Only one, albeit large-scale, population-based cross-sectional study reports an association between low serum testosterone concentrations and hepatic steatosis in men (Völzke et al. 2010)
  • This suggests that testosterone may confer some of its beneficial effects on hepatic lipid metabolism via conversion to E2 and subsequent activation of ERα.
  • hypogonadal men exhibiting a reduced lean body mass and an increased fat mass, abdominal or central obesity
  • visceral adipose tissue was inversely correlated with bioavailable testosterone
  • there was no change in visceral fat mass in aged men with low testosterone levels following 6 months of transdermal TRT, yet subcutaneous fat mass was significantly reduced in both the thigh and the abdominal areas when analysed by MRI (Frederiksen et al. 2012b)
  • ADT of prostate cancer patients increased both visceral and subcutaneous abdominal fat in a 12-month prospective observational study (Hamilton et al. 2011)
  • Catecholamines are the major lipolysis regulating hormones in man and regulate adipocyte lipolysis through activation of adenylate cyclase to produce cAMP
  • deficiency of androgen action decreases lipolysis and is primarily responsible for the induction of obesity (Yanase et al. 2008)
  • may be some regional differences in the action of testosterone on subcutaneous and visceral adipose function
  • proinflammatory adipocytokines IL1, IL6 and TNFα are increased in obesity with a downstream effect that stimulates liver production of CRP
  • observational evidence suggests that IL1β, IL6, TNFα and CRP are inversely associated with serum testosterone levels in patients
  • TRT has been reported to significantly reduce these proinflammatory mediators
  • This suggests a role for AR in the metabolic actions of testosterone on fat accumulation and adipose tissue inflammatory response
  • testosterone treatment may have beneficial effects on preventing the pathogenesis of obesity by inhibiting adipogenesis, decreasing triglyceride uptake and storage, increasing lipolysis, influencing lipoprotein content and function and may directly reduce fat mass and increase muscle mass
  • Early interventional studies suggest that TRT in hypogonadal men with T2DM and/or MetS has beneficial effects on lipids, adiposity and parameters of insulin sensitivity and glucose control
  • Evidence that whole-body insulin sensitivity is reduced in testosterone deficiency and increases with testosterone replacement supports a key role of this hormone in glucose and lipid metabolism
  • Impaired insulin sensitivity in these three tissues is characterised by defects in insulin-stimulated glucose transport activity, in particular into skeletal muscle, impaired insulin-mediated inhibition of hepatic glucose production and stimulation of glycogen synthesis in liver, and a reduced ability of insulin to inhibit lipolysis in adipose tissue
  • Nathan Goodyear on 08 May 13
     
    Great review of the Hypogonadal-obesity-adipocytokine hypothesis.
Nathan Goodyear

Distribution and Posttranslational Modification of Synaptic ERα in the Adult ... - 1 views

endo.endojournals.org/...819.full

estrogen receptors estrogen receptor receptors ER alpha

shared by Nathan Goodyear on 24 Feb 13 - No Cached
  • Nathan Goodyear on 24 Feb 13
     
    estrogen receptors are transported to the cell membrane after production in the rat hippocampus.  The membrane receptors have the same origin as the intracellular receptors.
Nathan Goodyear

Estrogen receptor (ER) β, a modulator of ERα in the uterus - 0 views

www.pnas.org/...5936.abstract

estrogen receptor receptors hormone hormones ER-beta ER-alpha uterus

shared by Nathan Goodyear on 10 Oct 12 - No Cached
  • Nathan Goodyear on 10 Oct 12
     
    ER-beta shown to have an anti-proliferative effect through it's counter regulatory action on ER-alpha.  This study looked at estradiol interaction between ER-alpha/beta in the uterus.
Nathan Goodyear

Age Increase of Estrogen Receptor-α (ERα) in Cortical Astrocytes Impairs Neur... - 0 views

endo.endojournals.org/...2101.abstract

ER alpha ER-alpha ER estrogen receptors brain neurology neurotrophic astrocytes

shared by Nathan Goodyear on 24 Jun 13 - No Cached
  • Nathan Goodyear on 24 Jun 13
     
    increased ER-alpha expression associated with decreased neurotrophic activity.  A decrease in the neurotrophic activity of the aging brain is associated with many of the diseases of the aging brain. The major point here is that ER-alph is known to increase inflammatory signaling.  So increased inflammation, just via the ER receptors, plays a role in the aging brain.
Nathan Goodyear

