Group items tagged

GnRH neurons have been shown to express insulin receptor mRNA and protein [27] and are activated by insulin

AgRP and NPY have the opposite (orexigenic) effect, inducing food intake.

Neuropeptides derived from POMC/CART neurons exert a potent anorectic action, thus decreasing food intake and body weight

Kisspeptins (encoded by KISS1) have been identified in the last decade as the most potent secretagogues of GnRH release.

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

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

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.

there is evidence from animal studies that leptin resistance, inflammation and oestrogens inhibit neuronal release of kisspeptin

Beyond hypothalamic action, leptin also directly inhibits the stimulatory action of gonadotrophins on the Leydig cells of the testis to decrease testosterone production; therefore, elevated leptin levels in obesity may further diminish androgen status

Prostate cancer patients with pre-existing T2DM show a further deterioration of insulin resistance and worsening of diabetic control following ADT

ADT for the treatment of prostatic carcinoma in some large epidemiological studies has been shown to be associated with an increased risk of developing MetS and T2DM

Non-diabetic men undergoing androgen ablation show increased occurrence of new-onset diabetes and demonstrate elevated insulin levels and worsening glycaemic control

increasing insulin resistance assessed by glucose tolerence test and hypoglycemic clamp was shown to be associated with a decrease in Leydig cell testosterone secretion in men

The response to testosterone replacement of insulin sensitivity is in part dependent on the androgen receptor (AR)

Low levels of testosterone have been associated with an atherogenic lipoprotein profile, characterised by high LDL and triglyceride levels

a positive correlation between serum testosterone and HDL has been reported in both healthy and diabetic men

up to 70% of the body's insulin sensitivity is accounted for by muscle

Testosterone deficiency is associated with a decrease in lean body mass

relative muscle mass is inversely associated with insulin resistance and pre-diabetes

GLUT4 and IRS1 were up-regulated in cultured adipocytes and skeletal muscle cells following testosterone treatment at low dose and short-time incubations

local conversion of testosterone to DHT and activation of AR may be important for glucose uptake

inverse correlation between testosterone levels and adverse mitochondrial function

orchidectomy of male Wistar rats and associated testosterone deficiency induced increased absorption of glucose from the intestine

(Kelley & Mandarino 2000). Frederiksen et al. (2012a) recently demonstrated that testosterone may influence components of metabolic flexibility as 6 months of transdermal testosterone treatment in aging men with low–normal bioavailable testosterone levels increased lipid oxidation and decreased glucose oxidation during the fasting state.

Decreased lipid oxidation coupled with diet-induced chronic FA elevation is linked to increased accumulation of myocellular lipid, in particular diacylglycerol and/or ceramide in myocytes

In the Chang human adult liver cell line, insulin receptor mRNA expression was significantly increased following exposure to testosterone

Testosterone deprivation via castration of male rats led to decreased expression of Glut4 in liver tissue, as well as adipose and muscle

oestrogen was found to increase the expression of insulin receptors in insulin-resistant HepG2 human liver cell line

FFA decrease hepatic insulin binding and extraction, increase hepatic gluconeogenesis and increase hepatic insulin resistance.

Only one, albeit large-scale, population-based cross-sectional study reports an association between low serum testosterone concentrations and hepatic steatosis in men (Völzke et al. 2010)

This suggests that testosterone may confer some of its beneficial effects on hepatic lipid metabolism via conversion to E2 and subsequent activation of ERα.

hypogonadal men exhibiting a reduced lean body mass and an increased fat mass, abdominal or central obesity

visceral adipose tissue was inversely correlated with bioavailable testosterone

there was no change in visceral fat mass in aged men with low testosterone levels following 6 months of transdermal TRT, yet subcutaneous fat mass was significantly reduced in both the thigh and the abdominal areas when analysed by MRI (Frederiksen et al. 2012b)

ADT of prostate cancer patients increased both visceral and subcutaneous abdominal fat in a 12-month prospective observational study (Hamilton et al. 2011)

