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Nathan Goodyear

Adipose Tissue as an Endocrine Organ - 0 views

jcem.endojournals.org/...2548.full

adipose tissue endocrine organ obesity overweight

shared by Nathan Goodyear on 05 Jan 12 - No Cached
  • Nathan Goodyear on 05 Jan 12
     
    You need to look at your fat differently.  It literally has developed a life of its own.  Adipose Tissue functions as an endocrine organ.  Just like your thyroid, adrenals...
Nathan Goodyear

ingentaconnect Adipose Tissue Macrophages, Low Grade Inflammation and Insulin Re... - 0 views

www.ingentaconnect.com/...art00009

ATMs obesity inflammation inflammatory reaction insulin resistance IR diabetes DM type II macrophages

shared by Nathan Goodyear on 10 Jan 12 - No Cached
  • “M1” or “classically activated” macrophages
  • PPAR-gamma agonists
  • “M2” or an “alternatively activated” anti-inflammatory phenotype
  • Nathan Goodyear on 10 Jan 12
     
    ATMs and obesity induced inflammation initiates insulin resistance and thus type II diabetes. The bodies reaction to a fat cell is no different than a bacterial, viral, or parasitic infection.  The body recognizes something (fat) that shouldn't be there and it attempts to destroy it and remove it.
Nathan Goodyear

Intestinal Lymphocyte Populations in Children with Regressive Autism: Evidence for Exte... - 0 views

mercola.fileburst.com/....lymphocytes%20in%20autism.pdf

ASD autism IBD inflammation gut intestine

shared by Nathan Goodyear on 29 Jan 12 - No Cached
  • Nathan Goodyear on 29 Jan 12
     
    inflammatory changes in the intestines of children with regression autism found that is different from others with inflammatory bowel diseases.
Nathan Goodyear

Vaccines backfire: Veterinary vaccines found to combine into new infectious viruses - 0 views

www.sciencedaily.com/...120712144754.htm

vaccine vaccines vaccinations

shared by Nathan Goodyear on 30 Jul 12 - No Cached
  • Nathan Goodyear on 30 Jul 12
     
    scary result.  Vaccine used in the prevention of ILT in chickens resulted in a new viral strain.  Two different virus strains were used.  These combined and resulted in a brand new viral strain. Apply this to our multi-dose vaccine schedule i.e. MMR
Nathan Goodyear

Purified eicosapentaenoic and docosahexaenoic acids have differential effects on serum ... - 0 views

www.ajcn.org/...1085.long

n-3 omega-3 DHA EPA fish oil

shared by Nathan Goodyear on 16 Jul 12 - No Cached
  • Nathan Goodyear on 16 Jul 12
     
    EPA and DHA have differing effects in men with Hyperlipidemia.  DHA increased LDL particle size, increased fasting insulin, but did not increase fasting glucose.
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

http://www.europeanurology.com/article/S0302-2838(08)01435-8/pdf/Oestrogens+and+Prostat... - 0 views

www.europeanurology.com/...el+Concepts+about+an+Old+Issue

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

shared by Nathan Goodyear on 20 Jan 14 - No Cached
  • Nathan Goodyear on 20 Jan 14
     
    Nice review of the proposed complex interaction between hormones and prostate cancer.  The complex nature of the development of cancer will likely eliminate the complete elucidation of the mechanism of prostate cancer.  However, there are many pieces that would favor: increased aromatase activity appears to play a significant role int he development of prostate cancer, clearly intraprostatic hormones are different than serum making serum evaluation of sex hormones irrelevant--the move should be to salivary hormones, and the growing knowledge of DHT metabolites in the protection of prostate cancer--3 beta androstanediol.
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

