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Nathan Goodyear

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

  • Around 50% of ageing, obese men presenting to the diabetes clinic have lowered testosterone levels relative to reference ranges based on healthy young men
  • 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.
  • A key concept relates to making a distinction between replacement and pharmacological testosterone therapy
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  • The presence of symptoms was more closely linked to increasing age than to testosterone levels
  • 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
  • low testosterone is more predictive of the metabolic syndrome in lean men
  • 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
  • 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.
  • 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
  • In a cross-sectional study of 490 men with type 2 diabetes, there was a strong independent association of low testosterone with anaemia
  • In men, low testosterone is a marker of poor health, and may improve our ability to predict risk
    • Nathan Goodyear
       
      probably the most important point made in this article
  • low testosterone identifies men with an adverse metabolic phenotype
  • Diabetic men with low testosterone are significantly more likely to be obese or insulin resistant
  • increased inflammation, evidenced by higher CRP levels
  • Bioavailable but not free testosterone was independently predictive of mortality
  • It remains possible that low testosterone is a consequence of insulin resistance, or simply a biomarker, co-existing because of in-common risk factors.
  • 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
  • In a study from the Framingham cohort, SHBG but not testosterone was prospectively and independently associated with incident metabolic syndrome
  • low SHBG (Ding et al. 2009) but not testosterone (Haring et al. 2013) with an increased risk of future diabetes
  • 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
  • SHBG may have biological actions beyond serving as a carrier protein for and regulator of circulating sex steroids
  • In men with diabetes, free testosterone, if measured by gold standard equilibrium dialysis (Dhindsa et al. 2004), is reduced
    • Nathan Goodyear
       
      expensive, laborious process filled with variables
  • 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.
  • 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.
  • testosterone promotes the commitment of pluripotent stem cells into the myogenic lineage and inhibits their differentiation into adipocytes
  • 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.
  • 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.
  • More recently testosterone has been shown to protect murine pancreatic β cells against glucotoxicity-induced apoptosis
  • 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.
  • There is also evidence that testosterone regulates insulin sensitivity directly and acutely
  • 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
  • More prolonged (>12 months) androgen deprivation therapy has been associated with increased risk of diabetes in several large observational registry studies
  • 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.
  • 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.
  • 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
  • there is increasing evidence that healthy ageing by itself is generally not associated with marked reductions in testosterone
  • Circulating testosterone, on an average 30%, is lower in obese compared with lean men
  • increased visceral fat is an important component in the association of low testosterone and insulin resistance
  • The vast majority of men with metabolic disorders have functional gonadal axis suppression with modest reductions in testosterone levels
  • obesity is a dominant risk factor
  • men with Klinefelter syndrome have an increased risk of metabolic disorders. Interestingly, greater body fat mass is already present before puberty
  • Only 5% of men with type 2 diabetes have elevated LH levels
  • 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 from GNRH neurons situated in the preoptic area
  • kisspeptin has emerged as one of the most potent secretagogues of GNRH release
  • 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
  • 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
  • suppression of the diabesity-associated HPT axis is functional, and may hence be reversible
  • 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
  • weight gain and development of diabetes accelerate the age-related decline in testosterone
  • Modifiable risk factors such as obesity and co-morbidities are more strongly associated with a decline in circulating testosterone levels than age alone
  • 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
  • Weight loss can reactivate the hypothalamic–pituitary–testicular axis
  • Leptin treatment resolves hypogonadism in leptin-deficient men
  • 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
  • change in BMI was associated with the change in testosterone (Corona et al. 2013a,b).
  • 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 men who improved their glycaemic control over time, testosterone levels increased. By contrast, in those men in whom glycaemic control worsened, testosterone decreased
  • 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.
  •  
    Article discusses the expanding evidence of low T and Metabolic syndrome.
Nathan Goodyear

Nature Clinical Practice Endocrinology & Metabolism | Testosterone and ill-health in ag... - 0 views

  • Levels of total and bioavailable testosterone and SHBG were reported to be inversely correlated with the prevalence of the metabolic syndrome in men aged 40–80 years
  • as were total testosterone and SHBG in men aged 65–96 years
  • and in a cross-sectional analysis of a large cohort of non-diabetic men aged 70–89 years
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  • In longitudinal studies, decreased levels of total testosterone and SHBG predicted an increased incidence of metabolic syndrome in nonobese men
  • Free testosterone level is not associated with the prevalence of metabolic syndrome in middle-aged and older men
  • Levels of free, bioavailable and total testosterone are lower in men with T2DM than in age-matched controls,34, 35 and decreased total testosterone level predicts incident T2DM in middle-aged men.
  • men with T2DM commonly have low total or free testosterone levels
  • Total, bioavailable and free testosterone levels are inversely correlated with fasting insulin level and insulin resistance in middle-aged men without T2DM
  • total testosterone is positively correlated with insulin sensitivity in men with normal or impaired glucose tolerance or T2DM
  • low SHBG level is more strongly associated with metabolic syndrome than low total testosterone in aging men
  • the recognized association between low SHBG level and insulin resistance
  • Low levels of SHBG are also associated with smaller, denser LDL-cholesterol molecules in nondiabetic men,58 and were found to predict increased cardiovascular disease mortality in one study of older men
  • Low levels of SHBG might reflect obesity, insulin resistance and overall poor health
  • Compared with those who have normal testosterone levels, men aged 40 years or more with total testosterone levels <9.8 nmol/l or elevated LH level have greater CIMT
  • In men aged 73–94 years, total testosterone was inversely correlated with CIMT
  • a prospective analysis of men aged 73–91 years, progression of CIMT was not related to total testosterone level, but it was inversely related to free testosterone level
  • A study of men aged 55 years or more found that those with total and bioavailable testosterone levels in the highest tertile had a lower risk of severe aortic atherosclerosis (detected by radiography as abdominal aortic calcification) than those with the lowest testosterone levels.
  • a large study of men aged 69–80 years, those with total or free testosterone in the lowest quartile had increased odds of lower-extremity peripheral arterial disease
  • the possibility of reverse causation has to be considered, as systemic illness can result in decreased testosterone levels
  • previous case–control studies and longitudinal studies have failed to identify low testosterone levels as strong predictors of clinically significant coronary disease
  • Reviews of trials on testosterone therapy in men with either low or low-to-normal testosterone levels have not shown consistent beneficial effects either on lipid profiles or on actual cardiovascular events.24, 54, 55 These trials, however, have not been designed or powered to detect treatment-related differences in cardiovascular outcome
  •  
    Declining Testosterone or low Testosterone is clearly associated with poor health in men.   Very nice review of the association between low Testosterone and metabolic dysfunction.  Low T is associated with increased metabolic syndrome, Diabetes, weight gain, insulin resistance...
Nathan Goodyear

