In the prostate, ERβ is highly expressed in the epithelial compartment, where it is the prevailing isoform
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shared by Nathan Goodyear on 03 Mar 14
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Changes in body composition during a... [J Clin Endocrinol Metab. 2002] - PubMed - NCBI - 0 views
www.ncbi.nlm.nih.gov/...11836291
body composition lean muscle mass obesity weight gain adipose tissue androgen deprivation therapy prostate cancer male men hormone hormones
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shared by Nathan Goodyear on 04 Feb 14
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Androgen deprivation therapy in men with prostate cancer: how should the side effects b... - 0 views
onlinelibrary.wiley.com/...full
androgen deprivation therapy Testosterone insulin sensitivity resistance diabetes prostate cancer men male hormone hormones
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Androgen deprivation therapy in men has been shown to worsen insulin resistance and precipitate type II Diabetes as well as stimulate weight gain. This suggests a cause effect relationship between Testosterone and insulin sensitivity. Other studies have pointed to a reciprocal decline in Testosterone due to hyperglycemia--both acute and chronic. Androgen deprivation has a significant long list of cardiovascular risks and this should be discussed with the patient.
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shared by Nathan Goodyear on 21 Jan 14
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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
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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
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ERβ signaling, in contrast to ERα, seems to act as a suppressor of prostate growth, and may be positively involved in breast cancer
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functional antagonism of 3β-Adiol appears to be molecularly independent from the activation of the androgenic pathway
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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.
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shared by Nathan Goodyear on 10 Jan 14
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Effects of androgens on telomerase activity in normal and malignant prostate cells in v... - 0 views
onlinelibrary.wiley.com/...AC2C88175F4E55359BA67DC.f03t03
androgen deprivation therapy Prostate cancer androgen deprivation therapy Testosterone Telomerase Telomere length
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shared by Nathan Goodyear on 03 Mar 14
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Androgen Deprivation Therapy, Insulin Resistance, and Cardiovascular Mortality: An Inco... - 0 views
onlinelibrary.wiley.com/...full
androgen deprivation therapy androgen male men hormone hormones deprivation therapy prostate cancer cardiovascular disease insulin resistance diabetes metabolic syndrome mortality CVD
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Androgen deprivation therapy is associated with increased diabetes, metabolic syndrome, insulin resistance, and cardiovascular mortality. The longer the duration of therapy, the more the progression of metabolic dysfunction. This process seems similar to chemotherapy i.e. secondary cancer due to chemotherapy. The treatment of one disease, prostate cancer in this case, leads to an increase in the risk of the #1 killer in men--logic seems severely flawed there.
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shared by Nathan Goodyear on 03 Feb 14
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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
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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
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progression to CRPC was associated with increased intratumoral accumulation or synthesis of testosterone.