Comparative Studies of the Estrogen Receptors β and α and the Androgen Recept... - 0 views

ajp.amjpathol.org/...fulltext

ER beta ER-beta AR androgen receptors ER alpha ER-alpha prostate disease cancer estrogen receptor hormone hormones men male

shared by Nathan Goodyear on 21 Jan 14 - No Cached
  • ER-β is predominately immunolocalized in basal cells and to a lesser extent in stromal cells of the morphologically normal human prostate
  • ER-α is detected in stromal cells and rarely in basal cells of the normal gland
  • AR was predominately localized in the nuclei of differentiated secretory cells and variably in basal cells of the normal acinar/duct unit as well as in stromal cells
  • ...9 more annotations...
  • Hall and colleagues44 have reported that ER-β functions as a transdominant inhibitor of ER-α transcription and that it acts to decrease overall cellular sensitivity to estradiol
  • The expression of ER-β was diminished in high-grade dysplasias when compared to normal glands and lower grade lesions.
  • The transition from normal to low/moderate dysplastic glands in the peripheral zone was marked by the appearance of ER-β homogeneously immunostained nuclei in secretory as well as basal cells with no changes in the localization of the other receptors.
  • proliferative signals mediated by AR in basal cells or by ER-α and AR in stromal cells may be opposed by the purported growth-inhibitory action of ER-β25, 26, 27, 28 localized in basal cells.
  • The diminution of ER-β expression in high-grade dysplasias and grade 4/5 cancers may be therefore related to the alteration of DNA methylation pattern in CpG islands of the promoter, resulting in down-regulation of the receptor at the transcriptional level
  • based on the proposed anti-proliferative function of the receptor,25, 26, 27, 28 the presence of ER-β in secretory cells of low/moderate-grade lesions may represent a transient abortive attempt to counter growth of these cells
  • the attrition of receptor-positive basal cells in the high-grade dysplasias may signify a continuing loss of growth inhibitory function mediated by ER-β in these precursor lesions
  • Our findings in prostate therefore differ from those reported for human colon cancer in which Folley and colleagues48 demonstrated that a selective loss of ER-β protein but not receptor message expression occurs in these neoplasms
  • Our findings therefore differed from those of Bonkhoff and colleagues33 who found immunostaining for the receptor in high-grade dysplasias and grade 4/5 carcinomas. Using in situ hybridization these authors also reported that a high percentage of dysplasias and carcinomas in their study contained cells that expressed ER-α message
  • Nathan Goodyear on 21 Jan 14
     
    Very nice study.  The authors looked at normal prostate, early disease and late stage prostate cancer.  The authors found that ER beta expression, as a general rule, was lost as progression occurred to the high-grade dysplasias and grad 4/5 carcinomas of the prostate.  Early low/moderate dysplasia was associated with an increase in ER beta--the authors propose that this was due to an attempt of the basal epithelium to counter the paracrine effect of ER alpha.   In contrast, androgen receptors appeared to be equally expressed across all.
Nathan Goodyear

Androgens and prostate disease Cooper LA, Page ST - Asian J Androl - 0 views

www.ajandrology.com/article.asp

prostate disease cancer Testosterone DHT 5-alpha reductase men male hormone hormones

shared by Nathan Goodyear on 15 Jan 14 - No Cached
  • intraprostatic androgens are not concomitantly increased when serum androgen levels are raised.
  • The "saturation model" proposes that the prostate is sensitive to very low concentrations of circulating androgens, but that once maximal AR binding is achieved, which occurs at relatively low concentrations of circulating T, further increases in serum T have little impact
  • men with metastatic prostate cancer given T who had been previously treated with castration had worsening of disease, whereas those without prior castration did not
  • ...3 more annotations...
  • There is little data to support the withholding of T therapy on the basis of concern for precipitating prostate cancer.
  • Both intervention data and physiology studies point to minimal effects on the prostate gland when serum T levels are increased to the mid-normal range with T therapy
  • an individualized care plan to assess the possible risks and benefits of T therapy for each patient is critical to optimizing the use of androgens in male health.
  • Nathan Goodyear on 15 Jan 14
     
    Nice review of the mixed data on Testosterone and Prostate disease. It is clear that Testosterone does not precipitate prostate cancer.  The intraprostatic hormone milieu likely is different than that present in the serum.  No surprise there.  5alpha reductase decreases prostate volume, PSA, and low-grade prostate cancer, but actually increases aggressive prostate cancer. Supraphysiologic doping in young men associated with no increase in prostate disease. PSA no longer to be followed in men < 55.  Mortality rate not changed.  PSA change of 1.4 ng/ml is appropriate for additional prostate evaluation.  Testosterone therapy on average increased 0.5 ng/ml. Still, no mention of aromatase activity in this article.  Why is it that hormone sensitive disease in men is only with regards to androgens and women estrogen.
Nathan Goodyear