Testosterone level in men with type 2 diabetes mellitus and related metabolic... - 0 views

  • defined by consistent symptoms and signs of androgen deficiency, and an unequivocally low serum testosterone level
  • the threshold serum testosterone level below which adverse clinical outcomes occur in the general population is not known
  • most population-based studies use the serum testosterone level corresponding to the lower limit, quoted from 8.7 to 12.7 nmol/L, of the normal range for young Caucasian men as the threshold
    • Nathan Goodyear
       
      this equals 251 to 366 in serum Total Testosterone
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  • Researchers tried to examine whether serum total or free testosterone would be a better/more reliable choice when studying the effect of testosterone. The results were mixed. Some reported significant associations of both serum total and free testosterone level with clinical parameters25, whereas others reported that only serum free testosterone26 or only serum total testosterone6 showed significant associations.
  • −0.124 nmol/L/year in serum total testosterone
    • Nathan Goodyear
       
      this equates to a 4 ng/dl decline annually in total Testosterone.
  • In experimental studies, androgen receptor knockout mice developed significant insulin resistance rapidly
  • In mouse models, testosterone promoted differentiation of pluripotent stem cells to the myogenic lineage
  • testosterone decreased insulin resistance by enhancing catecholamine induced lipolysis in vitro, and reducing lipoprotein lipase activity and triglyceride uptake in human abdominal tissue in vivo
  • by promoting lipolysis and myogenesis, testosterone might lead to improved insulin resistance
  • testosterone regulated skeletal muscle genes involved in glucose metabolism that led to decreased systemic insulin resistance
  • In the liver, hepatic androgen receptor signaling inhibited development of insulin resistance in mice
  • independent and inverse association of testosterone with hepatic steatosis shown in a cross-sectional study carried out in humans
  • In short, androgen improves insulin resistance by changing body composition and reducing body fat.
  • Although a low serum testosterone level could contribute to the development of obesity and type 2 diabetes through changes in body composition, obesity might also alter the metabolism of testosterone
  • In obese men, the peripheral conversion from testosterone to estrogen could attenuate the amplitude of luteinizing hormone pulses and centrally inhibit testosterone production
  • leptin, an adipokine, has been shown to be inversely correlated with serum testosterone level in men
  • Leydig cells expressed leptin receptors and leptin has been shown to inhibit testosterone secretion, suggesting a role of obesity and leptin in the pathogenesis of low testosterone
    • Nathan Goodyear
       
