Body Composition, Metabolic Syndrome and Testosterone in Aging Men

C A Allan; B J G Strauss; R I McLachlan

Disclosures

Int J Impot Res. 2007;19(5):448-457. 

In This Article

Testosterone and Body Composition

Skeletal Muscle, Fat-free Mass and Lean Body Mass

The term lean body mass is often used synonymously with fat free mass. Lean body mass measurements were originally derived from total body potassium measurements based on the assumption that potassium was distributed only in non-fat tissues. The subsequent development of more precise methods of estimating FM directly, for example, dual X-ray absorptiometry (DEXA), has allowed the determination of FM and therefore FFM. In practice, lean body mass and FFM measurements give similar results.[23] Skeletal muscle mass can then be calculated from FFM measurements.

Studies in established androgen deficiency states. Congenital or acquired (as a result of disease states or induced experimentally) hypoandrogenism is associated with a decline in FFM and skeletal muscle.[9] Adult men with acquired hypogonadism, but otherwise in good health, have lower FFM than age-matched eugonadal controls,[10] and young men subjected to short-term hypoandrogenism induced by the administration of a gonadotrophin releasing hormone (GnRH) analogue demonstrate a decrease in FFM and a reduction in the rate of protein synthesis.[24] Older men undergoing androgen deprivation for treatment of prostate cancer also experience a decrease in lean body mass and muscle size.[25] Testosterone replacement in hypogonadal men increases lean muscle mass (as defined by CT)[10] and muscle size (quantified by magnetic resonance imaging (MRI)).[26] Muscle strength is also increased significantly with testosterone replacement.[26] In a further study of hypogonadal men (who had not received testosterone therapy for at least 2 years before enrollment in the trial), 6 months of testosterone treatment was associated with a 15% increase in FFM and a 20% increase in muscle mass.[27] The effects of testosterone administration on FFM in hypogonadal men have been summarized by Bhasin,[28] with increases of 1--5 kg being evident, dependent upon baseline serum testosterone and the dose and duration of the testosterone treatment regimen. The importance of testosterone dose on the magnitude of increase in skeletal muscle was clearly demonstrated in a study of healthy young men with experimentally induced hypogonadism in whom increases in FFM and muscle volume were directly proportional to the dose of testosterone administered and serum testosterone concentration.[29] In this study, the doses of intramuscular testosterone ranged from sub-physiological to clearly supra-physiological, and despite achieving serum total testosterone (TT) levels >80 nM, no plateau effect on increasing FFM was identified. Furthermore, supra-physiological doses of testosterone administered to eugonadal men have been shown to significantly increase FFM, muscle size and strength.[30]

The effects of testosterone supplementation in the ageing male. The description of age-related sarcopaenia in the setting of the decline in serum testosterone in older men, and the knowledge that testosterone replacement increases FFM and muscle volume in young hypogonadal men, has led to the hypothesis that testosterone therapy in older men will increase FFM and skeletal muscle and may subsequently improve quality of life by increasing strength and stability. The largest placebo-controlled trial to test the hypothesis that testosterone supplementation in the older male will improve muscle mass and/or strength found that over 36 months of treatment, an increase in mean serum testosterone from 12.7 to 21.7 nM led to a 1.9 kg (3.5%) increase in lean mass; linear regression analysis showed an inverse relationship to pretreatment testosterone levels.[31] There was no demonstrable effect on dynamometric measures of muscle strength, although subjects with the lowest baseline testosterone levels reported that they perceived their physical performance to be improved. Other placebo-controlled trials have documented increases in lean body mass of 1.5--4.0 kg ( Table 1 ). In the majority of these studies, baseline testosterone levels have been in the low normal young adult range and increased to within the upper part of the reference range. Duration of therapy may be important in predicting the magnitude of demonstrable effect,[32] and greater increases in lean body mass are seen in those studies employing supra-physiological androgen treatment regimens.[33,34,35] This is consistent with a recent study of graded doses of testosterone administered to healthy older men (rendered hypogonadal with a long-acting GnRH agonist) who, akin to the younger cohort previously studied,[29] demonstrated a dose-dependent increase in FFM, with no evidence of a plateau effect;[36] the observed magnitude of increase in FFM was comparable for the young and older men (+7 to 8 kg or 12% increase from baseline). Of note, older men had a greater increase in serum testosterone than young men at set doses of testosterone, suggesting that older men have reduced testosterone clearance and may therefore potentially experience an enhanced tissue effect at a given testosterone dose. The increase in lean body mass has been linked to a decrease in muscle protein breakdown[35] and an increase in muscle protein synthesis.[37] Functional correlates of this increase in muscle mass are uncertain,[38] although measures of muscle strength assessed in short-term studies do suggest benefits with treatment.[39,40,41] Dihydrotestosterone[42] and human chorionic gonadotrophin (hCG)[43] over a 3-month period have also demonstrated improvement in selected aspects of muscle strength. While the favourable changes in FFM consistently demonstrated in short-term controlled studies may have important sequelae with regard to physical functioning, to date only surrogate predictors (strength, activity) of the desired end effects (for example, independent living, prevention of falls) have been studied.