Testosterone responses to intensive inte... [J Endocrinol Invest. 2012] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...23310924

exercise high intensity training HIT hormone hormones Testosterone free 3-alpha androstanediol

shared by Nathan Goodyear on 27 Jan 14 - No Cached
  • Nathan Goodyear on 27 Jan 14
     
    high intensity interval training versus steady state provides different results in post exercise FT.
Nathan Goodyear

Characteristics of Secondary, Primary, and Compensated Hypogonadism in Aging Men: Evide... - 0 views

press.endocrine.org/...jc.2009-1796

low T Testosterone obesity overweight men male hormone hormones

shared by Nathan Goodyear on 04 Feb 14 - No Cached
  • Older men were more likely to have primary [relative risk ratio (RRR) = 3.04; P &lt; 0.001] and compensated (RRR = 2.41; P &lt; 0.001) hypogonadism. Body mass index of 30 kg/m2 or higher was associated with secondary hypogonadism (RRR = 8.74; P &lt; 0.001)
  • Nathan Goodyear on 04 Feb 14
     
    The prevalence of low T varies significantly between lean versus overweight men.  This suggests a significant contribution of obesity and its biologic effects as a cause of low T.  The difference is 30%.
Nathan Goodyear

The 4-Pregnene and 5α-Pregnane Progesterone Metabolites Formed in Nontumorous... - 0 views

cancerres.aacrjournals.org/...936.long

progesterone metabolite metabolites hormone hormones 5-alpha pregnene 5-alpha pregnenes 3-alpha pregnene 3-alpha pregnenes breast cancer

shared by Nathan Goodyear on 28 Jan 14 - No Cached
  • Nathan Goodyear on 28 Jan 14
     
    Good discussion of the different effects of progesterone metabolites in breast cancer cell lines (in vitro).  This article focused on the biochemical balance of 5alpha pregnane: 3alpha HP.  The increase in this ration promoted proliferation and metastasis, where a decreased ratio did the opposite
Nathan Goodyear

Testosterone and glucose metabolism in men: current concepts and controversies - 0 views

joe.endocrinology-journals.org/...R37.full

shared by Nathan Goodyear on 04 Feb 14 - No Cached
    • Nathan Goodyear
      Nathan Goodyear on 04 Feb 14
       
      80% of E2 production in men, that will cause low T in men, comes from SQ adiposity.  This leads to increase in visceral adiposity.
  • Only 5% of men with type 2 diabetes have elevated LH levels (Dhindsa et al. 2004, 2011). This is consistent with recent findings that the inhibition of the gonadal axis predominantly takes place in the hypothalamus, especially with more severe obesity
  • Metabolic factors, such as leptin, insulin (via deficiency or resistance) and ghrelin are believed to act at the ventromedial and arcuate nuclei of the hypothalamus to inhibit gonadotropin-releasing hormone (GNRH) secretion
  • ...32 more annotations...
  • kisspeptin has emerged as one of the most potent secretagogues of GNRH release
  • Consistent with the hypothesis that obesity-mediated inhibition of kisspeptin signalling contributes to the suppression of the HPT axis, infusion of a bioactive kisspeptin fragment has been recently shown to robustly increase LH pulsatility, LH levels and circulating testosterone in hypotestosteronaemic men with type 2 diabetes
  • Figure 4
  • Interestingly, a recent 16-week study of experimentally induced hypogonadism in healthy men with graded testosterone add-back either with or without concomitant aromatase inhibitor treatment has in fact suggested that low oestradiol (but not low testosterone) may be responsible for the hypogonadism-associated increase in total body and intra-abdominal fat mass
    • Nathan Goodyear
      Nathan Goodyear on 04 Feb 14
       