      So what is "unequivocal"?
  • Baltimore Longitudinal Study of Aging (BLSA) cohort made up of 3,565 middle-class, mostly Caucasian men from the USA, the incidence of low serum total testosterone increased from approximately 20% of men aged over 60 years, 30% over 70 years, to 50% over 80 years-of-age
  • 30–44% sex hormone binding globulin (SHBG)-bound testosterone and 54–68% albumin-bound testosterone
  • As the binding of testosterone to albumin is non-specific and therefore not tight, the sum of free and albumin-bound testosterone is named bioavailable testosterone, which reflects the hormone available at the cellular level
  • Serum total testosterone is composed of 0.5–3.0% of free testosterone unbound to plasma proteins
  • alterations in SHBG concentration might affect total serum testosterone level without altering free or bioavailable testosterone
  • listed in Table​T
  • A significant, independent and longitudinal effect of age on testosterone has been observed with an average change of −0.124 nmol/L/year in serum total testosterone28. The same trend has been shown in Europe and Australia
  • Asian men residing in HK and Japan, but not those living in the USA, had 20% higher serum total testosterone than in Caucasians living in the USA, as shown in a large multinational observational prospective cohort of the Osteoporotic Fractures in Men Study
  • subjects with chronic diseases consistently had a 10–15% lower level compared with age-matched healthy subjects
  • In Caucasians, the mean serum total testosterone level for men in large epidemiological studies has been reported to range from 15.1 to 16.6 nmol/L
  • Asians, higher values, ranging from 18.1 to 19.1 nmol/L, were seen in Korea and Japan
  • Chinese middle-aged men reported a similar mean serum testosterone level of 17.1 nmol/L in 179 men who had a family history of type 2 diabetes and 17.8 nmol/L in 128 men who had no family history of type 2 diabetes
  • The reduction of total testosterone was 0.4% per year in both groups
  • HK involving a cohort of 1,489 community-dwelling men with a mean age of 72 years, a mean serum total testosterone of 19.0 nmol/L was reported
  • pro-inflammatory factors, such as tumor necrosis factor-α in the testes, could locally inhibit testosterone biosynthesis in Leydig cells47, and testosterone treatment in men was shown to reduce the level of tumor necrosis factor-α
  • In Asians, a genetic deletion polymorphism of uridine diphosphate-glucuronosyltransferase UGT2B17 was associated with reduced androgen glucuronidation. This resulted in higher level of active androgen in Asians as compared to Caucasians, as Caucasians' androgen would be glucuronidated into inactive forms faster.
  • Compared with Caucasians, the frequency of this deletion polymorphism of UGT2B17 was 22-fold higher in Asian subjects
  • Other researchers have suggested that environmental, but not genetic, factors influenced serum total testosterone
  • The basal and ligand-induced activity of the AR is inversely associated with the length of the CAG repeat chain
  • In the European Male Aging Study, increased estrogen/androgen ratio in association with longer AR CAG repeat was observed
  • a smaller number of AR CAG repeat had been shown to be associated with benign prostate hypertrophy and faster prostate growth during testosterone treatment
  • In India, men with CAG ≤19 had increased risk of prostate cancer
  • the odds of having a short CAG repeat (≤17) were substantially higher in patients with lymph node-positive prostate cancer than in those with lymph node-negative disease or in the general population
  • assessing the polymorphism at the AR level could be a potential tool towards individualized assessment and treatment of hypogonadism.
  • In elderly men, there was reduced testicular response to gonadotropins with suppressed and altered pulsatility of the hypothalamic pulse generator
  • a significant, independent and longitudinal effect of age on serum total testosterone level had been observed
  • A significant graded inverse association between serum testosterone level and insulin levels independent of age has also been reported in Caucasian men
  • Low testosterone is commonly associated with a high prevalence of MES
  • most studies showed that changes in serum testosterone level led to changes in body composition, insulin resistance and the presence of MES, the reverse might also be possible
  • MES predicted a 2.6-fold increased risk of development of low serum testosterone level independent of age, smoking and other potential confounders
  • Other prospective studies have shown that development of MES accelerated the age-related decline in serum testosterone level
  • In men with type 2 diabetes, changes in serum testosterone level over time correlated inversely with changes in insulin resistance
  • weight loss by either diet control or bariatric surgery led to a substantial increase in total testosterone, especially in morbidly obese men, and the rise in serum testosterone level was proportional to the amount of weight lost
  • To date, published clinical trials are small, of short duration and often used pharmacological, not physiological, doses of testosterone
  • In the population-based Osteoporotic Fractures in Men Study cohort from Sweden, men in the highest quartile of serum testosterone level had the lowest risk of cardiovascular events compared with men in the other three quartiles (hazard ratio [HR] 0.70
  • low serum total testosterone was associated with a significant fourfold higher risk of cardiovascular events when comparing men from the lowest testosterone tertile with those in the highest tertile
  • Shores et al. were the first to report that low serum testosterone level, including both serum total and free testosterone, was associated with increased mortality
  • low serum total testosterone predicted increased risk of cardiovascular mortality with a HR of 1.38
  • low serum total testosterone increased all-cause (HR 1.35, 95% CI 1.13–1.62, P < 0.001) and cardiovascular mortality (HR 1.25
  • European Association for the Study of Diabetes 2013 suggested there was an inverse relationship between serum testosterone level and acute myocardial infarction
  • Diabetic men in the highest quartile of serum total testosterone had a significantly reduced risk of acute MI when compared with those in the lower quartiles
  • serum total testosterone level in the middle two quartiles at baseline predicted reduced incidence of death compared with having the highest and lowest levels
  •  
    Nice review of Testosterone levels and some of the evidence linking Diabetes with low T.  However, the conclusion by the authors regarding what is causing the low T in men with Diabetes is baffling.  The literature does not point to one cause, it is clearly multifactorial--obesity, inflammation, high aromatase activity...I would suggest the authors continue their readings in the manner.
Nathan Goodyear

Diet-induced obesity and low testosterone increase neuroinflammation and impair neural ... - 0 views

  • both obesity and low testosterone are also risk factors for neural dysfunction, including cognitive impairment [58–61] and development of AD
  • Levels of obesity and testosterone are often inversely correlated
  • diet-induced obesity causes significant metabolic disturbances and impairs central and peripheral nervous systems.
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  • both obesity and low testosterone are linked with promotion of inflammatory pathways [70–72] and exert harmful actions on the central [73–75] and peripheral [29,76] nervous systems
  • In general, obesity-related changes were worsened by low testosterone and improved by testosterone treatment; however, this relationship was not statistically significant in several instances. Further, our data suggest that a common pathway that may contribute to obesity and testosterone effects is regulation of inflammation
  • fasting blood glucose levels were independently and additively increased by GDX-induced testosterone depletion and high-fat diet
  • testosterone treatment significantly reduced fasting glucose under both the normal and high-fat diets, demonstrating potential therapeutic efficacy of testosterone supplementation
  • fasting insulin, insulin resistance (HOMA index), and glucose tolerance, low testosterone tended to exacerbate and or testosterone treatment improved outcomes.
  • testosterone status did not significantly affect body weight
  • testosterone’s effects likely do not indicate an indirect result on adiposity but rather regulatory action(s) on other aspects of metabolic homeostasis
  • Prior work in rodents has shown diet-induced obesity induces insulin resistance in rat brain [63] and that testosterone replacement improves insulin sensitivity in obese rats [64]. Our findings are consistent with the human literature, which indicates that (i) testosterone levels are inversely correlated to insulin resistance and T2D in healthy [30,65] as well as obese men [66], and (ii) androgen therapy can improve some metabolic measures in overweight men with low testosterone
  • it has been shown that TNFα has inhibitory effects on neuron survival, differentiation, and neurite outgrowth
  • Our data demonstrate that low testosterone and obesity independently increased cerebrocortical mRNA levels of both TNFα and IL-1β
  • Testosterone status also affected metabolic and neural measures
  • many beneficial effects of testosterone, including inhibition of proinflammatory cytokine expression
  • neuroprotection [80,81], are dependent upon androgen receptors, the observed effects of testosterone in this study may involve androgen receptor activation
  • testosterone can be converted by the enzyme aromatase into estradiol, which is also known to exert anti-inflammatory [82] and neuroprotective [83] actions
  • glia are the primary sources of proinflammatory molecules in the CNS
  • poorer survival of neurons grown on glia from mice maintained on high-fat diet
  • Since testosterone can affect glial function [86] and improve neuronal growth and survival [87–89], it was unexpected that testosterone status exhibited rather modest effects on neural health indices with the only significant response being an increase in survival in the testosterone-treated, high-fat diet group
  • significantly increased expression of TNFα and IL-1β in glia cultures derived from obese mice
  • testosterone treatment significantly lowered TNFα and IL-1β expression to near basal levels even in obese mice, indicating a protective benefit of testosterone across diet conditions
  • IL-1β treatment has been shown to induce synapse loss and inhibit differentiation of neurons
  • Testosterone status and diet-induced obesity were associated with significant regulation of macrophage infiltration
  • testosterone prevented and/or restored thermal nociception in both diet groups
  • a possible mechanism by which obesity and testosterone levels may affect the health of both CNS and PNS
  •  
    Study points to obesity and low Testosterone contribution of neuroinflammation.  No effect of body weight was seen with TRT.  This animal model found similar positive effects of TRT in insulin sensitivity.  Obesity and low T increase inflammatory cytokine production: this study found an increase in TNF-alpha and IL-1beta and TRT reduced TNF-alpha and IL-1beta to near base-line.  Testosterone is neuroprotective and this study reviewed the small volume of evaded that pointed to benefit from estradiol.  Testosterone's effect on glial survival was positive but not significant.  Obesity and low T were found to be associated with increased macrophage infiltration in the PNS with increased TNF-alpha and IL-1beta.   Testosterone therapy improved peripheral neuropathy via its positive effects on nocicieption.
Nathan Goodyear

