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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

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

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

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

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

aging in men is associated with decreases in bone mineral density (BMD) (18, 19), lean body and muscle mass

strength (22, 23) and aerobic capacity (24), as well as with increases in total and abdominal body fat, low-density lipoprotein cholesterol, and/or low-density lipoprotein/high-density lipoprotein cholesterol ratios (25, 26, 27, 28), all of which also occur in nonelderly hypogonadal men

Most (1, 5, 6, 7, 8, 9), but not all (10, 11, 12), cross-sectional studies have demonstrated a decrease, with age, in total T in men

total T, but not free T index, tended to decrease with greater BMI is consistent with prior studies showing that obesity is associated with decreases in both SHBG and total T, with an unchanged T-to-SHBG ratio

The conventional definition for T levels is statistical (values more than 2 sd below the mean), rather than functional. Such a definition does not reflect clinical realities, such as the existence of characteristic individual set points for circulating hormone levels, below which one, but not another, individual may develop metabolic changes of hormone deficiency; nor does it address the concept of reserve capacity, the possibility that persons with hormone levels 2 sd below the population mean still may have adequate hormone concentrations to meet their metabolic needs.

both T and free T index (a calculated value related to free or bioavailable T) decreased progressively at a rate that did not vary significantly with age, from the third to the ninth decades.

contrasts with other studies showing diminished free, as well as total, T in with increasing total (48) or abdominal (49) obesity in men.

Our analysis of date-adjusted T and free T index levels, by decade, showed that relatively high numbers of older men in this generally healthy population had at least one hypogonadal value (defined as below the 2.5th percentile for young men)

The issue of how properly to define hypogonadism, or indeed any hormone deficiency, remains problematic

The decrease in free T index was somewhat steeper than that of total T, owing to a trend for an increase in SHBG with age

LH for gonadal function

It would clearly be better to define the lower limit of normal for a hormone as: the blood level at which metabolic and/or clinical sequelae of hormone deficiency begin to appear, or the level below which definite benefits can be demonstrated for hormone supplementation for a significant proportion of the population

an effect of aging to lower both total and bioavailable circulating T levels at a relatively constant rate, independent of obesity, illness, medications, cigarette smoking, or alcohol intake

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

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

In obese middle-aged men, testosterone treatment reduced visceral adipocity, insulin resistance, serum cholesterol and glucose levels

testosterone replacement has a favorable impact on body mass, insulin secretion and sensitivity, lipid profile and blood pressure in hypogonadal men with the metabolic syndrome as well as type 2 diabetes mellitus

Testosterone significantly inhibits lipoprotein lipase activity, which reduces triglycerides uptake into adipocytes in the abdominal adipose tissue

testosterone treatment decreased endogenous inflammatory cytokines (tumor necrosis factor-α and IL-1β) and lipids (total cholesterol) and increased IL-10 in hypogonadal men

Testosterone treatment reduced leptin and adiponectin levels in hypogonadal type 2 diabetic men after 3 months of testosterone replacement

available data clearly show a relationship between obesity, low testosterone levels and ED

Obesity adversely affects endothelial function and lowers serum testosterone levels through the development of insulin resistance and metabolic syndrome

Metabolic disturbances as well as production of cytokines and adipokines by inflamed fat cells may be causal factors in the development of ED

The onset of ED and the associated risk of CVD may be delayed through lifestyle modifications that affect obesity, such as diet and exercise

Very low testosterone levels contribute to the development of ED in obesity, metabolic syndrome and type 2 diabetes mellitus

Obesity is associated with low total testosterone levels that can be explained at least partially by lower sex hormone-binding globulin (SHBG) in obese men

epidemiological studies have shown a negative correlation between BMI and total testosterone and to a lesser extent with free and bioavailable (biologically active) testosterone levels

The Boston Area Community Health Study reported that 5.6% of men aged 30 to 70 were hypogonadal, as defined by total serum T < 300 ng/dL; or, free serum T < 5 ng/dL plus 3 or more symptoms of hypogonadism

In a health screening project among 819 men in Taiwan, the prevalence of hypogonadism (total serum T < 300 ng/dL) ranged from 16.5% for men in their 40s, 23.0% for men in their 50s, 28.9% for men in their 60s, and 37.2% for men older than 70 years of age

The prevalence of hypogonadism among men in Taiwan is higher than the prevalence reported in the Massachusetts Male Aging Study

CAG repeat sequence, within the androgen receptor (AR). Rajender et al[12] reviewed over 30 studies on the AR trinucleotide repeat and infertility

suggestion that CAG repeat length may determine androgen responsiveness, this issue is not clearly settled

reported prevalence of low T in older men range from 5.6% to 50%

Those in the hypogonadal group (n = 4269) had direct health care costs, that exceeded the eugonadal group (n = 4269) by an average of $7100 over the course of the observation window

higher economic burden and presence of co-morbidities for hypogonadism

minor to moderate improvements in lean mass and muscle strength

increased bone mineral density

modest enhancement in sexual function

reduced adiposity

lessening of depressive symptoms

Meta-analyses of clinical TRT trials as of 2010 have identified three major adverse events resulting from TRT: (1) polycythemia; (2) an increase in prostate-related events; and (3) and a slight reduction in serum high-density lipoprotein (HDL) cholesterol

polycythemia (> 3.5-fold increase in risk

TRT produced a 40% prostate enlargement in older hypogonadal male Veterans over 12 mo

no published analysis has reported measurable increases in prostate cancer risk or Gleason score in men undergoing TRT, or in hypogonadal men with a history of prostate cancer undergoing TRT

the prostate which highly expresses the type II 5α-reductase enzyme. Inhibition of this enzyme via finasteride (a type II 5α-reductase inhibitor) or dutasteride (a dual type I and II 5α-reductase inhibitor) reduces circulating DHT 50%-75% and > 90%, respectively[47], and reduces prostate mass[48] and prostate cancer risk

Normally estradiol partially regulates testosterone levels, at the hypothalamus, blunting LH and FSH release from the pituitary. As a selective estrogen receptor modulator, CC interrupts this pathway, and consequently there is a greater stimulation for the production of testosterone in Leydig cells