      This does not fit with the research on receptors, specifically estrogen receptors.  These studies that the authors are referencing are looking at "circulating" levels, not tissue levels.
  • A smaller study with a similar experimental design found that acute testosterone withdrawal reduced insulin sensitivity independent of body weight, whereas oestradiol withdrawal had no effects
  • Obesity and dysglycaemia and associated comorbidities such as obstructive sleep apnoea (Hoyos et al. 2012b) are important contributors to the suppression of the HPT axis
  • This is supported by observational studies showing that weight gain and development of diabetes accelerate the age-related decline in testosterone
  • Weight loss can reactivate the hypothalamic–pituitary–testicular axis
  • The hypothalamic–pituitary–testicular axis remains responsive to treatment with aromatase inhibitors or selective oestrogen receptor modulators in obese men
  • Kisspeptin treatment increases LH secretion, pulse frequency and circulating testosterone levels in hypotestosteronaemic men with type 2 diabetes
  • Several observational and randomised studies reviewed in Grossmann (2011) have shown that weight loss, whether by diet or surgery, leads to substantial increases in testosterone, especially in morbidly obese men
  • This suggests that weight loss can lead to genuine reactivation of the gonadal axis by reversal of obesity-associated hypothalamic suppression
  • There is pre-clinical and observational evidence that chronic hyperglycaemia can inhibit the HPT axis
  • in those men in whom glycaemic control worsened, testosterone decreased
  • successful weight loss combined with optimisation of glycaemic control may be sufficient to normalise circulating testosterone levels in the majority of such men
  • weight loss, optimisation of diabetic control and assiduous care of comorbidities should remain the first-line approach.
    • Nathan Goodyear
      Nathan Goodyear on 04 Feb 14
       
      This obviously goes against marketing-based medicine
  • In part, the discrepant results may be due to the fact men in the Vigen cohort (Vigen et al. 2013) had a higher burden of comorbidities. Given that one (Basaria et al. 2010), but not all (Srinivas-Shankar et al. 2010), RCTs in men with a similarly high burden of comorbidities reported an increase in cardiovascular events in men randomised to testosterone treatment (see section on Testosterone therapy: potential risks below) (Basaria et al. 2010), testosterone should be used with caution in frail men with multiple comorbidities
  • The retrospective, non-randomised and non-blinded design of these studies (Shores et al. 2012, Muraleedharan et al. 2013, Vigen et al. 2013) leaves open the possibility for residual confounding and multiple other sources of bias. These have been elegantly summarised by Wu (2012).
  • Effects of testosterone therapy on body composition were metabolically favourable with modest decreases in fat mass and increases in lean body mass
  • This suggests that testosterone has limited effects on glucose metabolism in relatively healthy men with only mildly reduced testosterone.
  • it is conceivable that testosterone treatment may have more significant effects on glucose metabolism in uncontrolled diabetes, akin to what has generally been shown for conventional anti-diabetic medications.
  • the evidence from controlled studies show that testosterone therapy consistently reduces fat mass and increases lean body mass, but inconsistently decreases insulin resistance.
  • Interestingly, testosterone therapy does not consistently improve glucose metabolism despite a reduction in fat mass and an increase in lean mass
  • the majority of RCTs (recently reviewed in Ng Tang Fui et al. (2013a)) showed that testosterone therapy does not reduce visceral fat
    • Nathan Goodyear
      Nathan Goodyear on 04 Feb 14
       
      visceral and abdominal adiposity are biologically different and thus the risks associated with the two are different.
    • Nathan Goodyear
      Nathan Goodyear on 04 Feb 14
       
      yet low T is associated with an increase in visceral adiposity--confusing!
  • testosterone therapy decreases SHBG
  • testosterone is inversely associated with total cholesterol, LDL cholesterol and triglyceride (Tg) levels, but positively associated with HDL cholesterol levels, even if adjusted for confounders
  • Although observational studies show a consistent association of low testosterone with adverse lipid profiles, whether testosterone therapy exerts beneficial effects on lipid profiles is less clear
  • Whereas testosterone-induced decreases in total cholesterol, LDL cholesterol and Lpa are expected to reduce cardiovascular risk, testosterone also decreases the levels of the cardio-protective HDL cholesterol. Therefore, the net effect of testosterone therapy on cardiovascular risk remains uncertain.
  • data have not shown evidence that testosterone causes prostate cancer, or that it makes subclinical prostate cancer grow
  • compared with otherwise healthy young men with organic androgen deficiency, there may be increased risks in older, obese men because of comorbidities and of decreased testosterone clearance
  • recent evidence that fat accumulation may be oestradiol-, rather than testosterone-dependent
Nathan Goodyear