Testosterone Deficiency, Cardiac Health, and Older Men - 0 views

  • Studies have shown pharmacological doses of testosterone to relax coronary arteries when injected intraluminally [39] and to produce modest but consistent improvement in exercise-induced angina and reverse associated ECG changes [40]. The mechanism of action is via blockade of calcium channels with effect of similar magnitude to nifedipine
    • Nathan Goodyear
       
      This directly refutes the recent studies (3) that Testosterone therapy increases cardiovascular events.
    • Nathan Goodyear
       
      Testosterone acts as a calcium channel blocker inducing vasodilation.
  • men with chronic stable angina pectoris, the ischaemic threshold increased after 4 weeks of TRT and a recent study demonstrates improvement continuing beyond 12 months [
  • Exercise capacity in men with chronic heart failure increased after 12 weeks
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  • Studies have shown an inverse relationship between serum testosterone and fasting blood glucose and insulin levels
  • Medications such as chronic analgesics, anticonvulsants, 5ARIs, and androgen ablation therapy are associated with increased risk of testosterone deficiency and insulin resistance
  • Women with T2D or metabolic syndrome characteristically have low SHBG and high free testosterone
    • Nathan Goodyear
       
      This stands in polar opposite of that with men.
  • Hypogonadism is a common feature of the metabolic syndrome
  • The precise interaction between insulin resistance, visceral adiposity, and hypogonadism is, as yet, unclear but the important mechanisms are through increased aromatase production, raised leptin levels, and increase in inflammatory kinins
  • levels of testosterone are reduced in proportion to degree of obesity
  • Men should be encouraged to combine aerobic exercise with strength training. As muscle increases, glucose will be burned more efficiently and insulin levels will fall. A minimum of 30 minutes exercise three times weekly should be advised
  • Testosterone increases levels of fast-twitch muscle fibres
  • By increasing testosterone, levels of type 2 fibres increase and glucose burning improves
  • Weight loss will increase levels of testosterone
  • studies now clearly show that low testosterone leads to visceral obesity and metabolic syndrome and is also a consequence of obesity
  • In the case of MMAS [43], a baseline total testosterone of less than 10.4 nmol/L was associated with a greater than 4-fold incidence of type 2 diabetes over the next 9 years
  • There is high level evidence that TRT improves insulin resistance
  • Low testosterone predicts increased mortality and testosterone therapy improves survival in 587 men with type 2 diabetes
  • A similar retrospective US study involved 1031 men with 372 on TRT. The cumulative mortality was 21% in the untreated group versus 10% ( ) in the treated group with the greatest effect in younger men and those with type 2 diabetes
  • the presence of ED has been shown to be an independent risk factor, particularly in hypogonadal men, increasing the risk of cardiac events by over 50%
  • A recent online publication on ischaemic heart disease mortality in men concluded optimal androgen levels are a biomarker for survival
  • inverse associations between low TT or FT (Table 2) and the severity of CAD
  • A recent 10 year study from Western Australia involving 3690 men followed up from 2001–2010 concluded that TT and FT levels in the normal range were associated with decreased all-cause and cardiovascular mortality, for the first time suggesting that both low and DHT are associated with all-cause mortality and higher levels of DHT reduced cardiovascular risk
  • TDS is associated with increased cardiovascular and all-cause mortality
  • The effect of treatment with TRT reduced the mortality rate of treated cohort (8.4%) to that of the eugonadal group whereas the mortality for the untreated remained high at 19.2%
  • hypogonadal men had slightly increased triglycerides and HDL
  • Men with angiographically proven CAD (coronary artery disease) have significantly lower testosterone levels [29] compared to controls ( ) and there was a significant inverse relationship between the degree of CAD and TT (total testosterone) levels
  • TRT has also been shown to reduce fibrinogen to levels similar to fibrates
  • men treated with long acting testosterone showed highly significant reductions in TC, LDL, and triglycerides with increase in HDL, associated with significant reduction in weight, BMI, and visceral fat
  • Low androgen levels are associated with an increase in inflammatory markers
  • In the Moscow study, C-reactive protein was reduced by TRT at 30 weeks versus placebo
  • In some studies, a decline in diastolic blood pressure has been observed, after 3–9 months [24, 26] and in systolic blood pressure
  • A decline was noted in IL6 and TNF-alpha
  • No studies to date show an increase in LUTS/BPH symptoms with higher serum testosterone levels
  • TRT has been shown to upregulate PDE5 [65] and enhance the effect of PDE5Is (now an accepted therapy for both ED and LUTS), it no longer seems logical to advice avoidance of TRT in men with mild to moderate BPH.
    • Nathan Goodyear
       
