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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

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

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

shared by Nathan Goodyear on 03 Feb 14 - No Cached
  • 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

Endocrinology of the Aging Male - 0 views

www.ncbi.nlm.nih.gov/...PMC3073592

aging male hormone hormones

shared by Nathan Goodyear on 30 Apr 13 - No Cached
  • All steps beyond the formation of pregnenolone take place in the smooth endoplasmic reticulum
  • Cytochrome P450 enzyme, CYP11A is located on the inner mitochondrial membrane and catalyses the rate limiting step of pregnenolone synthesis
  • Estrogen and related steroids, thyroid hormone and insulin increase SHBG levels.
  • ...21 more annotations...
  • SHBG decreases in response to androgens, and in the presence of hypothyroidism, and insulin resistance.
  • Plasma SHBG levels tend to increase with increasing age
  • The apparent metabolic clearance rate of testosterone is decreased in elderly as compared to younger men
  • Testosterone circulates predominantly bound to the plasma proteins SHBG and albumin, with high and low affinity respectively
  • Testosterone is secreted in a pulsatile fashion
  • Current clinical guidelines suggest at least two measurements
  • In adult men, there is a well-documented diurnal variation (particularly in younger subjects) in testosterone levels, which are highest in the early morning and progressively decline throughout the day to a nadir in the evening
  • In older men, the diurnal variation is blunted
  • it is standard practice for samples to be obtained between 0800 and 1100 h.
  • Testosterone and DHEA decline, whereas LH, FSH, and SHBG rise
  • DHT remains constant despite the decline of its precursor testosterone
  • Longitudinal studies show an average annual decline of 1–2% total testosterone levels, with decline in free testosterone more rapid because of increases in SHBG with aging
  • Massachusetts Male Aging Study (MMAS) data show DHEA, DHEAS, and Ae declining at 2–3% per year
  • DHT showed no cross-sectional age trend
  • Androstanediol glucuronide (AAG) declined cross-sectionally with age in the MMAS sample, at 0.6% per year
  • The EMAS data show that, consistent with the longitudinal findings of MMAS (Figure 1), the core hormonal pattern with increasing age is suggestive of incipient primary testicular dysfunction with maintained total testosterone and progressively blunted free testosterone associated with higher LH
    • Nathan Goodyear
      Nathan Goodyear on 01 May 13
       
      This author proves the point in the review of these two studies, that TT may remain constant in aging men, however, FT drops.
  • obesity impairs hypothalamic/pituitary function
  • Androgen deprivation in men with prostate cancer has been associated with increased insulin resistance, worse glycemic control, and a significant increase in risk of incident diabetes
  • Low serum testosterone is associated with the development of metabolic syndrome 116, 117 and type 2 diabetes. 118 SHBG has been inversely correlated with type 2 diabetes
  • Improvement in insulin sensitivity with testosterone treatment has been reported in healthy 121 and diabetic 122 adult men
  • In studies conducted in men with central adiposity, testosterone has been shown to inhibit lipoprotein lipase activity in abdominal adipose tissue leading to decreased triglyceride uptake in central fat depots. 123
  • Nathan Goodyear on 30 Apr 13
     
    great review of hormone changes associated with aging in men.
Nathan Goodyear

http://press.endocrine.org/doi/pdf/10.1210/jc.2014-1872 - 0 views

press.endocrine.org/...jc.2014-1872

low T Testosterone treatment therapy diabetes obesity men male hormone hormones

shared by Nathan Goodyear on 29 Jul 14 - No Cached
  • Nathan Goodyear on 29 Jul 14
     
    New study finds Testosterone therapy provides less than statistical significant improvement in constitutional/sexual symptoms, in obese men with type II diabetes with symptoms classified as mild-moderate with modest reductions in Total Testosterone.  This study highlights that low Testosterone is a biomarker of poor health and multiple comorbidities and that simply adding in Testosterone therapy will not cure all male woes.  The authors did state that ED and low T are separate issues and I will differ with them on this--they are in fact link.  This association may vary between individuals, but to flatly state they are completely separate issues is devoid of the fact that testosterone has been shown to reduce inflammatory cytokines and improve PDE5 therapy.  
Nathan Goodyear

Anticancer Testosterone Metabolite 3β-Adiol (July 2012) Townsend Letter for D... - 0 views

www.townsendletter.com/...anticancer0712.html

testosterone metabolite metabolites testosterone metabolites 3-beta androstanediol androgen androgens hormone hormones

shared by Nathan Goodyear on 14 May 13 - No Cached
  • Nathan Goodyear on 14 May 13
     
    interesting read on the testosterone metabolite 3beta androstanediol.
Nathan Goodyear

