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Nathan Goodyear

Total and free testosterone concentrations are strongly influenced by age and central o... - 0 views

onlinelibrary.wiley.com/...2B811BB37A876512D30CA68.f04t01

Testosterone low T obesity age aging male men hormone hormones diabetes

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  • Nathan Goodyear on 04 Feb 14
     
    Testosterone levels, measured as total, bioavailable and free, found to be associated with age and central (not visceral) obesity in those men with type I and II Diabetes.  Weakly with symptoms of low T and ED.
Nathan Goodyear

Perinatal exposure to low-dose bisphenol A affects the neuroendocrine stress response i... - 0 views

joe.endocrinology-journals.org/...207.abstract

bisphenol A Bisphenol-A BPA xenoestrogens stress hormone hormones

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  • Nathan Goodyear on 04 Feb 14
     
    intra uterine exposure to BPA disrupts stress response in rat model.
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

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  • 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

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

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

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    • 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

JAMA Network | JAMA Psychiatry | Mineralocorticoid Receptor Function in Major Depression - 0 views

archpsyc.jamanetwork.com/article.aspx

depression cortisol serotonin 5-HT1A receptors

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  • Nathan Goodyear on 03 Feb 14
     
    High cortisol reduce 5-HT1A receptors in major depression.
Nathan Goodyear

Depression and cortisol responses to psychological stress: A meta-analysis - 0 views

www.sciencedirect.com/...S0306453005000831

depression stress cortisol hormone hormones

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  • Nathan Goodyear on 03 Feb 14
     
    Depression found to have higher cortisol levels compared to non-depressed men and women.
Nathan Goodyear

Self-Reported Depressive Symptoms and Stress Levels in Healthy Young Men: Associations ... - 0 views

www.psychosomaticmedicine.org/...92.short

depression cortisol saliva salivary hormone hormones

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  • Nathan Goodyear on 03 Feb 14
     
    Elevated morning cortisol associated with depression in men. This study looked at saliva for assessment of free cortisol.
Nathan Goodyear

One year follow-up study of the association between chemical castration, sex hormones, ... - 0 views

www.sciencedirect.com/...S0306453003002208

hormone hormones depression memory beta-amyloid Testosterone Estradiol

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  • Nathan Goodyear on 03 Feb 14
     
    Chemical castration as seen in androgen deprivation therapy resulted in precipitous decline in Testosterone and Estradiol in men.  Associated increased in beta-amylloid found.
Nathan Goodyear

Depression in Men Receiving Androgen Deprivation Therapy for Prostate Cancer: A Pilot S... - 0 views

onlinelibrary.wiley.com/...abstract

androgen deprivation therapy depression men prostate cancer hormone hormones

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  • Nathan Goodyear on 03 Feb 14
     
    Significantly higher rates of depression in men with prostate cancer receiving ADT versus the general population.
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

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  • 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

Sex Hormones and Age: A Cross-sectional Study of Testosterone and Estradiol and Their B... - 0 views

aje.oxfordjournals.org/...750.short

hormone hormones men male Estradiol Estrogen testosterone

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  • Nathan Goodyear on 03 Feb 14
     
    Older men have Estradiol levels that are 3 x that of a post-menopausal women.  The bioavailable levels of Testosterone and Estradiol showed the greatest precipitous decline.
Nathan Goodyear

Intratumoral androgen biosynthesis in prostate cancer pathogenesis and response to therapy - 0 views

erc.endocrinology-journals.org/...R175.full

prostate cancer DHT 3-beta-diol 3-alpha-diol metabolites metabolite male men hormone hormones androgen deprivation therapy

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  • Additional studies have similarly found that prostate tissue levels of DHT in PCa patients treated with ADT therapy before prostatectomy declined by only ∼75% versus declines of ∼95% in serum levels
  • In a recent study in healthy men, treatment for 1 month with a GnRH antagonist to suppress testicular androgen synthesis caused a 94% decline in serum testosterone, but only a 70–80% decline in prostate tissue testosterone and DHT
  • progression to CRPC was associated with increased intratumoral accumulation or synthesis of testosterone.
  • ...9 more annotations...
  • the intraprostatic synthesis of testosterone from adrenal-derived precursors likely accounts for the relatively high testosterone levels in prostate after ADT
  • In addition, AR activity in these cells is likely further enhanced by multiple mechanisms that sensitize AR to low levels of androgens
  • higher affinity ligand DHT (approximately eightfold higher affinity
  • type 2 5α-reductase (SRD5A2) being the major enzyme in prostate
  • reduce DHT to 5α-androstane-3α,17β-diol (3α-androstanediol; Ji et al. 2003, Rizner et al. 2003), which is then glucuronidated to form 3α-androstanediol glucuronide by the enzymes UDP glycosyltransferase 2, B15 (UGT2B15) or UGT2B17
  • DHT in prostate is inactivated by the enzyme AKR1C2, which is also termed 3α-hydroxysteroid dehydrogenase type 3 (3α-HSD type 3
    • Nathan Goodyear
      Nathan Goodyear on 03 Feb 14
       