      What about just starting with normalization of Testosterone levels first.
  • Several meta-analyses have failed to show a link between TRT and development of prostate cancer [66] but some studies have shown a tendency for more aggressive prostate cancer in men with low testosterone
    • Nathan Goodyear
       
      And if one would have looked at their estrogen levels, I guarantee they would have been found to be elevated.
  • low bioavailable testosterone and high SHBG were associated with a 4.9- and 3.2-fold risk of positive biopsy
  • Current EAU, ISSAM, and BSSM guidance [1, 2] is that there is “no evidence TRT is associated with increased risk of prostate cancer or activation of subclinical cancer.”
  • Men with prostate cancer, treated with androgen deprivation, develop an increase of fat mass with an altered lipid profile
  • Erectile dysfunction is an established marker for future cardiovascular risk and the major presenting symptom leading to a diagnosis of low testosterone
Nathan Goodyear

Serum oestradiol levels in male partners of infer... [Andrologia. 2014] - PubMed - NCBI - 0 views

  •  
    Study points to association of low Estradiol and spermatogenesis in males in infertile couples.  The authors eluded to the association of low Estradiol with low Testosterone, and BMI which is the likely etiology.  Low BMI will result in low aromatase activity.  For men, the majority of Estradiol production occurs from Testosterone via aromatase activity.  Estradiol likely exists in a "U" shaped pattern of benefit: to low hinders optimal physiologic function and contributes to inflammation and disease in men.
Nathan Goodyear

Hypothalamo-Pituitary-Adrenal Axis Dysfunction in Chronic Fatigue Syndrome, and the Eff... - 0 views

  • We conclude that the improvement in fatigue seen in some patients with chronic fatigue syndrome during hydrocortisone treatment is accompanied by a reversal of the blunted cortisol responses to human CRH
  • These data further suggest that the hypocortisolism found in chronic fatigue syndrome may be secondary to reduced adrenal gland output.
  • 5-mg replacement dose of hydrocortisone, and the remainder 10 mg
  •  
    low dose hydrocortisone therapy (defined as 5-10 mg), in this study, was used to treat CFS.  This study found an improvement in symptoms in these patients.  Additionally, low cortisol was found in these patients with CFS.  Their conclusion, was that low adrenal function is a component of CFS and low dose hydrocortisone therapy is an effective treatment.   Now, is the low cortisol as the result of increased metabolism as well?
Nathan Goodyear

Combination of low free testosterone and low vitamin D predicts mortality in older men ... - 0 views

  •  
    low Testosterone is associated with increased CVD and mortality.  Add in low Vitamin D and you have lethal combination for men.  Low vitamin D and low T are a dangerous combination for men for CVD and all cause mortality.  
Nathan Goodyear

Testosterone and metabolic syndrome Cunningham GR - Asian J Androl - 0 views

  • The relationship of low testosterone to MetS often is considered to be bidirectional; however, the relationships probably are not direct
  • Many of the components of the MetS are recognized risk factors for the development of cardiovascular disease (CVD)
  • Multiple cross-sectional studies have found low TT and low sex hormone binding globulin (SHBG) levels in Caucasian and African-American men with the MetS, irrespective of age
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  • Low TT and SHBG levels also are prevalent in Chinese [7],[8] and Korean [9] men with the MetS
  • Normally 40%-50% of TT is bound to SHBG, so reducing SHBG levels will decrease TT.
  • Hyperinsulinism suppresses SHBG synthesis and secretion by the liver
  • significant increase in SHBG levels occurred after acutely lowering insulin levels in obese men
  • Estradiol levels are increased in men with the MetS, and they are positively correlated with the number of abnormal components of the MetS.
  • Although it is known that estrogen will increase SHBG levels, apparently the hyperinsulinism associated with obesity has a greater effect on SHBG levels
  • Estradiol also can inhibit luteinizing hormone (LH) secretion
  • Inflammatory cytokines are thought to have a direct effect on the pituitary to reduce LH secretion [15] and also a direct effect on Leydig cell secretion of testosterone
  • Low TT Levels have been shown to predict development of the MetS in men with normal BMI
  • Men in the lowest quartiles of serum TT, calculated free testosterone (cFT) and SHBG at baseline had the highest odds ratios for developing the MetS or DM during the 11 years follow-up
  • More recently, investigators conducting population-based studies have reported that only SHBG is associated with future development of the MetS
  • Additional evidence that low TT increases the risk of MetS comes from androgen deprivation treatment of prostate cancer
  • Low TT and low bioavailable testosterone (bT) were each significantly associated with elevated 20 years risk of CVD mortality in an older population in which cause-specific mortality was age, adiposity, and lifestyle-adjusted.
  • combination of low bT and ATP III-defined MetS is associated with increased cardiovascular mortality in men aged 40 years and above
  • in elderly men, testosterone may weakly protect against CVD. Alternatively, low TT may indicate poor general health
  • Muraleedharan and Jones [27] concluded that there is convincing evidence that low T is a biomarker for disease severity and mortality.
  • The evidence that TRT improves insulin sensitivity and glucose control is conflicted
  • It is widely recognized that testosterone treatment can reduce fat mass and increase lean body mass; however, until recently most reports have not been associated with much weight loss
  • Changes in body composition and weight loss are considered potential mechanisms by which testosterone treatment improves insulin sensitivity and glucose control in patients with diabetes. Effects on inflammatory cytokines [38] and changes in oxidative metabolism [39] also have been reported to improve glucose metabolism.
  • Testosterone replacement therapy has been reported to improve some or all of the components of the MetS.
  •  
    To be read article on Testosterone and Metabolic Syndrome.
Nathan Goodyear