Persistent Intraprostatic Androgen Concentrations after Medical Castration in Healthy M... - 0 views

press.endocrine.org/...jc.2006-0968

Testosterone androgen deprivation therapy prostate cancer men male hormone hormones

shared by Nathan Goodyear on 03 Feb 14 - No Cached
  • Nathan Goodyear on 03 Feb 14
     
    Serum Testosterone levels and intra-prostatic Testosterone levels in men are very different in men with androgen deprivation therapy.  Though there is a 94% serum reduction, intra-prostatic Testosterone levels remain 20-30% higher.  
Nathan Goodyear

Differential regulation of endothelium behavior by progesterone and medroxyprogesterone... - 0 views

joe.endocrinology-journals.org/...179.abstract

progesterone medroxyprogesterone acetate medroxyprogesterone hormone hormones women cardiovascular disease HRT

shared by Nathan Goodyear on 04 Feb 14 - No Cached
  • Nathan Goodyear on 04 Feb 14
     
    No surprise that progesterone and the synthetic progestin medroxyprogesterone acetate (MPA) have different effects on the vascular endothelium. MPA inhibits NO production, whereas Progesterone maintains NO production.  MPA promoted platelet adhesion whereas Progesterone did not--significant implication in plaque formation.
Nathan Goodyear

Roles of the gonadal steroid hormones in psychiatric depression in men and women - Rese... - 0 views

www.researchgate.net/...ic_depression_in_men_and_women

depression estradiol estrogen men Testosterone women hormones hormone

shared by Nathan Goodyear on 03 Feb 14 - No Cached
  • Nathan Goodyear on 03 Feb 14
     
    Fascinating difference in the sexes.  High estradiol is found to be associated with depression in men and high Testosterone is found to be associated with depression in women.  The exact mechanism or strength of association is unstated.
Nathan Goodyear

Progesterone metabolites regulate induction, growth, and suppression of estrogen- and p... - 0 views

www.ncbi.nlm.nih.gov/...PMC3706910

progesterone metabolites metabolite 5-alpha pregnene 5-alpha pregnenes 5alpha-dihydroprogesterone 4-pregnene 4-pregnenes 3alpha-dihydroprogesterone breast cancer ER PR hormone hormones receptors estrogen

