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Several longitudinal studies demonstrate a similar association with a low testosterone concentration independently predicting the future development of insulin resistance, MetS and T2DM Haffner et al. The causality of this relationship between low testosterone and metabolic disease is unclear with obesity-induced androgen deficiency and hypogonadism-induced obesity both likely contributing to a bidirectional effect on disease pathology.

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Indeed, increased body fat is a well-known clinical feature of hypogonadism, and men with MetS at baseline are at an increased risk of developing hypogonadism based on an year follow-up Laaksonen et al. The finding that obesity impairs testosterone levels while low testosterone levels promote increased fat deposition was initially proposed as the hypogonadal—obesity cycle hypothesis by Cohen Thus, with higher adipocyte expression of aromatase comes a subsequent reduction of circulating testosterone.

Falling testosterone promotes increasing adipocyte number and fat deposition, which gradually leads to a further lowering effect on testosterone levels. In addition, the majority of the normal negative feedback of testosterone on the hypothalamo—pituitary axis occurs via its aromatisation either in peripheral adipose tissue or centrally to E 2 Hayes et al.

Therefore, the excess aromatase activity from increased adipocyte numbers in obese men results in the suppression of gonadotrophin-mediated testosterone secretion leading to progressive hypogonadism. The hypogonadal—obesity—adipocytokine hypothesis Fig.

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This, in turn, reduces gonadal stimulation and inhibits testosterone release, thus causing a state of hypogonadotrophic hypogonadism. Leptin, an adipose-derived hormone with a well-known role in regulation of body weight and food intake, also induces LH release under normal conditions via stimulation of hypothalamic GNRH neurons. Kisspeptins are peptides secreted by specific neurons in the hypothalamus and may provide the functional link between leptin and downstream gonadal regulation as they play a central role in the modulation of GNRH secretion and subsequent LH release.

In human obesity, whereby adipocytes are producing elevated amounts of leptin, the hypothalamic—pituitary axis becomes leptin resistant Isidori et al. In addition, oestrogen receptors ERs are demonstrated on kisspeptin neurons and there is evidence from animal studies that leptin resistance, inflammation and oestrogens inhibit neuronal release of kisspeptin see George et al.

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 Isidori et al.

Moreover, 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 Pitteloud et al. High aromatase activity in adipocytes converts testosterone to oestradiol 1. Reduced tissue testosterone facilitates triglyceride storage in adipocytes by allowing increased lipoprotein lipase activity 2 and stimulating pluripotent stem cells to mature into adipocytes blue arrow.

Increased adipocyte mass is associated with greater insulin resistance 3. Kisspeptin neurons are inhibited by oestradiol, inflammation and leptin resistance and thus reduce GNRH stimulation of the pituitary and subsequent LH release. Reduced LH pulse decreases gonadal stimulation and testosterone release, thus causing a state of hypogonadotrophic hypogonadism.

Furthermore, leptin also directly inhibits the stimulatory action of gonadotrophins on the Leydig cells of the testis to decrease testosterone production. Citation: Journal of Endocrinology , 3; 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 Keating et al.

Non-diabetic men undergoing androgen ablation show increased occurrence of new-onset diabetes and demonstrate elevated insulin levels and worsening glycaemic control Keating et al. Prostate cancer patients with pre-existing T2DM show a further deterioration of insulin resistance and worsening of diabetic control following ADT Haider et al. The authors conclude that abdominal obesity and hyperglycaemia in relation to low testosterone were responsible for this higher prevalence, predisposing ADT patients to higher cardiovascular risk. Kapoor et al. Once fortnightly i.

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It is important to recognise that this benefit is similar to that of metformin, a first-line drug in the treatment of T2DM. Testosterone replacement has also been demonstrated to improve glycaemic control in some other studies in men with uncontrolled diabetes but these were not placebo controlled Boyanov et al.

One of these trials did compare the effects of a diet and exercise programme with the same programme in combination with testosterone replacement in hypogonadal newly diagnosed men with T2DM Heufelder et al. This study found a greater benefit on glycaemic control with testosterone replacement than those with diet and exercise alone. A benefit on HbA1c of testosterone therapy compared with placebo was observed after 9 months but not earlier Jones et al.

Chronic cardiac failure is associated with a state of insulin resistance and also of testosterone deficiency. TRT improves the insulin resistance but has no effect on body weight Malkin et al. The response to testosterone replacement of insulin sensitivity is in part dependent on the androgen receptor AR. There was no effect of transdermal TRT on hepatic insulin clearance in testosterone-deficient men Basu et al.

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In the double-blinded placebo-controlled Moscow study, men suffering from both MetS and hypogonadism showed significant decreases in weight, BMI and waist circumference following 30 weeks of testosterone replacement to the normal range Kalinchenko et al. Circulating lipid profiles are linked with obesity as central body fat is associated with altered lipoprotein ratios and composition, contributing to the risk of atherosclerosis James et al.