Progesterone metabolites in breast cancer - 1 views

erc.endocrinology-journals.org/...717.full

progesterone metabolism tumor tumorigenesis cancer risk growth hormone hormones 5-beta-pregnanediol 5-alpha-pregnanediol 4-pregnenediol 5-alpha reductase

shared by Nathan Goodyear on 20 Feb 12 - No Cached
  • P metabolites produced within breast tissues might be independently active hormones functioning as cancer-promoting or -inhibiting regulatory agents
  • these P metabolites function as independent pro-or anti-cancer autocrine/paracrine hormones that regulate cell proliferation, adhesion, apoptosis and cytoskeletal, and other cell status molecules via novel receptors located in the cell membrane and intrinsically linked to cell signaling pathways
  • only a fraction of all breast cancer patients respond to this estrogen-based therapy and the response is only temporary
  • ...30 more annotations...
  • P serves as the precursor for the major steroid hormones (androgens, estrogens, corticosteroids) produced by the gonadal and adrenal cortical tissues.
  • 5α-pregnane, 5β-pregnane, and 4-pregnene metabolites of P
  • These P-metabolizing enzymes included 5α-reductase, 5β-reductase, 3α-hydroxysteroid oxido-reductase (3α-HSO), 3β-HSO, 20α-HSO, 20β-HSO, 6α(β)-, 11β-, 17-, and 21-hydroxylase, and C17–20-lyase
  • Reduction of P to 5α-pregnanes is catalyzed by 5α-reductase and the direct 5α-reduced metabolite of P is 5α-pregnane-3,20-dione (5αP). The 5α-reductase reaction is irreversible
  • The two 4-pregnenes resulting from direct P conversion are 4-pregnen-3α-ol-20-one (3αHP) and 4-pregnen-20α-ol-3-one (20αHP), catalyzed by the actions of 3α-HSO and 20α-HSO respectively
  • the P-metabolizing enzyme activities identified in human breast tissues and cell lines were: 5α-reductase, 3α-HSO, 3β-HSO, 20α-HSO, and 6α-hydroxylase
  • In normal breast tissue, conversion to 4-pregnenes greatly exceeded the conversion to 5α-pregnanes, whereas in tumorous tissue, conversion to 5α-pregnanes greatly exceeded that to 4-pregnenes
  • The results indicated that P 5α-reductase activity is significantly higher, whereas P 3α-HSO and 20α-HSO activities are significantly lower in tumor than in normal tissues
  • he results showed that production of 5α-pregnanes was higher and that of 4-pregnenes was lower in tumorigenic (e.g. MCF-7) than in nontumorigenic (e.g. MCF-10A) cells (Fig. 3c⇑), while differences in ER/P status did not appear to play a role
  • The 5α-pregnane-to-4-pregnene ratios were 7- to 20-fold higher in the tumorigenic than in the nontumorigenic cell lines
  • altered direction in P metabolism, and hence in metabolite ratios, was due to significantly elevated 5α-reductase and depressed 3α- and 20α-HSO activities in breast tumor tissues and tumorigenic cells. It appeared, therefore, that changes in P-metabolizing enzyme activities might be related to the shift toward mammary cell tumorigenicity and neoplasia
  • In vivo, changes in enzyme activity can result from changes in levels of the enzyme due to changes in expression of the mRNA coding for the enzyme, or from changes in the milieu in which the enzyme operates (such as temperature and pH, and concentrations of cofactors, substrates, products, competitors, ions, phospholipids, and other molecules)
  • Overall, the enzyme activity and expression studies strongly suggest that 5α-reductase stimulation and 3α- and 20α-HSO suppression are associated with the transition from normalcy to cancer of the breast
  • The level of expression of 5α-reductase is up-regulated by estradiol and P in the uterus (Minjarez et al. 2001) and by 5α-dihydrotestosterone (DHT) in the prostate
  • 3αHP inhibited whereas 5αP-stimulated proliferation
  • Stimulation in cell numbers was also observed when cells were treated with other 5α-pregnanes, such as 5α-pregnan-3α-ol-20-one, 5α-pregnan-20α-ol-3-one, and 5α-pregnane-3α,20α-diol, whereas other 4-pregnenes such as 20α-HP and 4-pregnene-3α,20α-diol resulted in suppression of cell proliferation
  • Stimulation of cell proliferation with 5αP and inhibition with 3αHP were also observed in all other breast cell lines examined, whether ER/P-negative (MCF-10A, MDA-MB-231) or ER/P-positive (T47D, ZR-75-1) and whether requiring estrogen for tumorigenicity (MCF-7, T47D) or not (MDA-MB-231), or whether they are nontumorigenic (
  • αHP resulted in significant increases in apoptosis and decreases in mitosis, leading to significant decreases in total cell numbers. In contrast, treatment with 5αP resulted in decreases in apoptosis and increases in mitosis.
  • The opposing actions of 5αP and 3αHP on both cell anchorage and proliferation strengthen the hypothesis that the direction of P metabolism in vivo toward higher 5α-pregnane and lower 4-pregnene concentrations could promote breast neoplasia and lead to malignancy.
  • he effects on proliferation and adhesion were not due to P, but due to the 5α-reduced metabolites
  • The studies showed that binding of 5αP or 3αHP occurs in the plasma membrane fractions, but not in the nuclear or cytosolic compartments
  • separate high-specificity, high-affinity, low- capacity receptors for 5αP and 3αHP that are distinct from each other and from the well-studied nuclear/cytosolic P, estrogen, and androgen and corticosteroid receptors
  • The studies thus provided the first demonstration of the existence of specific P metabolite receptors
  • the receptor results suggest that the putative tumorigenic actions of 5αP may be significantly augmented by the estradiol-induced increases in 5αP binding and decreases in 3αHP binding.
  • Estradiol and 5αP resulted in significant dose-dependent increases, whereas 3αHP and 20αHP each resulted in dose-dependent decreases in total ER
  • In combination, estradiol + 5αP or 3αHP + 20αHP resulted in additive increases or decreases respectively in ER numbers.
  • The data suggest that the action of 5αP on breast cancer cells involves modulation of the MAPK signaling pathway
  • current evidence does not appear to support the notion that increased 5α-reductase activity/ expression might significantly alter androgen influences on breast tumor growth.
  • both testosterone and DHT inhibit cell growth more or less to the same extent
  • Note that 5α-reductase reaction is not reversible
  • Nathan Goodyear on 20 Feb 12
     