The rs5934505 single nucleotide polymorphism (SNP) is associated with low testosterone ... - 0 views

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    Four SNPs, rs12150660, rs727428, rs5934505, and rs10822184 associated with late-onset hypogonadism (low T) and obesity in men of European descent.  In Chinese populations, rs5934505 was associated with increased risk of low Total Testosterone and calculated free Testosterone.  OR was 2.01 for low TT and 2.14 for low calculated free Testosterone.
Nathan Goodyear

Access : Impact of the association between elevated oestradiol and low testosterone lev... - 0 views

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    low T and elevated E2 result in ED in men.  The authors conclude that E2 provides an additive effect on that of low T.  Yet, they fail to realize the previous research that high aromatase activity (Testosterone to Estradiol production) causes the low T.
Nathan Goodyear

Low-T3 Syndrome - 0 views

  • More than 80% of the biologically active hormone triiodothyronine (T3) derives from peripheral conversion of prohormone thyroxine (T4) secreted by the thyroid gland
  • Low thyroid hormone concentrations, in particular low serum T3 concentrations, are a common finding in patients with nonthyroidal illnesses, including cardiac disorders
  • a direct relationship between low circulating levels of T3 and adverse prognosis of cardiac patients
  • ...4 more annotations...
  • The present study clearly shows the existence of a strong association between the reduction of biologically active T3 and mortality in a large population of cardiac hospitalized patients
  • highly significant increase in the incidence of cardiac and cumulative deaths in patients with low T3 compared with patients with normal T3 levels
  • the relevance of the low T3 state as a strong, independent predictor of mortality in cardiac patients
  • low T3 concentrations are a strong independent predictive marker of poor prognosis in cardiac patients
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    low T3 associated with poor prognosis in cardiac patients.   Poor prognosis = death.  T3 is important in cardiac remodeling, which is inherently important with cardiac disease.
Nathan Goodyear

Elderly men over 65 years of age with late-onset hypogonadism benefit as much from test... - 0 views

  • The benefits of restoring serum testosterone in men with LOH were not significantly different between men older than 65 years of age and younger men. There were no indications that side effects were more severe in elderly men. The effects on prostate and urinary function and hematocrit were within safe margins.
  • obesity, but also impaired general health, are the more common causes of low testosterone in aging men
  • Severe LOH is associated with substantially higher risks of all-cause and cardiovascular mortality,
  • ...30 more annotations...
  • advanced age, obesity, a diagnosis of metabolic syndrome, and poor general health status were predictors of LOH
  • Diabetes mellitus was correlated with hypogonadism in most studies
  • coronary heart disease, hypertension, stroke, and peripheral arterial disease did not predict hypogonadism, they did correlate with the incidence of low testosterone
  • LOH can be defined by the presence of at least three sexual symptoms associated with a total testosterone level of less than 11 nmol/L (3.2 ng/mL) and a free testosterone level of less than 220 pmol/L (64 pg/mL)
    • Nathan Goodyear
       
      the European Male Aging study defined low T as total < 320 ng/dl and free < 64 pg/ml.  
  • Mean weight decreased
  • Waist circumference decreased
  • Total cholesterol decreased
  • Low-density lipoprotein decreased
  • Triglycerides decreased
  • High-density lipoprotein (HDL) increased
  • ratio of total cholesterol to HDL improved
  • Prostate volume increased
  • PSA increased
  • The benefits for men older than 65 years of age were compared with those of younger men, and the improvements in body weight, metabolic factors, psychological functioning, and sexual functioning were of the same magnitude in both age groups
  • weight loss was progressive over the 6-year period, effects of testosterone on lipids and on psychological and sexual functioning reached a plateau after approximately 3 years and these effects were sustained
  • Effects of testosterone on hematopoiesis, on the prostate, and on bladder function were not more severe in older men than in younger men
  • observe a mild increase in prostate volume and serum PSA over time, which is a normal finding in aging men. Maybe somewhat surprising, postvoiding residue and the IPSS did not deteriorate with aging but showed a degree of improvement
  • the severity of the metabolic syndrome is associated with the severity of lower urinary tract symptoms
  • The symptoms of the metabolic syndrome improve upon testosterone treatment and testosterone may thus have a favorable effect on lower urinary tract symptoms
  • it seems reasonable to conclude that the risks of testosterone administration to elderly men are not disproportionately higher in elderly men than in younger men.
  • Despite evidence to the contrary, physicians still harbor a wrongful association between testosterone and the development of prostate pathology (prostate cancer and benign prostate hyperplasia)
  • Not surprisingly, the incidence of prostate cancer was higher in older men; however, it was lower than expected in both groups
  • These observations suggest that the incidence of prostate cancer in patients receiving testosterone therapy, both in the younger and in the older group, was not greater than in the general population not receiving testosterone treatment
  • The historical fear that raising testosterone levels will result in more prostate cancer has been dispelled, particularly by the work of Abraham Morgentaler
  • Higher serum testosterone levels fail to show an increased risk of prostate cancer, and supraphysiological testosterone does not increase prostate volume or PSA in healthy men
  • This apparent paradox is explained by the "saturation model,"
  • Recent studies indicate no increased risk of prostate cancer among men with serum testosterone in the therapeutic range
  • In the present observational study, no cases of major adverse cardiovascular events occurred.
  • the benefits of testosterone therapy are fully achieved only by long-term treatment
  • To achieve maximal benefits, good patient adherence is a prerequisite
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    Study finds new difference in Testosterone benefits and/or side effects between men < 65 with low T and men > 65 with low T.
Nathan Goodyear

