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

Metabolic Syndrome

Although there remains debate about the existence and definition of the term metabolic syndrome,[59,60] it has found wide usage in describing that cluster of cardiovascular risk factors comprising abdominal adiposity, atherogenic dyslipidaemia, elevated blood pressure and elevated glucose (as an indicator of insulin resistance). The two most accepted criteria for the diagnosis are those of the United States Adult Treatment Panel III of the National Cholesterol Education Program (ATP III)[61] and the International Diabetes Federation (IDF).[62] A major difference between these criteria is the necessity of an elevated waist circumference (set according to ethnicity) by the IDF, underscoring the integral role played by visceral adiposity in the metabolic syndrome. The impact of testosterone therapy in modifying abdominal adiposity has been discussed above and its role in modifying other cardiovascular risk factors is reviewed in the following sections.

Relationship of Endogenous Testosterone to Markers of Cardiovascular Risk in Ageing Men

When considering the association between serum testosterone and cardiovascular risk factors, it is important to be aware that the precise nature of the relationship between testosterone and individual cardiovascular risk factors may be obscured by failure to control for other related variables, for example, not controlling for BMI when investigating the relationships between testosterone and glycaemia and hyperlipidaemia. A study of middle-aged men classified by TT levels (10 vs 20 nM) found that systolic blood pressure, fasting glucose and total and low-density lipoprotein (LDL) cholesterol levels were inversely related to testosterone, but after adjusting for measures of adiposity and insulin resistance, only insulin levels and triglycerides remained significantly correlated with testosterone.[63] Negative correlations between testosterone and hypertension,[64] fasting plasma glucose,[65] hyperinsulinaemia[63] and visceral adiposity[66] are documented, and there is an uncertain association with high-density lipoprotein (HDL) cholesterol.[67,68] Overall, the observational evidence suggests a neutral or beneficial effect of endogenous testosterone on cardiovascular risk factors in middle-aged and older men.[69]

The effects of testosterone therapy on markers of cardiovascular risk in ageing men

Hypertension. Testosterone therapy does not influence systolic or diastolic blood pressure readings in placebo-controlled trials. More detailed information about blood vessel function, specifically endothelial dysfunction, can be obtained by the technique of flow-mediated dilatation (FMD).[70] FMD measured in the brachial artery has a 95% positive predictive value for coronary artery endothelial dysfunction.[71] It declines with age in men,[72] although the relationship to serum testosterone is uncertain.[73] In eugonadal middle-aged men with coronary artery disease, supraphysiological doses of testosterone, administered intravenously, increased coronary blood flow.[74,75] Three randomized controlled trials (RCTs) in older men with low-normal serum testosterone have examined the effect of physiological androgen replacement on vascular reactivity.[42,76,77] No change in FMD was seen with 3 months of DHT[42] or hCG[76] or with 12 months of transdermal testosterone.[77] FMD was increased with short-term physiological and acute supraphysiological testosterone treatments in middle-aged men with underlying coronary artery disease.[78] In contradiction to the above data suggesting that testosterone has either a neutral or beneficial effect on vascular reactivity, men undergoing androgen deprivation for prostate cancer show increased FMD[79] and hypogonadal men exhibit increased FMD compared to their eugonadal peers; this is reversed by testosterone replacement.[80,81] More work is needed to clarify the relationship between testosterone and vascular reactivity.

Lipids. Many of the studies in ageing men have shown limited effects of testosterone treatment on lipid profiles, with falls of approximately 10% in total and LDL cholesterol,[82,83] although accompanied by falls of approximately 10% in HDL cholesterol. A meta-analysis of intramuscular testosterone treatment of hypogonadal men of all ages (mean TT 1.7 nM at baseline) suggested a dose-dependent fall not only in total and LDL cholesterol but also in HDL cholesterol;[84] the decline in HDL cholesterol became less prominent with age and with prolonged treatment.[85] Placebo-controlled studies in which serum testosterone was increased within the healthy young adult male normal range showed minimal effects on total and LDL cholesterol and triglycerides, although the decline in HDL cholesterol levels was significant in two of four studies of 12 months or longer[86] ( Table 3 ). Oxandrolone was associated with unfavourable lipid changes.[51] There are insufficient data from randomized controlled trials to conclude whether the route of administration of testosterone is a significant determinant of the observed changes in lipid profiles.[83]

Insulin resistance. An inverse association has been reported between endogenous testosterone levels and either hyperinsulinaemia[63] or an increased likelihood of developing type II diabetes mellitus.[87] Furthermore, clinical trial data documenting a decrease in FM, in particular a reduction in visceral adipose tissue, with testosterone therapy have led to the hypothesis that testosterone therapy may improve insulin sensitivity.[88] Results from studies of testosterone therapy addressing this matter have recently been reviewed.[89] Young, lean subjects did not demonstrate any change in insulin sensitivity across a wide range of serum testosterone levels in a dose-response study, despite a dose-related reduction in FM.[90] Centrally obese middle-aged men receiving testosterone showed an improvement in insulin sensitivity (by hyperinsulinaemic/euglycaemic clamp studies) and a lowering of serum insulin levels;[52] however, these results were not seen with DHT[53] or oxandrolone (when administered to a similarly obese cohort).[55] In ageing men, hCG administered for 3 months did not affect insulin sensitivity (as measured by euglycaemic clamp).[76] It is unclear as to whether changes in serum testosterone mediate insulin sensitivity independent of their effect on FM (specifically visceral fat). Comparison of data sets is difficult as those middle-aged men showing improved insulin sensitivity had higher FM and greater waist circumference at baseline[52] than the ageing men treated with hCG.[76] Furthermore, the middle-aged cohort had significant visceral fat loss with treatment,[52] and although total FM declined in the older men, there are no data regarding regional adipose tissue changes;[76] it is also possible that the duration of hCG treatment was insufficient. Although anabolic steroids (oxandrolone) demonstrate a significant reduction in abdominal fat, they have been associated with insulin resistance, thought to be mediated through hepatotoxicity.

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