    Fantastic read on the effects of progesterone metabolism on tumor and cancer growth.  Tumorigenesis is not just about the hormone, hormone balance, but about the metabolism of hormones.  This is why premarin is so carcinogenic: it is primarily metabolized by the 4-OH estrone pathway.
Nathan Goodyear

Differential Effects of Dehydroepiandrosterone and Testosterone in Prostate and Colon C... - 0 views

press.endocrine.org/...en.2012-2249

testosterone prostate colon colon cancer cancer NGF nerve growth factor dhea dehydroepiandrosterone

shared by Nathan Goodyear on 19 Nov 14 - No Cached
  • Several studies indicate that DHEA may enhance cancer-promoting activities in several prostate cancer cell lines acting as agonist or antagonist for the intracellular AR
  • the estrogenic metabolites of DHEA, 5a-androstane-3b, 17b-diol (3b-Adiol) and E2 bind to estrogen receptors but not to AR
  • no specific receptor has been identified for DHEA
  • ...16 more annotations...
  • Different members of neurotrophins are expressed during cancer progression, suggesting their involvement in cell proliferation, anoikis protection, and malignancy
  • Regulation of the apoptotic machinery in prostate and colon cancer cells by testosterone occurs rapidly and is initiated at the plasma membrane level through specific membrane-binding sites not involving the classical cytoplasmic AR
  • testosterone exerts potent regulatory effects on prostate and colon cancer cell apoptosis
  • Testosterone increased cell death in a dose-dependent manner
  • testosterone antagonizes the prosurvival effects of DHEA in neuronal cells, blocking its binding to NGF receptors
  • treatment of cells with DHEA exerted a strong antiapoptotic effect,
  • Androgens hold a central role in prostate and colon cancer biology
  • elevated levels of DHEA or its sulfate ester DHEA-sulfate in young adults are associated to low incidence of androgen-dependent tumors
  • DHEA may play a protective role in young prostate
  • The decline of DHEA with aging may contribute to prostate cancer progression associated with advanced age
  • DHEA is an effective antiapoptotic factor, reversing the serum deprivation-induced apoptosis in prostate cancer cells (DU145 and LNCaP cell lines) as well as in colon cancer cells
  • NGF appears to exert similar antiapoptotic actions in both prostate and color cancer cells
  • exposure of prostate DU145 and colon Caco2 cancer cells to testosterone totally blocked the protective effects of both DHEA and NGF. These findings suggest that testosterone acts as an antagonist of DHEA and NGF
  • These findings support the hypothesis that testosterone may inhibit cancer cell growth by antagonizing the proliferative, antiapoptotic effects of endogenous factors, such as DHEA or NGF, in the case of prostate and colon cancer cells
  • intratumor hormonal microenvironment may play a critical role in tumor progression.
  • The paracrine interactions of androgens with locally produced NGF may define tumor cell fate
  • Nathan Goodyear on 19 Nov 14
     