Estrogen receptor β and the progression of prostate cancer: role of 5α-andros... - 0 views

erc.endocrinology-journals.org/...731.long

3-beta androstanediol DHT Testosterone androgens prostate cancer ER beta ER-beta receptors ER men male hormone hormones

shared by Nathan Goodyear on 21 Jan 14 - No Cached
  • In the prostate, ERβ is highly expressed in the epithelial compartment, where it is the prevailing isoform
  • In the gland, DHT may be either reversibly 3α- or irreversibly 3β-hydroxylated by the different 3α- and 3β-hydroxysteroid dehydrogenases respectively (Steckelbroeck et al. 2004); these transformations generate two metabolites respectively 3α-diol and 3β-Adiol, which are both unable to bind the AR. Instead, 3β-Adiol displays a high affinity for ERβ (Kuiper et al. 1998, Nilsson et al. 2001), and it has been proposed that this metabolite may play a key role in prostate development
  • ERβ signaling, in contrast to ERα, seems to act as a suppressor of prostate growth, and may be positively involved in breast cancer
  • ...4 more annotations...
  • 3β-Adiol counteracts PC cell proliferation in vitro
  • 3β-Adiol counteracts the biological actions of its androgenic precursors testosterone and DHT
  • functional antagonism of 3β-Adiol appears to be molecularly independent from the activation of the androgenic pathway
  • the action of 3β-Adiol is mediated, at the molecular levels, by the estrogenic pathway.
  • Nathan Goodyear on 21 Jan 14
     
    another awesome article dealing with hormone metabolites. Physicians that don't understand metabolites and receptors may be doing more harm than good.   One of the mainstays of the treatment of metastatic prostate disease is androgen deprivation therapy.  This article requires a reassessment of this due to the DHT metabolite 3-beta androstanediol.  This metabolite is produced from DHT production via the enzyme 3beta HSD.  This metabolite binds to ER beta, an estrogen receptor, and inhibits proliferation, migration, promotes adhesion (limits spreading), and stimulates apoptosis.  This is contrast to 3-alpha androstanediol.  Androgen deprivation therapy will decrease 3-beta androstanediol.  This is the likely reason for the increased aggressive prostate cancer found in those men using 5 alpha reductase inhibitors.
Nathan Goodyear

The Androgen Derivative 5α-Androstane-3β,17β-Diol Inhibits Prostate Cancer Ce... - 0 views

cancerres.aacrjournals.org/...5445.full

prostate cancer 3-beta androstanediol DHT metabolite E-cadherin ER beta ER-beta male hormone hormones men

shared by Nathan Goodyear on 27 Jan 14 - No Cached
  • In the early stages, prostate cancer growth is dependent on circulating androgens
    • Nathan Goodyear
      Nathan Goodyear on 27 Jan 14
       
      This is in contrast to studies that show poor prognosis with Lower T at time of diagnosis of prostate cancer
  • 5α-reductase not only provides a potent amplification of the androgenic signal ( 4– 6), but it also prevents estrogen formation by subtracting testosterone from the action of aromatase ( 7, 8), thus blocking activation of the estrogen receptor subtypes (ERα and ERβ; refs. 9, 10)
  • ERβ is the prevailing subtype ( 11), and a growing body of evidence points to the protective role of this receptor in prostate cancer
  • ...3 more annotations...
  • It has been shown that the transformation of the dihydrotestosterone to 5α-androstane-3α,17β-diol (3α-diol) and 5α-androstane-3β,17β-diol (3β-Adiol), generates two metabolites unable to bind the androgen receptor, but possessing a very high affinity for the estrogen receptors
  • the effects of testosterone may result from the balance between the androgenic and the estrogenic molecules originating from its catabolism.
  • Recent data have been published postulating a direct estrogenic role of the 3β-hydroxylated derivatives of dihydrotestosterone in the prostate development and homeostasis
  • Nathan Goodyear on 27 Jan 14
     
    Here is the full article.
Nathan Goodyear

ERα/E2 signaling suppresses the expressi... [Mol Cell Endocrinol. 2012] - Pub... - 0 views

www.ncbi.nlm.nih.gov/...22683664

ER alpha ER-alpha Estradiol Nur77 low T Testosterone

shared by Nathan Goodyear on 15 Feb 14 - No Cached
  • Nathan Goodyear on 15 Feb 14
     
    Another support point for Estrogen as a cause of low Testosterone.  This animal study points to signaling of Estradiol through ER alpha.  This study found high expression of ER alpha and subsequent signaling by E2 decreased cAMP and Nur77 transcription factor.  Nur77 increases steroid synthesis.  This was confirmed with ER alpha knockout mice.
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