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the intraprostatic synthesis of testosterone from adrenal-derived precursors likely accounts for the relatively high testosterone levels in prostate after ADT
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In addition, AR activity in these cells is likely further enhanced by multiple mechanisms that sensitize AR to low levels of androgens
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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
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DHT in prostate is inactivated by the enzyme AKR1C2, which is also termed 3α-hydroxysteroid dehydrogenase type 3 (3α-HSD type 3
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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
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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
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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
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shared by Nathan Goodyear on 03 Feb 14
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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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shared by Nathan Goodyear on 08 May 13
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Beyond the male sex hormone: deciphering the metabolic and vascular actions of testoste... - 0 views
joe.endocrinology-journals.org/...C1.full
AR androgen receptors androgen receptor testosterone androgen receptors Diabetes metabolic syndrome MetS CVD cardiovascular disease men hormone hormones male
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androgen deprivation therapy results in unfavorable changes in body composition, insulin resistance, and dyslipidemia and predisposes men to develop atherosclerosis and an increased risk of cardiovascular mortality
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The hypogonadal–obesity cycle hypothesis was originally proposed by Cohen in 1999 to explain the relationship between low testosterone levels and metabolic disease. It was based on the finding that obesity impairs testosterone levels by increasing the aromatization of testosterone to estradiol, while low testosterone levels promote increased fat deposition
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adipocytokines contribute to low testosterone levels as well as to the processes underlying metabolic syndromes and type 2 diabetes
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The presence of estradiol and the adipocytokines TNF-α, IL6, and leptin (as a result of leptin resistance in obesity) inhibits the hypothalamic–pituitary–testicular axis response to decreasing androgen levels
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An increasing number of studies have illustrated the potential for applying metabolomics to the field of androgen research
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As early as the 1940s, the therapeutic use of testosterone was reported to improve angina pectoris in men with coronary artery disease
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most of the epidemiological studies reported increased cardiovascular risk and mortality in men with low testosterone levels
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long-term testosterone replacement appears to be a safe and effective means of treating hypogonadal elderly men
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a recent interventional trial showed that testosterone treatment was associated with decreased mortality when compared with no testosterone treatment in an observational cohort of men with low testosterone levels
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a number of short-term studies conducted support the notion that testosterone therapy reduces the cardiovascular risk
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The majority of animal studies support the hypothesis that the actions of testosterone on vascular relaxation are both endothelium-dependent and -independent vasodilatory effects
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Endothelial-dependent actions of testosterone increase the expression or activity of endothelial nitric oxide synthase and enhance nitric oxide production, which in turn activates cyclic guanosine monophosphate to induce vasorelaxation in smooth muscle cells
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Endothelial-independent mechanisms of testosterone are believed to occur primarily via inhibition of voltage-operated Ca2+ channels and/or activation of K+ channels in smooth muscle cells
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Testosterone may also inhibit intracellular Ca2+ influx via store-operated Ca2+ channels by blocking the response to prostaglandin F2α
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testosterone has demonstrated anti-inflammatory effects to protect against atherogenesis in animal studies
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both genomic AR activation to modulate gene transcription and non-genomic activation to modulate the rapid intracellular signaling pathways of ion channels may mediate testosterone effects on vascular function and inflammation.
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Butenandt & Ruzicka first showed how testosterone is synthesized and responsible for masculine characteristics in the early 1930s
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shared by Nathan Goodyear on 23 Sep 15
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JAMA Network | JAMA | Long-term Follow-up of a Randomized Trial of Radiation With or Wi... - 0 views
jama.jamanetwork.com/article.aspx
androgen deprivation therapy ADT prostate prostate cancer male hormones
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shared by Nathan Goodyear on 04 Feb 14
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Testosterone and glucose metabolism in men: current concepts and controversies - 0 views
joe.endocrinology-journals.org/...R37.full
Low T Testosterone metabolic syndrome MetS Diabetes men male glucose hormone hormones g
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Around 50% of ageing, obese men presenting to the diabetes clinic have lowered testosterone levels relative to reference ranges based on healthy young men
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The absence of high-level evidence in this area is illustrated by the Endocrine Society testosterone therapy in men with androgen deficiency clinical practice guidelines (Bhasin et al. 2010), which are appropriate for, but not specific to men with metabolic disorders. All 32 recommendations made in these guidelines are based on either very low or low quality evidence.
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A key concept relates to making a distinction between replacement and pharmacological testosterone therapy
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Findings similar to type 2 diabetes were reported for men with the metabolic syndrome, which were associated with reductions in total testosterone of −2.2 nmol/l (95% CI −2.41 to 1.94) and in free testosterone
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Cross-sectional studies uniformly show that 30–50% of men with type 2 diabetes have lowered circulating testosterone levels, relative to references based on healthy young men
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In a recent cross-sectional study of 240 middle-aged men (mean age 54 years) with either type 2 diabetes, type 1 diabetes or without diabetes (Ng Tang Fui et al. 2013b), increasing BMI and age were dominant drivers of low total and free testosterone respectively.