Fat Mass and Regional Adipose Tissue Distribution

Studies in established androgen deficiency states. In parallel with the decrease in FFM seen in hypogonadal men, there is also an increase in FM. In a study of men aged 22--69 years (mean age 53 years), hypogonadal subjects had 26% body fat compared to 19% in eugonadal men.[10] Similarly, induced hypogonadism (with a GnRH analogue) in young men resulted in a 1 kg increase in body fat over 10 weeks (body fat increased from 19 to 22%).[24] In older men with prostate cancer (and 22% body fat at baseline), the induction of profound hypogonadism resulted in a 9% increase in body fat after 48 weeks.[25] With respect to the role of testosterone replacement in otherwise healthy but hypoandrogenic men, the effects on FM were less marked than for the corresponding increase in lean body mass or FFM. Some studies have shown 10--15% decreases in FM with testosterone,[10,27] with the decreases in FM correlated to the changes in serum testosterone.[44] Others however have failed to find a significant decline in FM[26] even with high-percentage body fat at baseline and an equivalent or longer treatment duration.[11,41] Those studies failing to find a decrease in FM did not address the issue of regional fat distribution.

Quantitative CT analysis of hypogonadal men (mean age 52 years) has shown that they have a greater subcutaneous fat area and a trend towards an increased visceral fat area when compared to age-matched eugonadal men.[45] Testosterone replacement, in addition to decreasing FM (as above), decreased subcutaneous fat by 12% and visceral fat by 6%.[10] Young men downregulated with GnRH and administered increasing doses of intramuscular testosterone[46] had a 20--40% increase in FM at sub-physiological testosterone replacement doses and a significant 10% decrease in FM at the highest (supra-physiological) testosterone dose. Abdominal subcutaneous fat volume (as quantified by MRI) increased at the lowest testosterone doses and the change in both subcutaneous and intra-abdominal (visceral) fat was negatively correlated with testosterone dose and serum testosterone concentration. Changes in fat distribution with both lowering and elevating serum testosterone were evenly distributed between the trunk and the appendices.

The effects of testosterone supplementation in the ageing male. Ageing is associated with increase in FM; the pattern of distribution of adipose tissue is also altered, with more marked increases in visceral as compared to subcutaneous FM. Furthermore, middle-aged men with visceral adiposity have lower serum total and free testosterone and sex hormone binding globulin (SHBG) levels than their peers without excess abdominal adipose tissue (as determined by CT).[47]