Catecholamines are the major lipolysis regulating hormones in man and regulate adipocyte lipolysis through activation of adenylate cyclase to produce cAMP

deficiency of androgen action decreases lipolysis and is primarily responsible for the induction of obesity (Yanase et al. 2008)

may be some regional differences in the action of testosterone on subcutaneous and visceral adipose function

proinflammatory adipocytokines IL1, IL6 and TNFα are increased in obesity with a downstream effect that stimulates liver production of CRP

observational evidence suggests that IL1β, IL6, TNFα and CRP are inversely associated with serum testosterone levels in patients

TRT has been reported to significantly reduce these proinflammatory mediators

This suggests a role for AR in the metabolic actions of testosterone on fat accumulation and adipose tissue inflammatory response

testosterone treatment may have beneficial effects on preventing the pathogenesis of obesity by inhibiting adipogenesis, decreasing triglyceride uptake and storage, increasing lipolysis, influencing lipoprotein content and function and may directly reduce fat mass and increase muscle mass

Early interventional studies suggest that TRT in hypogonadal men with T2DM and/or MetS has beneficial effects on lipids, adiposity and parameters of insulin sensitivity and glucose control

Evidence that whole-body insulin sensitivity is reduced in testosterone deficiency and increases with testosterone replacement supports a key role of this hormone in glucose and lipid metabolism

Impaired insulin sensitivity in these three tissues is characterised by defects in insulin-stimulated glucose transport activity, in particular into skeletal muscle, impaired insulin-mediated inhibition of hepatic glucose production and stimulation of glycogen synthesis in liver, and a reduced ability of insulin to inhibit lipolysis in adipose tissue

kisspeptin has emerged as one of the most potent secretagogues of GNRH release

Consistent with the hypothesis that obesity-mediated inhibition of kisspeptin signalling contributes to the suppression of the HPT axis, infusion of a bioactive kisspeptin fragment has been recently shown to robustly increase LH pulsatility, LH levels and circulating testosterone in hypotestosteronaemic men with type 2 diabetes

Figure 4

Interestingly, a recent 16-week study of experimentally induced hypogonadism in healthy men with graded testosterone add-back either with or without concomitant aromatase inhibitor treatment has in fact suggested that low oestradiol (but not low testosterone) may be responsible for the hypogonadism-associated increase in total body and intra-abdominal fat mass

A smaller study with a similar experimental design found that acute testosterone withdrawal reduced insulin sensitivity independent of body weight, whereas oestradiol withdrawal had no effects

Obesity and dysglycaemia and associated comorbidities such as obstructive sleep apnoea (Hoyos et al. 2012b) are important contributors to the suppression of the HPT axis

This is supported by observational studies showing that weight gain and development of diabetes accelerate the age-related decline in testosterone

Weight loss can reactivate the hypothalamic–pituitary–testicular axis

The hypothalamic–pituitary–testicular axis remains responsive to treatment with aromatase inhibitors or selective oestrogen receptor modulators in obese men

Kisspeptin treatment increases LH secretion, pulse frequency and circulating testosterone levels in hypotestosteronaemic men with type 2 diabetes

Several observational and randomised studies reviewed in Grossmann (2011) have shown that weight loss, whether by diet or surgery, leads to substantial increases in testosterone, especially in morbidly obese men

This suggests that weight loss can lead to genuine reactivation of the gonadal axis by reversal of obesity-associated hypothalamic suppression

There is pre-clinical and observational evidence that chronic hyperglycaemia can inhibit the HPT axis

in those men in whom glycaemic control worsened, testosterone decreased

successful weight loss combined with optimisation of glycaemic control may be sufficient to normalise circulating testosterone levels in the majority of such men

weight loss, optimisation of diabetic control and assiduous care of comorbidities should remain the first-line approach.