      The metabolite 3-alpha androstanediol is NOT inactive as this author states.  This DHT metabolite actually can stimulate  ER alpha receptors in the prostate.
  • AKR1C1, is also expressed in prostate. However, in contrast to AKR1C2, it converts DHT primarily to 5α-androstane-3β,17β-diol (3β-androstanediol; Steckelbroeck et al. 2004), which is a potential endogenous ligand for the estrogen receptor β
  • Significantly, intraprostatic testosterone levels were not substantially reduced relative to controls with normal serum androgen levels, although DHT levels were reduced to 18% of controls
  • testosterone levels in many of the CRPC samples were actually increased relative to control tissues (Montgomery et al. 2008). While DHT levels were less markedly increased, this may have reflected DHT catabolism
  • Nathan Goodyear on 03 Feb 14
     
    This article discusses the failure of androgen deprivation therapy and prostate cancer.  This failure is quite common.  The authors point to alpha-DHT as the primary mechanism through AR stimulation.  However, we know that DHT metabolites also stimulate estrogen receptors.
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

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  • 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

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

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  • 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

Mechanisms mediating androgen receptor reactivation after castration - 0 views

www.urologiconcology.org/...abstract

androgen deprivation therapy male hormone hormones prostate cancer AR androgen receptor receptors

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  • Nathan Goodyear on 03 Feb 14
     
    In cases of CRPC, there is endogenous androgen synthesis from weaker adrenal androgens.  Also, the authors point to a unregulated AR sensitivity in the lower androgen environment created by ADT.
Nathan Goodyear

Potential Prostate Cancer Drug Target: Bioactivation of Androstanediol by Conversion to... - 0 views

clincancerres.aacrjournals.org/...5844.full

prostate cancer DHT metabolite metabolites men male hormone hormones 3-alpha-diol 3-alpha androstanediol

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  • Nathan Goodyear on 03 Feb 14
     
    Article discusses the the conversion of 3-alpha-diol back to DHT and this role in prostate cancer in androgen deprivation therapy.  What we now know is that this metabolite interacts with ER alpha receptor to promote proliferation.  Carcinogenesis appears to be primarily an estrogen driven process and her in prostate cancer, the androgen metabolites are promoting proliferation through estrogen receptors.
Nathan Goodyear

JCI - Alteration in the metabolism of dihydrotestosterone in elderly men with prostate ... - 0 views

www.jci.org/...pdf

DHT metabolite metabolites 3 alpha-androstanediol 3-alpha-diol male men hormone hormones metabolism prostate elderly

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  • Nathan Goodyear on 03 Feb 14
     
    Even back in 1980, DHT metabolism was known.  Elderly men, 3alpha oxidoreductase is decreased resulting in decreased DHT to 3-alpha-diol.  This study discussed the DHT metabolite as inactive.  We now know that is not the case.
Nathan Goodyear

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

www.jneurosci.org/...1448.long

DHT metabolite metabolites 3-beta androstanediol 3-beta-diol HPA stress ER estrogen receptor ER beta ER-beta hormone hormones

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  • Nathan Goodyear on 03 Feb 14
     
    Full article of previously posted abstract.  DHT metabolite 3beta-diol inhibits HPA stress response via ER beta.  
Nathan Goodyear

Dihydrotestosterone may inhibit hypothalamo-pi... [Neurosci Lett. 2004] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...15234470

hormone hormones DHT metabolite metabolites 3-beta androstanediol 3-beta-diol ER estrogen receptor ER beta ER-beta

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  • Nathan Goodyear on 03 Feb 14
     
    Mouse study finds that DHT metabolite provides negative feedback to HPA via 3beta androstaendiol.  What is interesting is that this signaling occurred through ER beta.  Androgen signaling processed through estrogen receptors.
Nathan Goodyear

Correlation between circulatory, local prostatic, a... [Prostate. 2011] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...21541968

prostate DHT hormone hormones men male metabolite metabolites

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  • Nathan Goodyear on 03 Feb 14
     
    No correlation was found between intra-prostate DHT and serum DHT levels.  Why do we continue to use serum?  This article also touches on the metabolites of DHT.
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