Testosterone Shbg And Obesity

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Table 2

Correlations Between Sex Hormone-Binding Globulin and Measures of Adiposity in Men

Relation Between Sex Hormone-Binding Globulin and

Author No. of Men Body Mass Index Waist-to-Hip Ratio

Table 2

Correlations Between Sex Hormone-Binding Globulin and Measures of Adiposity in Men

Relation Between Sex Hormone-Binding Globulin and

Author No. of Men Body Mass Index Waist-to-Hip Ratio

Stefanick (177)

73

-0.26

-0.37

Seidell (50)

23

-0.33

-0.54

Haffner (14)

178

-0.18

0.03

Longcope (60)

1563

-0.26

-0.22

Tchernof (178)

80

-0.42

-0.32

determine whether visceral fat is more closely linked to low testosterone than is total body fat, but results have been conflicting (26). Glass et al. (25) also first noted that low testosterone levels in obese men could be partly explained by a decrease in SHBG, but whether SHBG is more highly correlated with abdominal obesity or with body mass index remains controversial. A summary of several studies reporting cross-sectional correlations between SHBG and body mass index and waist-to-hip ratio (WHR) is found in Table 2. In massively obese men, weight loss after bariatric surgery can reverse the SHBG abnormalities when near-normal body weight is achieved (27).

Whereas a low level of SHBG is the major reason for low testosterone levels in mild to moderately obese men, free and non-SHBG-bound testosterone levels are also reduced in massive obesity (28,29) and correlate inversely with body mass index (30). The testosterone response to human chorionic gonadotropin (hCG) stimulation is normal in obesity (25), implying that Ley dig cell function is impaired because of gonadotropin insufficiency. Blood sampling every 10 min for 12 h in 8 massively obese men revealed lower mean luteinizing hormone (LH) levels and pulse amplitude than in controls, whereas pulse frequency (6.3/12h) was comparable in both groups (31). In moderately obese men (mean 127% above ideal body weight), by contrast, 24-h mean LH levels were similar, and follicle-stimulating hormone (FSH) levels were lower than in controls (32).

Reduced LH pulse amplitude may be explained by decreased gonadotropin-releas-ing hormone (GnRH) production or by reduced pituitary responsiveness to GnRH. A leading hypothesis is that reduced LH pulse amplitude in obesity results from increased estrogen production, because estradiol suppresses the pituitary LH response to GnRH stimulation in males (33). Testosterone is converted to estradiol by aromatase P450, the product of the CYP19 gene (34). Aromatase is expressed in Leydig cells where it is upregulated by LH/hCG (35); however, most of the estrogen in men is from aromatase in adipose and skin stromal cells, with a lesser contribution from aortic smooth muscle cells, kidney, skeletal cells, and the brain. The promoter sequences of the P450 aromatase genes are tissue specific because of differential splicing, but the translated protein is the same in all tissues. The conversion of androstenedione to estrone was more than 10-fold greater in the upper thigh, buttock, and flank than in the breast, lower thigh, abdomen, or omentum (36). Thus, aromatase may be increased in obesity because of increased subcutaneous adipose tissue mass, or adipose-derived factors could upregulate aromatase in selected tissues. Through either mechanism, increased bioconversion of androgens to estrogens could cause LH pulse amplitude to decrease.

The plasma concentration of estradiol in normal adult men is 20-40 pg/mL, and its production rate in blood is 25-40 ^g/24 h; both of these values are higher than in postmenopausal women. Mean serum estrone and estradiol levels are elevated in obese men (29,37), and urinary estrone and estradiol production rates were positively correlated to percent above ideal body weight (37). Moreover, FSH, LH, and testosterone levels rose normally when obese men were treated with the antiestrogen clomiphene for 5 d (37). However, in the aforementioned study showing reduced LH pulse amplitude in massive obesity, estradiol levels were comparable in men with mild and moderate obesity (38).

In addition, Stanik et al. (39) found that circulating estrone levels fell and total testosterone levels increased in obese men with weight loss, although another study did not confirm these results (26). In the study by Stanik et al. (39), obese men lost weight because they consumed a 320-kCal liquid diet. With prolonged dieting, the free testosterone concentration declined and SHBG was unchanged. Gonadotropins were not studied, and this research is open to various interpretations insofar as caloric deprivation also reduces LH secretion in men (40), which would affect testosterone and estra-diol production.

Men with Cushing's syndrome have central obesity and are generally hypogonadal (41). Glucocorticoids suppress GnRH transcription (42), suggesting that the hypogo-nadotropic hypogonadism of obese men could also be explained by hypercortisolemia. However, studies of cortisol production in obese men have produced mixed results (43). Leptin, a cytokine-like product of adipocytes, is secreted into the circulation in proportion to the body mass index. Gonadotropin deficiency in leptin-deficient mice and humans, together with gonadotropin stimulation by leptin treatment, is consistent with an action of leptin to stimulate GnRH. On the other hand, leptin suppressed testosterone secretion by testicular slices and blocked hCG upregulation of SF-1, StAR, and P450scc (44). Excess leptin could contribute to low testosterone levels in obesity through the latter mechanism.

The relationship between low testosterone and obesity is bidirectional. Bjorntorp (43) has proposed that hypogonadism predisposes to central obesity and insulin resistance in men. In support of this idea, Becker et al. (45) reviewed the clinical records of 50 hypogonadal men with Klinefelter syndrome seen at the Mayo Clinic, and reported in 1966 that 50% were obese as adults. Furthermore, men with prostate cancer who were receiving androgen deprivation therapy with GnRH analogs had a higher fat mass by dual energy x-ray absorptiometry (DEXA) scan than did age-matched men with nonmetastatic prostate cancer who were postprostatectomy and/or radiotherapy or age-matched normal men (46). In a longitudinal study, fat mass increased 5% (from 20.2 + 9.4 to 21.9 + 9.6 kg) after 3 mo of androgen-deprivation therapy (47). In a study of healthy Japanese American men, lower baseline total testosterone predicted an increase in intraabdominal fat (48). Finally, testosterone replacement of middle-aged men with central obesity reduced visceral fat measured by computed tomography scan without affecting subcutaneous fat (49).

Although there are many studies of low testosterone, only one study (32) includes data on sperm output in obese men. In that study, a semen sample was provided by 16 obese men who were 52-332% above ideal body weight. Ejaculate volumes ranged from 0.5 to 4.0 mL. The mean sperm count was 46 million/mL (95% confidence limits 10-200 million), and the percent motile forms was 69% ± 18%. The authors concluded that spermatogenesis is normal in obese men.

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  • Bingo
    Can a high sex hormone binding globulin cause a low pulse ox/?
    7 years ago

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