In part, the discrepant results may be due to the fact men in the Vigen cohort (Vigen et al. 2013) had a higher burden of comorbidities. Given that one (Basaria et al. 2010), but not all (Srinivas-Shankar et al. 2010), RCTs in men with a similarly high burden of comorbidities reported an increase in cardiovascular events in men randomised to testosterone treatment (see section on Testosterone therapy: potential risks below) (Basaria et al. 2010), testosterone should be used with caution in frail men with multiple comorbidities

The retrospective, non-randomised and non-blinded design of these studies (Shores et al. 2012, Muraleedharan et al. 2013, Vigen et al. 2013) leaves open the possibility for residual confounding and multiple other sources of bias. These have been elegantly summarised by Wu (2012).

Effects of testosterone therapy on body composition were metabolically favourable with modest decreases in fat mass and increases in lean body mass

This suggests that testosterone has limited effects on glucose metabolism in relatively healthy men with only mildly reduced testosterone.

it is conceivable that testosterone treatment may have more significant effects on glucose metabolism in uncontrolled diabetes, akin to what has generally been shown for conventional anti-diabetic medications.

the evidence from controlled studies show that testosterone therapy consistently reduces fat mass and increases lean body mass, but inconsistently decreases insulin resistance.

Interestingly, testosterone therapy does not consistently improve glucose metabolism despite a reduction in fat mass and an increase in lean mass

the majority of RCTs (recently reviewed in Ng Tang Fui et al. (2013a)) showed that testosterone therapy does not reduce visceral fat

testosterone therapy decreases SHBG

testosterone is inversely associated with total cholesterol, LDL cholesterol and triglyceride (Tg) levels, but positively associated with HDL cholesterol levels, even if adjusted for confounders

Although observational studies show a consistent association of low testosterone with adverse lipid profiles, whether testosterone therapy exerts beneficial effects on lipid profiles is less clear

Whereas testosterone-induced decreases in total cholesterol, LDL cholesterol and Lpa are expected to reduce cardiovascular risk, testosterone also decreases the levels of the cardio-protective HDL cholesterol. Therefore, the net effect of testosterone therapy on cardiovascular risk remains uncertain.

data have not shown evidence that testosterone causes prostate cancer, or that it makes subclinical prostate cancer grow

compared with otherwise healthy young men with organic androgen deficiency, there may be increased risks in older, obese men because of comorbidities and of decreased testosterone clearance

recent evidence that fat accumulation may be oestradiol-, rather than testosterone-dependent

In the setting of MetS, hypertriglyceridemia and increased WC have been reported as the most important determinants of hypogonadism

recent literature consistently associates obesity not only with higher risk of hypogonadism [4, 6, 27] but also with lower T levels

Visceral adiposity has been particularly related with reduction of T and SHBG levels (independent of other metabolic disorders)

WC was one of the MetS parameters with the greatest influence in T levels decrease, presenting itself as a strong risk factor for hypogonadism development

MetS-related T decline was not accompanied by an increase in pituitary LH levels, suggesting impairment in gonadotropin secretion

The molecules behind this smoothing compensatory effect of GnRH/LH are still unknown, but estrogens and insulin, as well as leptin, TNF-α, and other adipokines, were proposed candidates

fat stores undertake an increase aromatization of androgens, therefore raising estrogen levels [9, 15], which in turn decrease LH secretion

our data contradicts the concept that estradiol exerts a negative feedback on hypothalamic GnRH secretion

taking into account that high estradiol levels have already been described as the only abnormality in a subset of patients with ED, the hypothesis that the later might not only be caused by androgen deficiency is becoming increasingly evident

it has been reported that the chronic exposure to phosphodiesterase type 5 inhibitors (PDE5i), widely used for the treatment of ED, may influence serum estradiol levels

thyroid disorders (specially hyperthyroidism) have been related to ED and hypogonadism, and so must be considered in a sexual-dysfunction setting

It is clear from the current literature that collecting a more thorough hormonal panel might be a wise approach to further uncover hormonal relations

We concluded that in ED patients with hypogonadism and MetS, the attenuated response of HPG axis (normal or low LH levels) might not always be due to an underlying adiposity-dependent estrogen-raising effect.

our findings indicate that ED, aging, and estradiol might have a stronger connection than what is currently described in the literature.

this study underlines the importance of the collection of a full hormonal panel in ED men

the intraprostatic synthesis of testosterone from adrenal-derived precursors likely accounts for the relatively high testosterone levels in prostate after ADT