Placebo-controlled trials of testosterone therapy in ageing men have shown decreases in FM ranging from 1 to 4.5 kg in studies of 3--36 months duration ( Table 2 ). In studies of 36 months duration,[31,32] the magnitude of fat loss was greatest within the first 6 months of treatment, but unlike the increase in lean body mass, which plateaued after this time, the decrease in FM continued, albeit at a reduced rate. In these studies, a 70%[31] or greater[32] increase in mean serum testosterone from baseline readings of 12.7 nM[31] and 9.9 nM[32] led to 2.9 kg (12%) and 4.5 kg (16%) decreases in FM, respectively. A positive correlation between the change in FM and serum testosterone was seen in the Page et al.[32] study. Smaller decreases in FM are seen after 6--12 months of testosterone supplementation in older eugonadal men[35,39,48,49] and following 90 days of treatment in overweight/obese hypogonadal older men.[50] Synthetic androgens (oxandrolone, oxymetholone) are associated with greater loss of FM than is native testosterone in short-term studies.[34,51]

In each of the studies in Table 2 , the mean baseline BMI of enrolled subjects was in the overweight range, thus making it likely that they included men with BMIs ranging from normal to obese. There are no studies, however, that have reported the observed change in FM as a function of baseline BMI. The magnitude of the decrease in FM identified in these studies may also be influenced by baseline serum testosterone, as noted in the 12-week study of oxandrolone therapy,[51] wherein men with baseline serum testosterone <10.4 nM had a significantly greater loss of FM than subjects with baseline serum testosterone >10.4 nM (-2.5 vs -1.5 kg; P=0.04).

Further to the reduction in total FM that has been consistently demonstrated, several studies have examined the effects of androgen supplementation on regional fat loss. Testosterone supplementation (oral for 8 months, transdermal for 9 months) of middle-aged men with mean BMI 29 kg/m2 and abdominal obesity (and serum testosterone levels within the normal range) decreased visceral adiposity by 5--10% (0.4--0.6 kg), as assessed by CT, although total body fat (by total body potassium calculations) and subcutaneous adipose tissue mass (by CT) did not change.[52,53] These findings were not able to be replicated with dihydrotestosterone (DHT),[54] and a further study of similar duration using intramuscular testosterone could not reproduce these results despite selecting for obese subjects.[55]

Regional DEXA examinations in one study of older men showing significant loss of FM with testosterone treatment suggested that this loss was significant only in the appendices and not within the trunk.[31] More detailed analyses of regional adipose tissue distribution have yielded conflicting reports of the effects of androgens. Older eugonadal (baseline serum testosterone 15.3 nM) men with a mean BMI 26 kg/m2 treated with intramuscular testosterone for 6 months had a non-significant 10% decrease in subcutaneous abdominal fat area, with no change in visceral or total intra-abdominal fat (at the level of L4--L5 on MRI);[56] similarly, transdermal testosterone administered for 24 months to men with median BMI 28 kg/m2 did not decrease visceral fat on CT examination.[57] Studies of 17-alkylated androgens (oxymetholone and oxandrolone) have shown both preferential loss of truncal FM[34] and an equivalent loss in both the trunk and the appendices.[51] Within the abdomen, both subcutaneous and visceral fat areas were decreased (as determined by a single MRI slice at the level of L4--L5), although neither change was significant when compared to change within the placebo group.[51] The change in subcutaneous fat area was greater in those men with lower baseline testosterone levels (<10.4 nM). Finally, dehydroepiandrosterone (DHEA) administered for 6 months to eugonadal, ageing overweight men resulted in a decrease in both visceral and subcutaneous abdominal fat, as analysed by cross-sectional MRI scans;[58] treatment resulted in an 8% increase in serum testosterone levels.

A major deficiency in the literature is that there have been no studies of androgen replacement in older men that have examined the effects of treatment on visceral or subcutaneous fat area as a function of baseline adiposity and none has examined abdominal fat (visceral, subcutaneous) volumes.

One of the most important considerations when assessing the influence of testosterone on FM and visceral fat, in particular, is the potential to modify lipid metabolism and insulin sensitivity. These data are reviewed below.

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