    Full article of previously posted abstract.  Cancers are unique.  Not all cancers are alike.  Whether they are tissue specific or not, cancers are unique.  This article describes the uniqueness of DHEA and Testosterone cancer, with particular attention to colon.
Nathan Goodyear

Urinary concentrations of di(2-ethylhexyl) phthalat... [J Androl. 2011] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...21597090

low T testosterone free androgen index urinary phthalate metabolites DEHP MEHP MEHHP MEOHP

shared by Nathan Goodyear on 12 Dec 11 - No Cached
  • three metabolites of DEHP [mono(2-ethylhexyl) phthalate (MEHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) and mono(2-ethyl-5-oxohexyl) phthalate (MEOHP)] were inversely associated with the free androgen index (FAI = T/SHBG) and calculated free testosterone (FT)
  • Nathan Goodyear on 12 Dec 11
     
    analysis of 3 urinary phthalate metabolites found to be associated with low free androgen index and a low free Testosterone
Nathan Goodyear

Review of health risks of low testosterone and testosterone administration - 0 views

www.ncbi.nlm.nih.gov/...PMC4391003

low Testosterone low T Testosterone men male hormone hormones health

shared by Nathan Goodyear on 28 Apr 15 - No Cached
  • Hypogonadism may be defined either as serum concentration of T (either total T, bioavailable T or free T) or as low T plus symptoms of hypogonadism
  • The Baltimore Longitudinal Study on Aging reported the incidence of total serum T < 325 ng/dL to be 20% for men in their 60s, 30% for men in their 70s and 50% for men over 80
  • The Massachusetts Aging Male Study reported that 12.3% of men aged 40 to 70 had a total serum T of < 200 ng/dL with 3 or more symptoms of hypogonadism
  • ...19 more annotations...
  • The Boston Area Community Health Study reported that 5.6% of men aged 30 to 70 were hypogonadal, as defined by total serum T < 300 ng/dL; or, free serum T < 5 ng/dL plus 3 or more symptoms of hypogonadism
  • In a health screening project among 819 men in Taiwan, the prevalence of hypogonadism (total serum T < 300 ng/dL) ranged from 16.5% for men in their 40s, 23.0% for men in their 50s, 28.9% for men in their 60s, and 37.2% for men older than 70 years of age
  • The prevalence of hypogonadism among men in Taiwan is higher than the prevalence reported in the Massachusetts Male Aging Study
  • CAG repeat sequence, within the androgen receptor (AR). Rajender et al[12] reviewed over 30 studies on the AR trinucleotide repeat and infertility
  • suggestion that CAG repeat length may determine androgen responsiveness, this issue is not clearly settled
  • reported prevalence of low T in older men range from 5.6% to 50%
  • Those in the hypogonadal group (n = 4269) had direct health care costs, that exceeded the eugonadal group (n = 4269) by an average of $7100 over the course of the observation window
  • higher economic burden and presence of co-morbidities for hypogonadism
  • minor to moderate improvements in lean mass and muscle strength
  • increased bone mineral density
  • modest enhancement in sexual function
  • reduced adiposity
  • lessening of depressive symptoms
  • Meta-analyses of clinical TRT trials as of 2010 have identified three major adverse events resulting from TRT: (1) polycythemia; (2) an increase in prostate-related events; and (3) and a slight reduction in serum high-density lipoprotein (HDL) cholesterol
  • polycythemia (> 3.5-fold increase in risk
  • TRT produced a 40% prostate enlargement in older hypogonadal male Veterans over 12 mo
  • no published analysis has reported measurable increases in prostate cancer risk or Gleason score in men undergoing TRT, or in hypogonadal men with a history of prostate cancer undergoing TRT
  • the prostate which highly expresses the type II 5α-reductase enzyme. Inhibition of this enzyme via finasteride (a type II 5α-reductase inhibitor) or dutasteride (a dual type I and II 5α-reductase inhibitor) reduces circulating DHT 50%-75% and > 90%, respectively[47], and reduces prostate mass[48] and prostate cancer risk
  • Normally estradiol partially regulates testosterone levels, at the hypothalamus, blunting LH and FSH release from the pituitary. As a selective estrogen receptor modulator, CC interrupts this pathway, and consequently there is a greater stimulation for the production of testosterone in Leydig cells
    • Nathan Goodyear
      Nathan Goodyear on 28 Apr 15
       
