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Nathan Goodyear

Urinary Estrogens and Estrogen Metabolites and Subsequent Risk of Breast Cancer among P... - 0 views

  • both 2- and 4-catechol estrogen metabolites bind to the ER with affinities comparable with estradiol, 4-catechol estrogen metabolites have lower dissociation rates than estradiol and an enhanced ability to upregulate ER-dependent processes
  • 2-catechol estrogen metabolites act as either weak mitogens (39) or weak inhibitors of cell proliferation
  • While 16α-hydroxyestrone binds to the ER with lower affinity than estradiol, it binds covalently (41) and leads to a constitutively activated ER
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  • 4-hydroxyestradiol and 16α-hydroxyestrone increasing proliferation and decreasing apoptosis in a manner similar to estradiol; however, these effects were achieved only at concentrations 10-fold higher than estradiol (39). In contrast, 2-hydroxyestradiol did not have substantial proliferative or antiapoptotic effects
  • In our study, the associations with both 2-hydroxyestrone and 16α-hydroxyestrone were nonsignificantly inverse and we did not observe a consistent trend or significant associations between the 2-hydroxyestrone:16α-hydroxyestrone ratio and breast cancer risk
  • Ratios of the 3 hydroxylation pathways were not significantly associated with risk although the 2:16-pathway and 4:16-pathway ratios were suggestively inversely associated
  • a significant inverse association with the ratio of parent estrogens to estrogen metabolites
  • several potentially estrogenic and genotoxic mechanisms
  • Estrogen metabolites also can be genotoxic
  • Catechol estrogens can be oxidized into quinones and induce DNA damage directly through the formation of DNA adducts, or indirectly via redox cycling and generation of reactive oxygen species
  • the oxidized forms of the catechol estrogens differ in their ability to damage DNA through adducts, with oxidized 2-catechols forming stable and reversible DNA adducts and oxidized 4-catechols forming unstable adducts, which lead to depurination and mutations
  • 2- and 4-catechols have been shown to produce reactive oxygen species and induce oxidative DNA damage
  • act independently from the ER
  • 16α-Hydroxyestrone also may be genotoxic
  • While the catechol estrogens have estrogenic and genotoxic potential, the methylated catechol estrogens, which are catechol estrogens with one hydroxyl group methylated, have been hypothesized to lower the risk of breast cancer
  • The suggested mechanisms are indirect, by decreasing circulating levels of catechol estrogens and thereby the opportunity for catechols to exert genotoxic or proliferative effects, or direct, by inhibiting tumor growth and inducing apoptosis
  • the balance between phase I (oxidation) and phase II (methylation) metabolism of estrogen may be important in hormonally related cancer development.
  • Despite the estrogenic and genotoxic potential of many of the estrogen metabolites, we only observed a significantly increased breast cancer risk with one estrogen metabolite, 17-epiestriol, which has particularly strong estrogenic activity and binds to both ERα and ERβ with an affinity comparable with estradiol
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    review of estrogen metabolites and breast cancer risk in premenopausal women.
Nathan Goodyear

Circulating 2-hydroxy and 16-α hydroxy estrone levels and risk of breast canc... - 1 views

  • 2-OH estrogens bind to the estrogen receptor (ER) with affinity equivalent to or greater than estradiol
  • previous prospective studies have not observed any significant associations with either 2-OH or 16α-OH estrone or the ratio of the two metabolites and breast cancer risk overall.
    • Nathan Goodyear
       
      whether that risk is increased or decreased
  • it has been hypothesized that metabolism favoring the 2-OH over the 16α-OH pathway may be inversely associated with breast cancer risk (28).
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  • they may act as only weak mitogens (14, 15), or as inhibitors of proliferation
  • No significant associations have been observed between 2-OH estrone and breast cancer risk
  • While 16α-OH estrone binds to the ER with lower affinity than estradiol, it binds covalently (18-20) and once bound, fails to down-regulate the receptor (21). Thus, 16α-OH estrone stimulates cell proliferation in a manner comparable to estradiol in ER+ breast cancer cell lines
  • In this large prospective study of 2-OH and 16α-OH estrone metabolites and breast cancer risk, we did not observe any significant associations overall with either individual metabolite or with the ratio of the two metabolites
  • we observed positive associations with 2-OH estrone and the 2:16α-OH estrone ratio among women with lower BMI and women with ER-/PR-tumors,
  • To date, several epidemiologic studies have examined the association between the 2-OH and 16α-OH estrogen metabolites and breast cancer risk with inconclusive results.
  • circulating estrogen levels have been associated more strongly with ER+/PR+ tumors than with ER-/PR- tumors
  • our results do not support the hypothesis that metabolism favoring the 2-OH estrone pathway is more beneficial to breast cancer risk than that favoring the 16α-OH estrone pathway
  • we observed significant positive associations of both 2-OH estrone and the 2:16α-OH estrone ratio with ER-/PR-tumors
  • Three (30, 32, 33) of four (30-33) studies observed RRs above 1 for the association between 16α-OH estrone and breast cancer risk (range of RRs=1.23-2.47); none of the point estimates was statistically significant though one trend was suggestive
  • based on animal studies, 2-OH estrone and the 2:16α-OH estrone ratio have been hypothesized to be inversely associated with breast cancer risk
  • No significant associations have been observed between 2-OH estrone, 16α-OH estrone, or the 2:16α-OH estrone ratio and breast cancer risk and the direction of the estimates is not consistent across studies.
    • Nathan Goodyear
       
