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Unlike the situation in women, in men there is an inverse relationship between serum testosterone levels and visceral fat mass. The visceral obesity in men is associated with relative hypogonadism. Obesity itself is one of the several conditions that can result in a low SHBG level.
[43] In the HERITAGE Family Study, increasing total body fat content and visceral adiposity were associated with decreased plasma levels of SHBG.
[44] As a result, total testosterone is frequently low but the free testosterone is normal, suggesting that this not a true clinical hypogonadism.
[43] This is generally seen in moderate obesity.
By contrast, other studies have shown that free testosterone levels are low in obese individuals (
Table 2 ) and the relative hypogonadism is proportional to the degree of obesity.
[45] Abdominal or upper body obesity is more strongly related to free testosterone levels than other forms of obesity. Haffner
et al.[46] found, in a population of 178 men recruited to the San Antonio Heart Study, that BMI was inversely related to total and free testosterone as well as SHBG level. Waist/hip ratio was also strongly inversely related to total and free testosterone. Similarly, Abate
et al.[47] showed that subcutaneous fat accumulation in the truncal area is highly predictive of low plasma concentrations of free testosterone. Studies by Seidell
et al.[48] and Phillips
[49] have also reported that waist/hip ratio in men was significantly inversely correlated with total testosterone, free testosterone and SHBG levels. Pasquali
et al.,
[50] on the other hand, found a significant inverse relationship between BMI and both total and free testosterone and SHBG but no association between waist/hip ratio and any sex hormone or binding protein.
The prevalence of obesity in ageing men has increased and is a strong predictor of the testosterone deficiency seen in ageing males. Hypogonadal men also have a reduced lean body mass and an increased fat mass. Vermeulen
et al.[51] reported in a study of 57 men between 70 and 80 years that testosterone levels correlated negatively with percentage of body fat, abdominal fat and insulin levels. Chang
et al.[52] also showed that elderly men with type 2 diabetes had higher BMI, waist/hip ratio and lower serum testosterone levels than elderly men without type 2 diabetes. Testosterone levels correlated negatively with BMI, waist/hip ratio and skinfold thickness.
The changes in total and free testosterone concentrations are reversible with weight loss. Strain
et al.[53] assessed the effect of weight loss on sex hormones in 11 healthy obese men. Weight loss of between 26 and 129 kg over 5–39 months produced significant increases in mean plasma total and free testosterone and SHBG levels. The increases in plasma free and total testosterone and SHBG levels were also proportional to the degree of weight loss. Similar Results have also been reported in other smaller studies.
[54]
The underlying mechanisms responsible for the reduced testosterone levels in obese men are unknown. The reduction in free testosterone seen in massive obesity is not accompanied by a reciprocal increase in LH, suggesting a form of hypogonadotrophic hypogonadism.
[54] One hypothesis postulated for the decreased free testosterone in massively obese individuals is functional alterations at the hypothalamicpituitary level of the testicular axis characterized by decreased amplitude of the LH pulses.
[43] Some rare hypothalamic syndromes, such as Prader–Willi syndrome, are associated with both obesity and hypogonadotrophic hypogonadism.
Another possible mechanism to explain the aetiology of low testosterone levels and the subsequent insulin resistance in obese men is hyperoestrogenemia. Earlier studies found increased serum levels of oestradiol and oestrone in obese men.
[55] This primarily occurs as a result of increased peripheral conversion of androgens to oestrogens through the action of the enzyme aromatase, which is present in higher levels in the adipose tissue as compared to other tissues. This increase in serum oestrogen concentration is, however, not accompanied by overt signs of feminization. It is thus possible that the increased oestradiol levels contribute to the insulin resistance in obese men. Phillips
et al.[56] found in 80 adult men that both total and free testosterone correlated inversely, and the ratio of oestradiol to testosterone directly, with insulin levels. However, after controlling for visceral adipose tissue, only the oestradiol to testosterone ratio and insulin concentration remained significant. Similarly, another study found higher oestradiol levels in diabetic subjects compared to the nondiabetic ones.
[57] A small study of six obese men treated with the aromatase inhibitor testolactone showed a decrease in oestradiol and an increase in testosterone levels.
[58] However, others have found no relationship between oestradiol concentrations and glucose or insulin levels or insulin resistance.
[59] Administration of ethinyl oestradiol to normal men has been reported to induce insulin resistance.
[60] There are case reports of two men, one with oestrogen resistance caused by a mutation of the oestrogen receptor alpha gene
[61] and another with low oestradiol and elevated testosterone levels as a result of a mutation in the aromatase gene.
[62] These men had glucose intolerance and insulin resistance.
At the cellular level, adipocytes express androgen receptors.
[63] Testosterone inhibits the activity of lipoprotein lipase, the main enzymatic regulator of triglyceride uptake in adipose tissue.
[64] This Results in inhibition of triglyceride uptake, increase in lipid mobilization and a subsequent decrease in visceral adipose tissue mass (Fig. 3). In the ageing male the natural diminution in testosterone is contributory to visceral adiposity. Furthermore, the relative hypogonadism produced in abdominally obese men also contributes to an increase in fat mass. Tsai
et al.[65] reported that a low baseline total testosterone level in Japanese-American men predisposed to an increase in visceral adiposity.