      this would only apply if E1 and/or E2 levels were elevated, which the authors make no mention of.
  • Nathan Goodyear on 28 Apr 15
     
    to be read
Nathan Goodyear

PLOS ONE: The Gut Microbiota and Developmental Programming of the Testis in Mice - 0 views

journals.plos.org/...article

hormone hormones Testosterone gut flora gut microbiome gut microbiota

shared by Nathan Goodyear on 30 Apr 15 - No Cached
  • The intra-testicular level of testosterone in GF mice was found to be significantly lower than in SPF and CBUT mice
  • Manipulation of the gut microbiotia through dietary modification, pre- and probiotics can therefore be beneficial for the host's reproductive health.
  • Absence of the normal microbiota influences the formation and the integrity of the BTB as well as the intra-testicular levels of testosterone and serum levels of LH and FSH.
  • ...8 more annotations...
  • Nutritional, socioeconomic, lifestyle and environmental factors (among others) are involved in the regulation of normal spermatogenesis.
  • he gut microbiota is one such potential source of environmental factors/products that has developed an intimate symbiotic relationship with host's physiology.
  • This study establishes a novel role for the commensal gut microbiota in the regulation of testicular development and function
  • In the current study, colonizing GF mice with CBUT resulted in an increased sperm production, suggesting that bacterial products, e.g. of fermentation, directly or indirectly, can affect the testis.
  • the absence of gut microbiota influenced testosterone levels
  • A recent study demonstrated that dietary supplementation of the probiotics Lactobacillus reuteri increased and restored testosterone levels in aging mice
  • bacterial metabolites such as butyrate have been shown to increase the levels of LH [43] and FSH
  • This suggests that butyrate most likely regulates testosterone production at the testicular level by stimulation of gene expression in Leydig cells and with little or no effect at the pituitary- hypothalamic levels.
  • Nathan Goodyear on 30 Apr 15
     
    gut micro biome effects spermatogenesis, Testosterone production, and the brain-testicle-barrier.
Nathan Goodyear

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

www.researchgate.net/...aromatase_inhibitor_resistance

breast cancer aromatase aromatase inhibitors estradiol estrogen 3-beta androstanediol Testosterone DHT 3 beta HSD receptor receptors ER alpha ER-alpha ER beta ER-beta hormone hormones women

shared by Nathan Goodyear on 21 Jan 14 - No Cached
  • Nathan Goodyear on 21 Jan 14
     
    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

JAMA Network | Archives of Internal Medicine | Combined Estrogen and Testosterone Use a... - 0 views

archinte.jamanetwork.com/article.aspx

hormones synthetic bioidentical BHRT breast cancer estrogen testosterone

shared by Nathan Goodyear on 16 May 12 - No Cached
  • Nathan Goodyear on 16 May 12
     
    this study revealed increased breast cancer risk in women on "estrogen" and "testosterone" therapy.  Now, several problems here: first, are these synthetic hormone or bioidentical.  Second, the dosages appear, in what is written, to be supra physiologic.  Third, giving supra physiologic estradiol and testosterone will obviously create imbalances and growth potential.  Fourth, how were the women evaluated prior to starting hormone therapy and then were they remonitered (unlikely), fifth, were hormone metabolites evaluated (too, also unlikely).  This study has serious flaws and very little can be extrapolated other than: don't take supra physiologic hormone levels without appropriate evaluation.  Enough said
Nathan Goodyear

The safety of testosterone supplementation ther... [Nat Rev Urol. 2014] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...25069737

prostate cancer testosterone men male hormone hormones

shared by Nathan Goodyear on 30 Jul 14 - No Cached
  • Nathan Goodyear on 30 Jul 14
     
    Review, only abstract available--Testosterone therapy does not affect prostate size, intraprostatic Testosterone levels, or prostate cancer progression.  Carcinogenesis of the prostate is not a androgen driven process.  It is an aromatase process.  DHT metabolites can promote tumor growth via Estrogen receptors later, but initiation, via all accounts, occurs through aromatase expression and production of estrogen in the prostate.
Nathan Goodyear