      better worded is no consistent, significant associations.   There are some studies that point to the 16 catecholestrogen and increased cancer risk; limited studies show negative effects of 2 catecholestrogens on cancer risk and prospective studies available pretty much dispel the idea that the 2:16 ratio has an risk predictability.
  • we observed a suggestive inverse association with 16α-OH estrone and a significant positive association with the 2:16α-OH estrone ratio among lean women, suggesting possible associations in a low estrogen environment.
  • 16α-OH estrone increases unscheduled DNA synthesis in mouse mammary cells (27) and hence also may be genotoxic
  • Although 2-OH estrogens are capable of redox cycling, the semiquinones and quinones (i.e., the oxidized forms) form stable DNA adducts that are reversible without DNA destruction
  • In our population of PMH nonusers, we observed no associations with ER+/PR+ tumors, but significant positive associations with 2-OH estrone and the 2:16α-OH estrone ratio among women with ER-/PR- tumors
    • Nathan Goodyear
       
      one of the few studies to find this association between 2 catecholestrogens and the 2:16 ratio and ER-/PR-tumors
  • Animal and in vitro studies have shown that hydroxy estrogens can induce DNA damage either directly, through the formation of quinones and DNA adducts, or indirectly, through redox cycling and the generation of reactive oxygen species
    • Nathan Goodyear
       
      genotoxic via directe DNA adducts and indirectly via ROS; this is in addition to the proliferative effect
  • we observed a significant positive association between the 2:16α-OH estrone ratio and breast cancer risk among lean women
  • No significant associations have been observed with the 2:16α-OH estrone ratio
  • In the Danish study, no associations were observed with either ER+ or ER- tumors among PMH nonusers
  • significant positive associations with 2-OH estrone and the 2:16α-OH estrone ratio were observed among PMH users with ER+, but not ER-, tumors
  • it is possible that the genotoxicity of 2-OH estrone plays a role in hormone receptor negative tumors
  • 4-OH estrogens have a greater estrogenic potential than 2-OH estrogens, given the lower dissociation rate from estrogen receptors compared with estradiol (61), and are potentially more genotoxic since the quinones form unstable adducts, leading to depurination and mutation in vitro and in vivo
  • the balance between the catechol (i.e., 2-OH and 4-OH) and methoxy (i.e., 2-Me and 4-Me) estrogens may impact risk
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    The risks of estrogen metabolism are not clear cut.  Likely never will be due to the complexity of individual metabolism.  This study found no correlation between 2OH-Estrone and 2OH:16alpha-Estrone and breast cancer risk in ER+/PR+ breast cancer.  Translated: no benefit in breast cancer risk in 2OH-Estrone metabolism or increased 2OH:16alpha estrone metabolism.  There was a positive association between 2OH-Estrone and 2:16alpha-Estrone in women with ER-/PR- tumors and low BMI.
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Nathan Goodyear

Urinary estrogens and estrogen metabolites and subsequent risk of breast cancer among p... - 0 views