Testosterone deficiency and cardiovascular mortality Morgentaler A, - Asian J Androl - 0 views

  • overall mortality and CV mortality were inversely associated with serum T concentrations.
  • men with low serum T, defined as &lt; 8.7 nmol l−1 (250 ng dl−1 ), demonstrated significantly greater all-cause mortality than men with higher serum T (hazard ratio [HR]: 2.24; 95% CI: 1.41-3.57), as well as greater CV mortality
  • lower T levels were significantly associated with the presence of any CV disease
  • ...19 more annotations...
  • more than 30 years of studies suggesting that low levels of T represent an increased risk for CV and overall mortality,
  • lower serum T concentrations also are associated with CV disease, including incident coronary artery disease [17],[18],[19] and atherosclerosis,
  • the actual rate of adverse events was only half as great in the T group (123 events in 1223 men at risk = 10.1%) as in the untreated group (1587 events in 7486 men = 21.2%)
  • The study by Vigen et al. [7] has already undergone two published corrections,
  • 29 medical societies have called for retraction of the article, asserting "gross data mismanagement and contamination," that rendered the study "no longer credible
  • Mortality in T-treated men was reduced by approximately half in treated men compared with untreated men, at 10.3% versus 20.7%, respectively
  • The mortality rate for men who received TTh was 3.4 deaths per 100 person-years, and 5.7 deaths per 100 person-years in untreated men
  • HR of 0.61 (95%CI: 0.42-0.88; P = 0.008), indicating a significant reduction in mortality with TTh
  • men in the highest prognostic MI risk quartile, treatment with TTh was associated with reduced risk
  • tripling in T prescriptions in the US over the last decade
  • a majority of observational studies have found that low endogenous serum T levels are associated with increased mortality.
  • Men who received TTh were able to exercise significantly longer without ischemia compared with men who received placebo
  • In men with congestive heart failure, those who received T demonstrated greater walking distance and other functional endpoints compared with those who received placebo
  • TTh has been shown uniformly and repeatedly to improve several known CV risk factors, including reduced fat mass, body fat percent, and waist circumference, and increased lean mass
  • improved glycemic control
  • reductions in insulin resistance.
  • the evidence strongly points to improved CV status with normal serum T or treatment with TTh in men with TD
  • analysis of health insurance claims data that reported a 36% increased rate of nonfatal MI in the 90d following receipt of a T prescription compared with the 12 prior months.
  • Comparison with men who received a prescription for a phosphodiesterase type 5 inhibitor (PDE5i) revealed no increased rate of MI following the prescription
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    Great review by Morgentaler of Testosterone and CVD.  He highlights the significant flaws in the JAMA and the NEJM articles of Testosterone therapy risks.  Morgentaler highlights the significant evidence that points to low T and increased risk of CVD. On contention I have, is Morgantaler seems to flip aside the massive uptick of Testosterone use in the US as compared to other countries.  The evidence definitely points to Testosterone therapy as being safe in those with low T, but there is definitely a problem of significant Testosterone doping that is taking place as well.
Nathan Goodyear

http://press.endocrine.org/doi/pdf/10.1210/jc.2014-3818 - 0 views

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    Study finds that low free T and low Total T were associated with decline in desire, ED and activity versus none with Estradiol and SHBG in older men.  The difficult issue is the threshold of "low T".  The definition of "low T" is not uniform and varies with age.  Thus baseline evaluations and correlation with symptoms, metabolic dysfunction must be done.
Nathan Goodyear

Interleukin‐2 enhances the natural killer cell response to Herceptin‐coated H... - 1 views

  • administration of low‐dose IL‐2 results in expansion of a CD3– / CD56+ NK cell population in patients with advanced cancer
  • approximately 20 % will overexpress theHer2 / neu proto‐oncogene
  • In breast cancer, Her2 / neu overexpression is associated with a worse histologicalgrade, decreased relapse‐free and overall survival periods, and altered sensitivity to chemotherapeutic regimens
  • ...17 more annotations...
  • NK cells are large granular lymphocytes that comprise approximately 10 % of circulating lymphocytes
  • all human NK cells express the CD56 antigen
  • treatment with various concentrations of IL‐2 in vivo may induce distinct functions within the NK cell compartment and, therefore, may have profound effects on NK cell‐mediated cytotoxicity
  • CD56bright
  • CD56dim
  • We show here that ADCC conducted by NK cells in vitro is enhanced by IL‐2 activation and is critically dependent on interactions between FcγRIII on NK cells and Herceptin‐coated tumor targets
  • administration of low‐dose IL‐2 to patients results in the marked expansion of a CD56+ population of immune effectors with the ability to lyse antibody‐coated cancer targets
  • NK cells represented only 7 % of lymphocytes prior to therapy but comprised over 50 % of the population after 10 weeks of low‐dose IL‐2
  • These data suggest that the enhanced ADCC seen following the expansion of NK cells with low‐dose IL‐2 is likely due to an increase in the overall number of NK cells
  • co‐administration of IL‐2 with rhu4D5 mAb will enhance activation of NK cell effector functions
  • Stimulation of NK cells with IL‐2 resulted in a significant increase in the lysis of rhu4D5‐coated targets
  • We have shown that costimulation with IL‐2 plus rhu4D5 results in significant production of IFN‐γ by NK cells with concomitant up‐regulation of cell‐surface activation and adhesion molecules
  • It has been previously demonstrated that continuous low‐dose IL‐2 can expand a CD56+ lymphocyte population, and we have now shown that this cell population is a potent mediator of ADCC against rhu4D5 mAb‐coated Her2 / neu+ targets
  • These results suggest that administration of low‐dose IL‐2 can be used to expand NK cell numbers, while higher doses may be used to enhance their cytolytic capacity in the setting of mAb therapy
  • we have demonstrated that NK cell lysis of Her2 / neu+ breast cancer cell lines in the presence of rhu4D5 mAb is markedly enhanced following stimulation with IL‐2
  • we have presented evidence that administration of low‐dose IL‐2 in vivo results in the expansion of a potent NK cell effector population
  • Our experiments suggest that NK cells costimulated with IL‐2 and immobilized IgG can secrete potent immunomodulatory cytokines which may serve to potentiate the anti‐tumor immune response.
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    low dose IL-2 found to expand NK levels in conjuction in with herceptin in HER-2 positive breast cancer cell lines.
Nathan Goodyear