shared by Nathan Goodyear on 28 Jan 14 - No Cached
  • in vitro studies had shown that the progesterone metabolites, 5α-dihydroprogesterone (5αP) and 3α-dihydroprogesterone (3αHP), respectively, exhibit procancer and anticancer effects on receptor-negative human breast cell lines
  • Onset and growth of ER/PR-negative human breast cell tumors were significantly stimulated by 5αP and inhibited by 3αHP
  • When both hormones were applied simultaneously, the stimulatory effects of 5αP were abrogated by the inhibitory effects of 3αHP and vice versa
  • ...31 more annotations...
  • Treatment with 3αHP subsequent to 5αP-induced tumor initiation resulted in suppression of further tumorigenesis and regression of existing tumors
  • Tumorigenesis of ER/PR-negative breast cells is significantly enhanced by 5αP and suppressed by 3αHP, the outcome depending on the relative concentrations of these two hormones in the microenvironment in the breast regions
  • The findings show that the production of 5αP greatly exceeds that of 3αHP in ER/PR-negative tumors and that treatment with 3αHP can effectively block tumorigenesis and cause existing tumors to regress
  • hypothesis that a high 3αHP-to-5αP concentration ratio in the microenvironment may foster normalcy in noncancerous breast regions.
  • a large proportion (about 30% to 60%) of breast tumors are ER and/or PR negative
  • about 90% of normal proliferating breast epithelial cells are receptor negative
  • Our previous in vitro studies had shown that breast tissues and cell lines readily convert progesterone to 5α-pregnanes, such as 5αP, and delta-4-pregnenes, such as 3αHP (Figure ​(Figure1),1), and that tumorous breast tissues [15] and tumorigenic breast cell lines [16] produce higher levels of 5αP and lower levels of 3αHP than do normal breast tissues and nontumorigenic cell lines
  • The progesterone metabolism studies suggested that increases in 5αP and decreases in 3αHP production accompany the shift toward breast cell neoplasia and tumorigenicity
  • In vitro studies on five different human breast cell lines showed that cell proliferation and detachment are significantly increased by 5αP and decreased by 3αHP
  • the prevailing theory of hormonal regulation of breast cancer, as well as hormone-based therapies, revolves around estrogen and/or progesterone and ER/PR-positive breast cells and tumors.
  • Not only do these "receptor-negative" breast cancers fail to benefit from current hormonal therapies, but they also generally exhibit more-aggressive biologic behaviors and poorer prognosis than the receptor-positive ones
  • The results of the studies reported here show for the first time that the progesterone metabolites, 5αP and 3αHP, act as hormones that regulate ER/PR-negative breast tumor formation, growth, and regression
  • The onset of the ER/PR-negative human breast cell tumors in mice was considerably accelerated, and the growth significantly stimulated, by just one or two applications of 5αP
  • In contrast, 3αHP retarded onset of tumor formation, suppressed tumor growth, and inhibited or regressed existing 5αP-induced tumors
  • When both hormones were administered simultaneously, the effects of one were abrogated by the effects of the other.
  • The 5αPR and 3αHPR (which are associated with the plasma membranes of both ER/PR-positive [19] and ER/PR-negative [29] cells) are distinct from each other and from known ER, PR, androgen, and corticosteroid receptors, and lack affinity for other steroids, such as progesterone, estrogen, androgens, corticosteroids, and other progesterone metabolites
  • Levels of 5αPR are upregulated by 5αP itself and estradiol, and downregulated by 3αHP in both ER/PR-positive and -negative cells
  • ndications are that 5αP acts via the surface receptor-linked mitogen-activated protein kinase (MAPK; Erk1/2) pathway; 5αP significantly stimulates activation of Erk1/2 [30], increases the Bcl-2/Bax expression ratio [18] and actin depolymerization [31], and decreases expression of actin and adhesion plaque-associated vinculin [31], resulting in decreased apoptosis and increased mitosis and cell detachment
  • 3αHP appears to suppress protein kinase C (PKC), phospholipase C (PLC), Ca2+ mobilization (unpublished observations), and the Bcl-2/Bax expression ratio [18], and increases expression of the cell-cycle inhibitor p21 [18], resulting in increased apoptosis and decreased proliferation and detachment of breast cell lines.
  • serum from mice with tumors had significantly more 5αP than 3αHP
  • the tumors, which on average had about threefold higher concentrations of 5αP than the respective sera, and &gt;10-fold higher 5αP than 3αHP levels
  • Previous in vitro metabolism studies showed that human breast tumor tissues convert significantly more progesterone to 5α-pregnanes like 5αP and less to 4-pregnenes like 3αHP than do paired normal (nontumorous) tissues
  • Similar differences in progesterone metabolism and enzyme gene expressions were observed between tumorigenic and nontumorigenic breast cell lines
  • breast carcinomas are able to synthesize progesterone
  • The current findings, along with the previous in vitro studies, suggest that the relative concentrations of 5αP and 3αHP in the breast microenvironment constitute important autocrine/paracrine determinants not only for tumorigenesis but also for potential regression of tumors and the maintenance of normalcy of ER/PR-negative breast cells/tissues.
  • Evidence presented here shows that a high concentration of 5αP, relative to 3αHP in the microenvironment, promotes initiation and growth of tumors, whereas a higher concentration of 3αHP, relative to 5αP, suppresses tumorigenesis and promotes normalcy
  • 5α-reductase and 5αPR levels are upregulated by 5αP
  • in the 3αHP-treated mice, the elevated 3αHP levels, relative to 5αP, in the microenvironment could have opposed progression to xenograft neoplasia by its inherent anticancer actions and the suppression of 5αP synthesis and 5αPR expression
  • the opposing actions of the progesterone metabolites also appear to exert some control over the estrogen-regulated effects on breast cancer by their ability to modulate ER numbers in ER-positive cells
  • because both ER/PR-negative and ER/PR-positive, as well as normal and tumorigenic human breast cell lines, have been shown to respond to 5αP and 3αHP in vitro, it is suggested that these endogenously produced progesterone metabolites may also play regulatory hormonal roles in ER/PR-positive breast cancers, as well as in the maintenance of normalcy in nontumorous breast tissues.
  • The in vivo data provide further evidence that progesterone metabolites, such as 5αP and 3αHP, deserve to be considered as active hormones in their own right, rather than inactive waste products
  • Nathan Goodyear on 28 Jan 14
     