  • While the catechol estrogens have estrogenic and genotoxic potential, the methylated catechol estrogens, which are catechol estrogens with one hydroxyl group methylated, have been hypothesized to lower risk of breast cancer.
  • Despite the estrogenic and genotoxic potential of many of the EM, we only observed a significantly increased breast cancer risk with one EM, 17-epiestriol, which has particularly strong estrogenic activity and binds to both ERα and ERβ with an affinity comparable to estradiol
  • We did not observe reduced risk for higher concentrations of 2-pathway EM relative to 16-pathway EM, nor did we observe a consistent benefit of higher concentrations of methylated catechol EM compared with catechol EM.
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  • EM also can be genotoxic, but the individual EM vary in their ability to induce DNA damage
  • Catechol estrogens can be oxidized into quinones and induce DNA damage directly through the formation of DNA adducts, or indirectly via redox cycling and generation of reactive oxygen species
  • the oxidized forms of the catechol estrogens differ in their ability to damage DNA through adducts, with oxidized 2-catechols forming stable and reversible DNA adducts and oxidized 4-catechols forming unstable adducts, which lead to depurination and mutations
  • 2- and 4-catechols have been shown to produce reactive oxygen species and induce oxidative DNA damage (46). These catechols also induce neoplastic transformation in ER-cells, and thus act independently from the ER
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    Estrogen metabolites.
Nathan Goodyear

The Estrogen Receptor β Subtype: A Novel Mediator of Estrogen Action in Neuro... - 0 views

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    Estrogen receptors are one mechanism of the transmission of the estrogen signal.  The signal can be from estrogens themselves, estrogenic like compounds (xenoestrogens) and via non-estrogens like 3-beta androstane idol that interacts with ER beta to decrease prostate cancer cell proliferation.
Nathan Goodyear

4-Hydroxytamoxifen binds to and deactivates the estrogen-related receptor γ - 0 views

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    estrogen-related receptors.  There are 3 types: alpha, beta, and gamma.  These don't respond to estrogens, but to estrogen related elements
Nathan Goodyear

Transcriptional targets shared by estrogen receptor-related receptors (ERRs) and estrog... - 0 views

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    estrogen related receptors play a role in estrogen signaling, though they don't bind estradiol. They bind estrogen related elements. Exact role is unknown. They are called "orphan" members of the nuclear family of receptors.
Nathan Goodyear

Urinary estrogen metabolites in women at high risk for breast cancer - 0 views

  • obesity has also been linked to preferential estrogen metabolism via the 16-alpha-hydroxylation pathway; thus, a prediction of the mechanism by which obesity could increase breast cancer risk would be through a lowering of the 2:16 ratio in favor of the 16 pathway
  • increased BMI was associated with a lower 2:16 OHE ratio
  • Our data show a significant association between alcohol use, defined as at least one drink per day or an average of seven per week, and 2:16 OHE ratio
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  • An alcohol-induced rise in estrogens as a consequence of alcohol catabolism in the liver has been reported
  • The only study that looked at the association between alcohol and wine consumption in healthy women did not report a clear association
  • smoking has been reported to increase induction of the 2-hydroxylation metabolic pathway (24). However, the few epidemiological studies conducted on healthy women showed no difference in estrogen metabolites with smoking status (22) or smoking dose (20), in line with our findings.
  • Family history of a first-degree family member with breast cancer confers a 2- to 4-fold risk of developing breast cancer
  • 16% of breast cancers are due to unidentified hereditary factors
  • Estrogen metabolism occurs through enzymes whose activity is determined by the presence of specific genetic polymorphisms, thus can be defined as unique to each individual.
  • the metabolism is also influenced by a number of environmental factors, which change over a lifetime
  • significantly lower 2:16 OHE ratio in women who have known breast cancer risk factors compared with healthy women
  • There was an additional significant association specifically with BMI and alcohol use, which also supports the evidence that these factors affect estrogen metabolism
  • Profiling estrogen metabolites may identify women who are more likely to develop breast cancer within a population of women with known risk factors
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    urinary estrogen metabolites shown to provide insight into breast cancer risk.  This study suggested that a low 2:16 OHE ratio increase breast cancer risk.
Nathan Goodyear

Estrogen receptor transcription and transactivation: Estrogen receptor alpha and estrog... - 1 views

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    estrogen receptors are not created equally.  ER-alpha is the predominant pro-stimulatory signal receptor, whereas the ER-beta is the inhibitory receptor signaling pathway.  SERMS are not created equally as well dependent on how they bind the respective ER receptors.
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    Thank you for sharing
Nathan Goodyear

Oral estrogen antagonizes the metabolic actions of growth hormone in growth hormone-def... - 0 views

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    One really wonders if estrogen should ever be given orally at all.  Though this study is small, this is consistent with other studies that show that estrogen therapy, particularly oral therapy interferes with growth hormone signaling and thus action.  Oral estrogen decreases IGF-1, increases growth hormone binding protein, lowers metabolism and reduces protein metabolism as monitored by leucine turnover.
Nathan Goodyear