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both diabetes and the metabolic syndrome are associated with a modest reduction in testosterone, in magnitude comparable with the effect of 10 years of ageing
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In a cross-sectional study of 490 men with type 2 diabetes, there was a strong independent association of low testosterone with anaemia
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In men, low testosterone is a marker of poor health, and may improve our ability to predict risk
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It remains possible that low testosterone is a consequence of insulin resistance, or simply a biomarker, co-existing because of in-common risk factors.
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In prospective studies, reviewed in detail elsewhere (Grossmann et al. 2010) the inverse association of low testosterone with metabolic syndrome or diabetes is less consistent for free testosterone compared with total testosterone
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In a study from the Framingham cohort, SHBG but not testosterone was prospectively and independently associated with incident metabolic syndrome
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low SHBG (Ding et al. 2009) but not testosterone (Haring et al. 2013) with an increased risk of future diabetes
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In cross-sectional studies of men with (Grossmann et al. 2008) and without (Bonnet et al. 2013) diabetes, SHBG but not testosterone was inversely associated with worse glycaemic control
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SHBG may have biological actions beyond serving as a carrier protein for and regulator of circulating sex steroids
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In men with diabetes, free testosterone, if measured by gold standard equilibrium dialysis (Dhindsa et al. 2004), is reduced
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Low free testosterone remains inversely associated with insulin resistance, independent of SHBG (Grossmann et al. 2008). This suggests that the low testosterone–dysglycaemia association is not solely a consequence of low SHBG.
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Experimental evidence reviewed below suggests that visceral adipose tissue is an important intermediate (rather than a confounder) in the inverse association of testosterone with insulin resistance and metabolic disorders.
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testosterone promotes the commitment of pluripotent stem cells into the myogenic lineage and inhibits their differentiation into adipocytes
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testosterone regulates the metabolic functions of mature adipocytes (Xu et al. 1991, Marin et al. 1995) and myocytes (Pitteloud et al. 2005) in ways that reduce insulin resistance.
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Pre-clinical evidence (reviewed in Rao et al. (2013)) suggests that at the cellular level, testosterone may improve glucose metabolism by modulating the expression of the glucose-transported Glut4 and the insulin receptor, as well as by regulating key enzymes involved in glycolysis.
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More recently testosterone has been shown to protect murine pancreatic β cells against glucotoxicity-induced apoptosis
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Interestingly, a reciprocal feedback also appears to exist, given that not only chronic (Cameron et al. 1990, Allan 2013) but also, as shown more recently (Iranmanesh et al. 2012, Caronia et al. 2013), acute hyperglycaemia can lower testosterone levels.
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In men with prostate cancer commencing androgen deprivation therapy, both total as well as, although not in all studies (Smith 2004), visceral fat mass increases (Hamilton et al. 2011) within 3 months
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More prolonged (>12 months) androgen deprivation therapy has been associated with increased risk of diabetes in several large observational registry studies
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Testosterone has also been shown to reduce the concentration of pro-inflammatory cytokines in some, but not all studies, reviewed recently in Kelly & Jones (2013). It is not know whether this effect is independent of testosterone-induced changes in body composition.
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the observations discussed in this section suggest that it is the decrease in testosterone that causes insulin resistance and diabetes. One important caveat remains: the strongest evidence that low testosterone is the cause rather than consequence of insulin resistance comes from men with prostate cancer (Grossmann & Zajac 2011a) or biochemical castration, and from mice lacking the androgen receptor.