In addition, AR activity in these cells is likely further enhanced by multiple mechanisms that sensitize AR to low levels of androgens

higher affinity ligand DHT (approximately eightfold higher affinity

type 2 5α-reductase (SRD5A2) being the major enzyme in prostate

reduce DHT to 5α-androstane-3α,17β-diol (3α-androstanediol; Ji et al. 2003, Rizner et al. 2003), which is then glucuronidated to form 3α-androstanediol glucuronide by the enzymes UDP glycosyltransferase 2, B15 (UGT2B15) or UGT2B17

DHT in prostate is inactivated by the enzyme AKR1C2, which is also termed 3α-hydroxysteroid dehydrogenase type 3 (3α-HSD type 3

AKR1C1, is also expressed in prostate. However, in contrast to AKR1C2, it converts DHT primarily to 5α-androstane-3β,17β-diol (3β-androstanediol; Steckelbroeck et al. 2004), which is a potential endogenous ligand for the estrogen receptor β

Significantly, intraprostatic testosterone levels were not substantially reduced relative to controls with normal serum androgen levels, although DHT levels were reduced to 18% of controls

testosterone levels in many of the CRPC samples were actually increased relative to control tissues (Montgomery et al. 2008). While DHT levels were less markedly increased, this may have reflected DHT catabolism

testosterone suppression by GnRH agonist treatment of central precocious puberty in boys increases leptin levels

Testosterone levels decreased with increasing central obesity in healthy men, while they increase with increasing obesity in healthy women, the latter irrespective of menstrual status

this could be due to obesity-related hyperleptinemia that inhibits testosterone secretion at the testicular level.46,47 These changes, which are proposed to be components of the insulin resistance syndrome,48 are associated with increased risk for cardiovascular disease in both men and women

in the more obese subjects, the higher leptin levels due to increased adiposity might reduce secretion of testosterone

loss of regulation of leptin by testosterone in obese men and women could be an important feature of the insulin resistance syndrome

Bioavailable and free testosterone are known to correlate better than total testosterone with clinical sequelae of androgenization such as bone mineral density and muscle strength

peak levels seen in the morning following sleep, which can be maintained into the seventh decade

Samples should always be taken in the morning before 11 am

The reliable measurement of serum free testosterone requires equilibrium dialysis. This is not appropriate for clinical use as it is very time consuming and therefore expensive.

With increasing age, a greater number of men have total testosterone levels just below the normal range or in the low-normal range. In these patients total testosterone can be an unreliable indicator of hypogonadal status.

It is advised that at least two serum testosterone measurements, taken before 11 am on different mornings, are necessary to confirm the diagnosis.

Patients with serum total testosterone consistently below 8 nmol/l invariably demonstrate the clinical syndrome of hypogonadism and are likely to benefit from treatment. Patients with serum total testosterone in the range 8–12 nmol/l often have symptoms attributable to hypogonadism and it may be decided to offer either a clinical trial of testosterone treatment or to make further efforts to define serum bioavailable or free testosterone and then reconsider treatment. Patients with serum total testosterone persistently above 12 nmol/l do not have hypogonadism and symptoms are likely to be due to other disease states or ageing per se so testosterone treatment is not indicated.

Total testosterone levels fall at an average of 1.6% per year whilst free and bioavailable levels fall by 2%–3% per year.

With advancing age there is also a reduction in androgen receptor concentration in some target tissues and this may contribute to the clinical syndrome of LOH

Metabolic clearance declines with age

Gonadotrophin levels rise during aging (Feldman et al 2002) and testicular secretory responses to recombinant human chorionic gonadotrophin (hCG) are reduced

There are changes in the lutenising hormone (LH) production which consist of decreased LH pulse frequency and amplitude, (Veldhuis et al 1992; Pincus et al 1997) although pituitary production of LH in response to pharmacological stimulation with exogenous GnRH analogues is preserved

the decreases in testosterone levels with aging seem to reflect changes at all levels of the hypothalamic-pituitary-testicular axis