The 20-Year Public Health Impact and Direct Cost of Testosterone Deficiency in U.S. Men... - 0 views

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    This study assumes a 13% low T prevalence.  Probably too low.  This will only grow.  Low T contributes to many disease states in men. This study showed a cost of 190-525$ billion in cost from these disease states over a 20 year time period.
Nathan Goodyear

Low Free Testosterone Is Associated with Hypogonadal Signs and Symptoms in Men with Nor... - 0 views

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    low free Testosterone, though calculated in this study, found to be associated with low T symptoms despite normal total Testosterone.  Though the "normal" total Testosterone in this study is abnormal low in other studies.  Only abstract available.
Nathan Goodyear

Testosterone Treatment and Sexual Function in Older Men with Low Testosterone Levels: T... - 0 views

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    new study finds that men >65 with low libido and Testosterone levels < 275 increase sexual function with Testosterone therapy.  Only libido was improved; no benefit to erectile function was noted--note that is likely due to depleted NO.  Given time that should improve with he increase in NO synthase and thus NO.  I have a fault with on elf the comments on this study: they point out that increased free Testosterone and estradiol levels were associated with improved sexual activity.  This lacks an understanding of the physiology.  In men with low T > 65, the majority are dealing with inflammation and excess weight; all of which increase aromatase activity and thus estradiol activity.  This does not indicate that an increase in estradiol activity is associated with improved libido in men.  How can elevated estrogen levels lead to low T and then increase levels are associated with improved libido?  This is merely a reflection of the body's dysfunctional physiology.  This observation of increased estradiol by no means shows cause and effect.  Scientists need to due a better job in vetting what they write!
Nathan Goodyear

Lowered testosterone in male obesity: Mechanisms, morbidity and management Tang Fui MN,... - 0 views

  • The number of overweight people is expected to increase from 937 million in 2005 to 1.35 billion in 2030
  • Similarly the number of obese people is projected to increase from 396 million in 2005 to 573 million in 2030
  • By 2030, China alone is predicted to have more overweight men and women than the traditional market economies combined
  • ...37 more annotations...
  • 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.
  • bariatric surgery achieves 10%-30% long-term weight loss in controlled studies
  • The fact that obese men have lower testosterone compared to lean men has been recognized for more than 30 years
  • Reductions in testosterone levels correlate with the severity of obesity and men
  • 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.
  • healthy ageing by itself is uncommonly associated with marked reductions in testosterone levels
  • obesity blunts this LH rise, obesity leads to hypothalamic-pituitary suppression irrespective of age which cannot be compensated for by physiological mechanisms
  • Reductions in total testosterone levels are largely a consequence of reductions in sex hormone binding globulin (SHBG) due to obesity-associated hyperinsulinemia
  • 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
  • SHBG increases with age
  • 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
  • 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
  • diabetic obesity is associated with decreases in circulatory E 2
  • 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
  • In the prospective Massachusetts Male Aging Study (MMAS), moving from a non-obese to an obese state resulted in a decline of testosterone levels
  • weight loss, whether by diet or surgery, increases testosterone levels proportional to the amount of weight lost
  • fat is androgen-responsive
  • low testosterone may augment the effects of a hypercaloric diet
  • In human male ex vivo adipose tissue, testosterone decreased adipocyte differentiation by 50%.
  • Testosterone enhances catecholamine-induced lipolysis in vitro and reduces lipoprotein lipase activity and triglyceride uptake in human abdominal adipose tissue in vivo
  • 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
  • severe sex steroid deficiency can increase fat mass rapidly
  • bidirectional relationship between testosterone and obesity
  • 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
  • androgens may play a more significant role in VAT than SAT
  • men undergoing androgen depletion for prostate cancer show more marked increases in visceral compared to subcutaneous fat following treatment
    • Nathan Goodyear
       
      Interesting: low T increases VAT, yet T therapy does not reduce VAT, yet T therapy reduces SAT.
  • irisin, derived from muscle, induces brown fat-like properties in rodent white fat
  • androgens can act via the PPARg-pathway [37] which is implicated in the differentiation of precursor fat cells to the energy-consuming phenotype
  • low testosterone may compound the effect of increasing fat mass by making it more difficult for obese men to lose weight via exercise
  • 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
  • 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;
  • observational evidence associating higher endogenous testosterone with reduced loss of muscle mass and crude measures of muscle function in men losing weight
  • genuine reactivation of the HPT axis in obese men requires more substantial weight-loss
  • 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
  • men, regardless of obesity level, can benefit from the effect of weight loss.
  • inconsistent effect of testosterone on VAT
  •  
    to be read
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