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Several large prospective studies have shown that weight gain or development of type 2 diabetes is major drivers of the age-related decline in testosterone levels
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there is increasing evidence that healthy ageing by itself is generally not associated with marked reductions in testosterone
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increased visceral fat is an important component in the association of low testosterone and insulin resistance
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The vast majority of men with metabolic disorders have functional gonadal axis suppression with modest reductions in testosterone levels
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men with Klinefelter syndrome have an increased risk of metabolic disorders. Interestingly, greater body fat mass is already present before puberty
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inhibition of the gonadal axis predominantly takes place in the hypothalamus, especially with more severe obesity
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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 from GNRH neurons situated in the preoptic area
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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
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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
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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
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Modifiable risk factors such as obesity and co-morbidities are more strongly associated with a decline in circulating testosterone levels than age alone
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55% of symptomatic androgen deficiency reverted to a normal testosterone or an asymptomatic state after 8-year follow-up, suggesting that androgen deficiency is not a stable state
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The hypothalamic–pituitary–testicular axis remains responsive to treatment with aromatase inhibitors or selective oestrogen receptor modulators in obese men
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Kisspeptin treatment increases LH secretion, pulse frequency and circulating testosterone levels in hypotestosteronaemic men with type 2 diabetes
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weight loss can lead to genuine reactivation of the gonadal axis by reversal of obesity-associated hypothalamic suppression
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There is pre-clinical and observational evidence that chronic hyperglycaemia can inhibit the HPT axis
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in men who improved their glycaemic control over time, testosterone levels increased. By contrast, in those men in whom glycaemic control worsened, testosterone decreased
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testosterone levels should be measured after successful weight loss to identify men with an insufficient rise in their testosterone levels. Such men may have HPT axis pathology unrelated to their obesity, which will require appropriate evaluation and management.
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shared by Nathan Goodyear on 15 Jan 14
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Lowered testosterone in male obesity: Mechanisms, morbidity and management Tang Fui MN,... - 0 views
www.ajandrology.com/article.asp
Testosterone male obesity overweight men hormone hormones low T Low T
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The number of overweight people is expected to increase from 937 million in 2005 to 1.35 billion in 2030
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Similarly the number of obese people is projected to increase from 396 million in 2005 to 573 million in 2030
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By 2030, China alone is predicted to have more overweight men and women than the traditional market economies combined
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diacylglycerol O-acyltransferase 2 (DGAT2), mechanistically implicated in this differential storage, [10] is regulated by dihydrotestosterone, [11] suggesting a potential role for androgens to influence the genetic predisposition to either the MHO or MONW phenotype.
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The fact that obese men have lower testosterone compared to lean men has been recognized for more than 30 years
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epidemiological data suggest that the single most powerful predictor of low testosterone is obesity, and that obesity is a major contributor of the age-associated decline in testosterone levels.
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obesity blunts this LH rise, obesity leads to hypothalamic-pituitary suppression irrespective of age which cannot be compensated for by physiological mechanisms
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Reductions in total testosterone levels are largely a consequence of reductions in sex hormone binding globulin (SHBG) due to obesity-associated hyperinsulinemia
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although controversial, measurement of free testosterone levels may provide a more accurate assessment of androgen status than the (usually preferred) measurement of total testosterone in situations where SHBG levels are outside the reference range
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marked obesity however is associated with an unequivocal reduction of free testosterone levels, where LH and follicle stimulating hormone (FSH) levels are usually low or inappropriately normal, suggesting that the dominant suppression occurs at the hypothalamic-pituitary level
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adipose tissue, especially when in the inflamed, insulin-resistant state, expresses aromatase which converts testosterone to estradiol (E 2 ). Adipose E 2 in turn may feedback negatively to decrease pituitary gonadotropin secretion