Endogenous Estrogen Regulation of Inflammatory Arthritis and Cytokine Express... - 0 views

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    this study looked at estrogen in rheumatoid arthritis in mice. They found an anti-inflammatory effect of estrogen in men through ER-alpha. This is in contrast to other studies. Maybe the immunomodulatory effects of estrogen is, in part, through which receptors are activated.
Nathan Goodyear

Estrogen receptor acts as a dominant regulator of estrogen signaling - 0 views

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    ER-beta expression appears to regulate estrogenic activity through ER-alpha expression.  Co-expression of ER-alpha and ER-beta is associated with reduced estrogenic signaling, indicating a significant counter regulatory role for ER-beta.
Nathan Goodyear

Associations of the Fecal Microbiome With Urinary Estrogens and Estrogen Metabolites in... - 0 views

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    women with increased gut microbiome diversity found to have increased estrogen metabolites compared to parent estrogen i.e. gut microbiome diversity in women effects estrogen metabolism. 
Nathan Goodyear

Association between endogenous sex steroid hormones and inflammatory biomarkers in US men - 0 views

  • modest statistically significant inverse associations for total and calculated free testosterone, and modest positive associations for total and calculated free estradiol with CRP concentration
  • Estradiol concentrations were also weakly positively associated with WBC count
  • SHBG was weakly inversely associated with WBC
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  • An association between testosterone and WBC count was not observed
  • These findings are consistent with the hypothesis that in men higher androgen concentration is anti-inflammatory, and higher estrogen concentration is pro-inflammatory.
  • the probability of elevated CRP concentrations (≥ 3 mg/L) decreased with higher total and calculated free testosterone concentrations, while the probability increased with higher total and calculated free estradiol concentrations
  • there is ample evidence supporting the immunosuppressive effect of androgens
  • The incidence of autoimmune diseases is higher in androgen-deficient men
  • Studies have shown that the induction of hypogonadism in older men is followed by a significant increase in IL-6 concentrations (Khosla et al. 2002), a potent stimulator of inflammation, and that activation of the androgen receptor exerts a direct anti-inflammatory effect
  • It has been suggested that the mechanisms for the immunosuppressive effect of androgens could be either a direct effect on the expression of inflammatory genes (Bellido et al. 1995; Asirvatham et al. 2006), or an indirect effect through inhibition of nuclear factor-kB activation
  • Estradiol is the major biologically active estrogen, and about 80% is formed in adult men from the aromatization of testosterone primarily in the adipose tissue
  • estrogen can stimulate the transcription factor C/EBP-β, which is involved in CRP transcription
  • Most prior cross-sectional studies have observed inverse associations between androgen concentrations and inflammatory biomarkers
  • A recent study in Chinese men showed that lower concentrations of total and calculated free testosterone were associated with higher CRP concentration
  • Data from the Boston Area Community Health Survey also reported inverse associations between testosterone and CRP concentrations
  • Total testosterone was inversely associated with WBC count (Tang et al. 2007; Schneider et al. 2009; Brand et al. 2012), but calculated free testosterone was not associated with WBC
  • The first trial found a decrease in CRP, interleukin-1β (IL-1β), and tumor necrosis factor-α (TNFα) but no changes in IL-6 and IL-10 concentrations between the active treatment and placebo arms
  • the majority of studies in the literature have not observed statistically significant associations between estradiol and inflammatory biomarkers in men, although several of them observed point estimates in the positive direction
  • total testosterone and estradiol compete for binding to SHBG, and seem to have opposite effects on the concentration of inflammatory biomarkers
  • A small randomized controlled trial of estrogen replacement therapy in prostate cancer patients showed an increase in CRP in the active treatment group versus the comparator group
  • Obese men are known to have lower androgen concentrations compared to their normal-weight counterparts
  • The strongest suggestion of an interaction was the inverse association between androstanediol glucuronide and CRP concentrations in obese participants, while the association was positive in the non-obese
  • A recent Chinese cross-sectional study observed stronger inverse associations between total testosterone and CRP concentrations in individuals with a BMI of 27.5 kg/m2 or greater
  • our results suggest that total and calculated free testosterone are modestly inversely associated with CRP concentrations, and that total and calculated free estradiol are modestly positively associated with CRP and WBC
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    Study results suggest that higher Testosterone and lower Estrogen levels provide anti-inflammatory effects in men.  The inflammatory biomarker assessed here was CRP.  Low total and calculated free Testosterone was associated with an increase in CRP.  In contrast, total and free Estrogen was associated with an increase in CRP.  Estradiol increased WBC count and SHBG was inversely related to WBC count in this study.
Nathan Goodyear