Urinary Phthalate Metabolites Are Associated With Decreased Serum Testosterone in Men, ... - 0 views

press.endocrine.org/...jc.2014-2555

phthalate phthalates EDC endocrine disrupting chemicals low T low Testosterone low T Testosterone hormone hormones

shared by Nathan Goodyear on 16 Aug 14 - No Cached
  • Nathan Goodyear on 16 Aug 14
     
    Phthalate exposure is a cause of low Testosterone in men, women, and children.   In boys 6-12, exposure was associated with a 24-34% reduction in Testosterone.
Nathan Goodyear

Analysis of Relations between serum levels of Epitestosterone, Estradiol, Testosterone,... - 0 views

www.biomed.cas.cz/...49_S113.pdf

PSA hormone hormones BPH Prostate cancer prostate cancer Epitestosterone men male aromatase Estradiol IGF-1

shared by Nathan Goodyear on 21 Aug 13 - No Cached
  • Nathan Goodyear on 21 Aug 13
     
    Great confusion exists in the medical profession about Testosterone and PSA and the health of the prostate. The conversion of Estrogen, whether E2 or E1, and other variables are responsible for increases in PSA while on Testosterone therapy. This study points out that Estradiol in men stimulates cell line growth of prostate cancer. In contrast, Epitestosterone, an androgen metabolite, has antiandrogen, inhibits this estrogen activity. Epitestosterone exists in an inverse relationship to Estradiol and IGF-1.
Nathan Goodyear

Promoting effects and mechanisms of action of androgen in bladder c... - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...9129932

bladder cancer bladder cancer Testosterone men male hormone hormones

shared by Nathan Goodyear on 04 Jan 15 - No Cached
  • Nathan Goodyear on 04 Jan 15
     
    Another animal study finds Testosterone plays a role in bladder cancer development.  The study used anti androgen and 5 alpha reductase inhibitor therapy to see if these add on therapies provided anything to ADR whether via castration or pituitary suppression--the answer was no.  The authors concluded that Testosterone played more of a role with AR versus the more active 5alpha-DHT metabolite.
Nathan Goodyear

5alpha-androstane-3alpha,17beta-diol supports... [J Cell Biochem. 2008] - PubMed - NCBI - 0 views

www.ncbi.nlm.nih.gov/...18320593

5-alpha androstanediol 3-alpha androstanediol DHT metabolite prostate cancer hormone hormones metabolites androgen receptors AR estrogen ER

shared by Nathan Goodyear on 23 Jan 14 - No Cached
  • Nathan Goodyear on 23 Jan 14
     
    5 alpha androstanediol promotes prostate cancer growth and survival independent of androgen receptors.   This study didn't clarify the mechanism.  We no know that this occurs via estrogen receptor alpha.  Thus a Testosterone metabolite signals through an estrogen receptor.
Nathan Goodyear

Diabetic neuropathic pain: a role for testosterone metabolites - 0 views

joe.endocrinology-journals.org/...1.abstract

diabetes neuropathy pain diabetic DHT androgens 3 alpha-androstanediol metabolites Testosterone androgen male hormone hormones

shared by Nathan Goodyear on 24 Mar 14 - No Cached
  • Nathan Goodyear on 24 Mar 14
     
    Great article.  Really shows the depth of the androgens and androgen metabolites in diabetes and diabetic complications.  In this study, DHT and its metabolis 3-alpha androstanediol were shown to reduce inflammation and pain associated with diabetic neuropathy.  Significant reduction in inflammation signaling (IL-1beta, TNF-alpha) was seen as was potential neurodegenerative processes (glutamate release and astrocyte immunoreactivity).
Nathan Goodyear

The role of androst-5-ene-3β,17β-diol (androstenedi... [Steroids. 2014] - Pub... - 0 views

www.ncbi.nlm.nih.gov/...25065586

DHT metabolite 3-beta androstanediol 3-beta-diol 3 beta androstanediol PCOS endometrial proliferation cancer women hormone hormones Testosterone

shared by Nathan Goodyear on 30 Jul 14 - No Cached
  • Nathan Goodyear on 30 Jul 14
     
    The DHT metabolite 3beta-androstanediol found to increase proliferation of endometrial tissue in women with PCOS.  In contrast, Testosterone repressed proliferation.  
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