Testosterone and glucose metabolism in men: current concepts and controversies - 1 views
joe.endocrinology-journals.org/...R37.full
Low T Testosterone metabolic syndrome MetS Diabetes men male glucose hormone hormones g
shared by Nathan Goodyear on 04 Feb 14
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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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The presence of symptoms was more closely linked to increasing age than to testosterone levels
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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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low testosterone is more predictive of the metabolic syndrome in lean men
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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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low testosterone identifies men with an adverse metabolic phenotype
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Diabetic men with low testosterone are significantly more likely to be obese or insulin resistant
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increased inflammation, evidenced by higher CRP levels
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Bioavailable but not free testosterone was independently predictive of mortality
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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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There is also evidence that testosterone regulates insulin sensitivity directly and acutely
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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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Circulating testosterone, on an average 30%, is lower in obese compared with lean men
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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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obesity is a dominant risk factor
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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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Only 5% of men with type 2 diabetes have elevated LH levels
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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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kisspeptin has emerged as one of the most potent secretagogues of GNRH release
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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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suppression of the diabesity-associated HPT axis is functional, and may hence be reversible
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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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weight gain and development of diabetes accelerate the age-related decline in testosterone
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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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Weight loss can reactivate the hypothalamic–pituitary–testicular axis
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Leptin treatment resolves hypogonadism in leptin-deficient men
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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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change in BMI was associated with the change in testosterone (Corona et al. 2013a,b).
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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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Article discusses the expanding evidence of low T and Metabolic syndrome.