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In addition to E 2 , increased visceral fat also releases increased amounts of pro-inflammatory cytokines, insulin and leptin; all of which may inhibit the activity of the HPT axis at multiple levels
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In the prospective Massachusetts Male Aging Study (MMAS), moving from a non-obese to an obese state resulted in a decline of testosterone levels
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weight loss, whether by diet or surgery, increases testosterone levels proportional to the amount of weight lost
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Testosterone enhances catecholamine-induced lipolysis in vitro and reduces lipoprotein lipase activity and triglyceride uptake in human abdominal adipose tissue in vivo
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in men with prostate cancer receiving 12 months of androgen deprivation therapy, fat mass increased by 3.4 kg and abdominal VAT by 22%, with the majority of these changes established within 6 months
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increasing body fat suppresses the HPT axis by multiple mechanisms [30] via increased secretion of pro-inflammatory cytokines, insulin resistance and diabetes; [19],[44] while on the other hand low testosterone promotes further accumulation of total and visceral fat mass, thereby exacerbating the gonadotropin inhibition
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men undergoing androgen depletion for prostate cancer show more marked increases in visceral compared to subcutaneous fat following treatment
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androgens can act via the PPARg-pathway [37] which is implicated in the differentiation of precursor fat cells to the energy-consuming phenotype
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low testosterone may compound the effect of increasing fat mass by making it more difficult for obese men to lose weight via exercise
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pro-inflammatory cytokines released by adipose tissue may contribute to loss of muscle mass and function, leading to inactivity and further weight gain in a vicious cycle
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Sarcopenic obesity, a phenotype recapitulated in men receiving ADT for prostate cancer, [55] may not only be associated with functional limitations, but also aggravate the metabolic risks of obesity;
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observational evidence associating higher endogenous testosterone with reduced loss of muscle mass and crude measures of muscle function in men losing weight
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A number of intervention studies have confirmed that both diet- and surgically-induced weight losses are associated with increased testosterone, with the rise in testosterone generally proportional to the amount of weight lost
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shared by Nathan Goodyear on 27 Jan 15
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Effect of bipolar androgen therapy for asymptomatic men with castra... - PubMed - NCBI - 0 views
www.ncbi.nlm.nih.gov/...25568070
prostate cancer BAT bipolar androgen therapy PSA AR androgen receptor ADT androgen deprivation therapy men male hormone hormones
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shared by Nathan Goodyear on 18 Mar 14
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Effectiveness of Primary Androgen-Deprivation Therapy for Clinically Localized Prostate... - 0 views
jco.ascopubs.org/...JCO.2013.52.5782
PADT primary androgen deprivation therapy prostate cancer male men hormone hormones
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shared by Nathan Goodyear on 21 Nov 13
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Diabetes and Cardiovascular Disease During Androgen Deprivation Therapy: Observational ... - 0 views
jnci.oxfordjournals.org/...39.full
diabetes cardiovascular disease stroke androgen deprivation therapy prostate cancer
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shared by Nathan Goodyear on 30 Apr 14
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Intermittent androgen deprivation therapy for pro... [Can J Urol. 2014] - PubMed - NCBI - 0 views
www.ncbi.nlm.nih.gov/...24775721
androgen deprivation therapy ADT prostate cancer men male hormone hormones
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shared by Nathan Goodyear on 05 Nov 14
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Association of androgen-deprivation therapy with excess cardiac-specific mortality in m... - 0 views
onlinelibrary.wiley.com/...1FB6E68961FAD6E8D59FE72.f04t04
androgen deprivation therapy ADT CVD cardiovascular disease men male hormone hormones prostate cancer
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shared by Nathan Goodyear on 21 Aug 14
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Adverse Effects of Androgen Deprivation Therapy and... [Eur Urol. 2014] - PubMed - NCBI - 0 views
www.ncbi.nlm.nih.gov/...25097095
androgen deprivation therapy ADT prostate men male cancer cardiovascular disease obesity diabetes fatigue muscle loss
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shared by Nathan Goodyear on 30 Dec 15
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Androgen Deprivation Therapy and Future Alzheimer's Disease Risk - 0 views
jco.ascopubs.org/...JCO.2015.63.6266
ADT androgen deprivation therapy low T low Testosterone alzheimer's disease Alzheimer's brain
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shared by Nathan Goodyear on 09 Dec 15
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Androgen Deprivation Therapy and Future Alzheimer's Disease Risk - 0 views
jco.ascopubs.org/...JCO.2015.63.6266.abstract
alzheimer's disease prostate cancer ADT androgen deprivation therapy male hormones Testosterone
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