This highlights the need for careful management of hyperlipidaemia in the prevention of cardiovascular events Jones b. Additionally, a positive correlation between serum testosterone and HDL has been reported in both healthy and diabetic men Simon et al. In contrast to these studies, however, Khaw et al. A few cross-sectional studies, however, have found no association between serum lipid measurements and endogenous testosterone Kiel et al.

The majority of data from studies investigating TRT in hypogonadal and eugonadal men show some improvements in lipid and lipoprotein profiles. Indeed, meta-analysis of clinical trials in hypogonadal men report that significant reductions in total cholesterol and LDL-C are associated with intramuscular TRT Whitsel et al.

Heufelder et al. Similarly, over a 1-year period of testosterone replacement, HDL levels were reported to increase in men with MetS Saad et al. The majority of studies on the effect of testosterone on HDL-C, however, have generated contradictory results with either a decreases Thompson et al. A long-term TRT investigation may support this hypothesis by demonstrating that after an initial fall in their serum concentrations, HDL-C levels return to baseline levels after 12 months Jones et al.

The mechanisms linking testosterone with insulin resistance and T2DM are still not fully understood and there are few published papers that have investigated potential mechanisms by which testosterone increases insulin sensitivity and regulates glucose and lipid metabolism. The major insulin-responsive target tissues, such as skeletal muscle, liver and adipose tissue, inadequately respond to the physiologic effects of circulating insulin in T2DM. 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.

In turn, this lipid accumulation contributes to impaired insulin responsiveness and abnormalities in glucose control Fig.

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Indeed, fat in liver and muscle correlates more strongly with insulin sensitivity than abdominal fat in rats Lim et al. A growing body of studies has pointed to the presence of heterogeneity regarding insulin resistance and insulin sensitivity among different tissues Stumvoll et al. Chronic excessive dietary fat and carbohydrate intake coupled with a decrease in energy expenditure leads to a sustained rise in circulating free fatty acids FFA and blood glucose concentration.

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Excess FFA yellow arrows are incorporated into adipocyte triglyceride storage increasing visceral and subcutaneous fat mass. With accumulation of intramyocellular lipid, insulin-mediated skeletal muscle glucose uptake and utilisation is impaired along with decreased glycogen synthesis and lipid oxidation. As a result, excess glucose is diverted to the liver. In the liver, increased liver lipid also impairs the ability of insulin to regulate gluconeogenesis and activate glycogen synthesis. Hepatic lipogenesis further increases lipid content and can lead to hepatic steatosis.

Impaired insulin action in the adipose tissue allows for increased lipolysis, which additionally promotes re-esterification of lipids in other tissues such as liver and muscle and further exacerbates insulin resistance. At the same time, adipose-derived inflammatory mediators contribute to the development of tissue insulin resistance dark blue arrows. Hyperglycaemia ensues. Testosterone deficiency contributes to tissue-specific mechanisms involved in the development of insulin resistance in liver, adipose and muscle tissue and promotes inflammation green arrows.

TRT may potentially improve the negative consequences of tissue-specific insulin insensitivity and improve metabolic function. AA Ramirez et al. Currently, however, little is known regarding the influence of testosterone on insulin action in skeletal muscle and the subsequent consequences on glucose metabolism and T2DM. It has been long known that castration is followed by decreased muscle glycogen levels in rat perineal and levator ani muscles and that the administration of testosterone induces a considerable increase in glycogen content Leonard , Apostolakis et al.

An equal increase in skeletal muscle glycogen synthesis is apparent in castrated male rats supplemented with testosterone, diminishing the elevated blood glucose levels seen in untreated controls Ramamani et al. A testosterone-induced increase in glycogen synthase activity was implicated for the alteration in the rate of glycogen synthesis from blood glucose. Concurrently, testosterone administration returned the enhanced glycogen phosphorylase activity in castrated rats to a normal level, thus reducing glycogen breakdown and the subsequent rise in free glucose.

By contrast, the rate of glycogenesis was shown to be depressed by testosterone in rat skeletal muscle with increased glycogen content postulated rather as a result of decreased glycogenolysis Bergamini In perineal muscle, however, glycogenesis was increased in response to testosterone, suggesting differential mechanisms in different tissue locations. Insulin-stimulated glucose uptake into muscle and adipose tissue is largely mediated by the Glut4 glucose transporter isoform.

Under normal resting conditions, most of the Glut4 molecules reside in membrane vesicles inside the cell. To increase glucose transport, GLUT4 translocates to the cell membrane in response to insulin via signalling through the insulin receptor, subsequent binding of insulin receptor substrate 1 IRS1 and activation of intracellular signalling pathways Bryant et al. In agreement with androgen action on glucose control, GLUT4 and IRS1 were up-regulated in cultured adipocytes and skeletal muscle cells following testosterone treatment at low dose and short-time incubations Chen et al.

Sato et al. Additionally, testosterone increased phosphorylation of Akt and protein kinase C PKC , as key steps in the insulin receptor signalling pathways for regulation of GLUT4 translocation Sato et al. These effects were blocked by a dihydrotestosterone DHT inhibitor, suggesting that local conversion of testosterone to DHT and activation of AR may be important for glucose uptake.