    Progesterone metabolites and breast cancer
Nathan Goodyear

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

cancerres.aacrjournals.org/...5445.short

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

shared by Nathan Goodyear on 27 Jan 14 - No Cached
  • the dihydrotestosterone metabolite 5α-androstane-3β,17β-diol (3β-Adiol), a steroid which does not bind androgen receptors, but efficiently binds the estrogen receptor β (ERβ), exerts a potent inhibition of prostate cancer cell migration through the activation of the ERβ signaling
  • estradiol is not active
  • 3β-Adiol, through ERβ, induces the expression of E-cadherin, a protein known to be capable of blocking metastasis formation in breast and prostate cancer cells
  • Nathan Goodyear on 27 Jan 14
     
    DHT metabolite 3-beta androstanediol inhibits prostate cancer via its interaction with ER beta not AR.  This study finds increased E-cadherin transcription to reduce metastasis.  Estrogen was not active, according to this study.  This implies that estrogen in early disease may have a different signal than late.
Nathan Goodyear

Activity and expression of progesterone metabolizing 5α-reductase, 20α-hydrox... - 0 views

www.ncbi.nlm.nih.gov/...PMC154104

progesterone metabolites breast cancer 5alpha-reductase 5-alpha pregnene 5-alpha pregnenes 4-pregnene 4-pregnenes

shared by Nathan Goodyear on 30 Jan 14 - No Cached
  • Exposure of human breast cell lines (MCF-7, MCF-10A, and ZR-75-1) to 5α-pregnanes results in changes associated with neoplasia, including increased proliferation and decreased attachment [1], depolymerization of F-actin [2] and decreases in adhesion plaque-associated vinculin
  • Exposure to 4-pregnenes results, in general, in opposite (anti-cancer-like) effects
  • 5αR1 has been detected in various androgen-independent organs, such as the liver and brain
  • ...10 more annotations...
  • 5αR2 has been found predominantly in androgen-dependent organs, such as epididymis and prostate
  • The 5α-pregnanes:4-pregnenes ratio was about 8-fold higher in tumorous than in nontumorous breast tissue after an 8-hour incubation with [14C]progesterone
  • Studies with breast cell lines, showing that 5α-pregnanes stimulate proliferation and decrease attachment of cells
  • both tissue and breast cell line studies suggest that an elevated level of progesterone 5α-reductase activity may be an indicator of breast tumorigenesis, regardless of presence or absence of ER and/or PR
  • 5αR1 is the main isoform expressed in human breast carcinomas [29] and that 5αR2 may not be associated with risk of breast cancer
  • the differences in 5α-pregnane production between the cells is due primarily to a difference in 5αR1 expression
  • As in the case of 5α-reductase activity, the presence or absence of ER and PR do not appear to be related to 5α-reductase expression.
  • the conversion of progesterone to the cancer promoting 5α-pregnanes is significantly higher in the human tumorigenic breast cell lines
  • lthough both 5αR1 and 5αR2 are expressed by these cells, the elevated 5α-reductase activity appears to be the result of significantly greater expression of 5αR1
  • Changes in progesterone metabolizing enzyme expression (resulting in enzyme activity changes) may be responsible for promoting breast cancer progression due to increased production of tumor-promoting 5α-pregnanes and decreased production of anti-cancer 20α – and 3α-4-pregnenes
  • Nathan Goodyear on 30 Jan 14
     
    balance of enzyme production between 5alpha-reductase and 20alpha-hydroxysteroid oxidoreductase and 3alpha(beta)-hydroxysteroid oxidoreductase play role in carcinogenesis and proliferation in the balance of production of progesterone metabolites. The 5alpha pregnenes are pro carcinogenic  and the 4-pregnenes are anti carcinogenic.
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