Environmental Estrogen Exposure During Fetal Life: A Time Bomb for Prostate Cancer: End... - 0 views

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    environmental toxins that have estrogenic activity, i.e. BPA alter the prostate stem cells.  These and other xenoestrogens, as they are collectively called, increase the sensitivity of the prostate to estrogen.  This increases the risk of prostate Ca.  This just sets the pattern of signal interpretation and sensitivity.  Add in the continued estrogenic environment, add in the excess weight, the increased aromatase activity and resultant estrogen production and one has all the ingredients for prostate cancer.
Nathan Goodyear

Estrogen receptor related beta is expressed in human endometrium throughout the normal ... - 0 views

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    ER-beta found throughout both the proliferative and secretory phases of the menstrual cycle.  ER-beta expression was higher in the proliferative versus the secretory phases, though not statistically significant.  This makes since as estrogen stimulation dominates the proliferative phase.  Additionally, ER-beta expression was found throughout all levels of the endometrium and the myometrium.
Nathan Goodyear

The androgen metabolite 5alpha-androstane-3beta,17beta-diol (3betaAdiol) induces breast... - 0 views

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    Great article!!  Nice discussion of the complexity of hormones.  Women on aromatase inhibitors can make estrogen from Testosterone.  This is important with estrogen sensitive cancer as in breast cancer.  This will occur via alternative pathways: Testosterone to DHT via 5 alpha reductase and then DHT to 3 beta androstanediol via 3 beta HSD.  3 beta androstanediol is a male hormone metabolite that binds to estrogen receptors.  The affinity is less than Estradiol, but appears to have a higher affinity for ER beta over ER alpha. 
Nathan Goodyear

Mechanisms of Estrogen Action - 0 views

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    good discussion of estrogen receptors and their role of estrogen signaling transmission.This article goes deep into coregulators, corepressors, cofactors, agonists, antagonists...
Nathan Goodyear

Effects of estrogen on memory funct... [Psychoneuroendocrinology. 1992] - PubMed - NCBI - 0 views

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    estrogen therapy in surgical menopause preserves memory.  Rapid decline in estrogen levels post surgical menopause is associated with cognitive/memory decline.  Versus placebo, estrogen therapy preserved memory function.
Nathan Goodyear

Is Timing Everything? New Insights into Why the Effect of Estrogen Therapy on Memory Mi... - 0 views

  • Women who have an oophorectomy before the normal age at menopause show an increased risk for cognitive impairment or dementia later in life unless they are treated with estrogen until the normal age at menopause
  • SIRT1 has been implicated in the disruption of mitochondrial bioenergenetics in Alzheimer's disease and mild cognitive impairment
  • the increase in dementia observed with CEE/MPA rather than CEE alone suggests potential deleterious effects of MPA on brain function in older women
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  • SIRT 1 as a potential mediator of the impact of E2
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    Early estrogen therapy in perimenopause and early menopause, with Estradiol, provides more health benefits than later therapy.  This article looked at Estrogen's effects on a woman's brain.  This likely has its origins in the change in estrogen receptors. The signal is not changing, but the reception of that signal is.  How else can one explain a different response to the same hormone dosage?
Nathan Goodyear

High Estrogen in Men After Injectable Testo... [Am J Mens Health. 2014] - PubMed - NCBI - 0 views

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    Again, Testosterone and here Estradiol are merely there for libido and sex.  What tunnel vision?!  What about hsCRP?  What about fibrinogen?  What about IL-1beta?  What about TNF-alpha?  These inflammatory cytokines have all been reported to elevate as a result of estrogen production in men.   And PSA?  No mention of it here.   This linear, tunnel vision thinking on hormones has got to stop! The study points out that all clients were using AIs and SERMs irregardless of whether they had elevated estrogens or not.  That is not a well designed study.  One group should have had AI's if elevated estrogens were present and another group should not--this would compare the effects of aromatase activity.  Second, this was simply a retrospective chart review.  Third, a 50% conversion of 34,000 + men is very high when you look at the literature.  Fourth, they point to gynecomastia as a means of negative?  The cardiovascular implications are more significant.  These studies just seem to focus on superficial things.  Fifth, did libido problems exist before?  What were the free levels?   This falls in the paucity of data (2 studies) that point to excessive lowering of estradiol effecting libido and sexual performance.
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