Visceral obesity is associated with other endocrine abnormalities than that of cortisol. Indeed, visceral obese individuals with the metabolic syndrome may have all the hormonal abnormalities of the elderly, suggesting that this condition may be a sign of premature ageing (58). The most common deficiencies are those of growth hormone (GH) and sex steroids (59). Whereas men have low testosterone levels (60), women have irregular menstrual cycles (61). Functionally, the growth axis and the reproductive axis are influenced at many levels by the HPA axis. Prolonged activation of the HPA axis thus leads to suppression of GH secretion as well as inhibition of sex steroids (23,62).
These endocrine abnormalities have a profound effect on peripheral tissues. While cortisol promotes accumulation of visceral fat and insulin resistance in muscle tissue, the GH and sex steroids, often in concert, do the opposite (42). Low GH and sex steroid secretions will thereby multiply the pathogenetic effects of cortisol. In fact, there is evidence that low concentrations of GH and sex steroids without HPA axis perturbations may cause such effects. As a result, visceral obesity with the metabolic syndrome may originate on the basis of the following endocrine subgroups: one characterized by HPA axis perturbation, the other character ized by low secretion of GH and sex steroid, and finally, a combination of both these events.
This issue was addressed in a recently performed cohort study of middle-aged men (44). Subgroups were constructed based on the current clinical definition of low testosterone and insulin-like growth factor I (IGF-I), a mediator of the major actions of GH (63), and the dexamethasone suppression test as a measurement of the feedback regulation system. In the total cohort of men (N = 284), assessments of visceral obesity correlated strongly and consistently with all metabolic parameters except total and low density lipoprotein cholesterol. Furthermore, visceral obesity was found to be associated with elevated blood pressure and heart rate. Identical findings appeared within the subgroup characterized by HPA axis perturbation, defined as a blunted response to dexamethasone. This was also the case in the subgroup characterized by low secretion of testosterone and IGF-I. These results support the concept of endocrine subgrouping of visceral obesity with the metabolic syndrome.
In addition to these analyses, structural equation modelling (path analysis) was performed to examine potential causal models between the endocrine (testosterone and IGF-I), the anthropometric (WHR and D), and selected metabolic measurements (insulin and triglycerides). The results obtained are summarized in Figure 23.1. A blunted response to dexamethasone, that is, a HPA axis characterized by poor feedback regulation, was directly associated with low concentrations of testosterone and IGF-I as well as elevated levels of insulin. Low testosterone and IGF-I in turn was linked to increased WHR and D, and these anthropomet-ric measurements were associated with hyperin-sulinaemia, which was related to elevated levels of triglycerides. This chain of events suggests that HPA axis perturbations contribute to the outgrowth of central obesity and insulin resistance. The latter is also further influenced by central obesity measured as WHR or D. Figure 23.1 illustrates the impact of low testosterone and IGF-I on centralization of body fat stores. Thus, input into this chain of events, resulting in metabolic aberrations, may occur at different levels: the HPA axis, isolated testosterone and IGF-I deficiency, or by visceral obesity itself. This interpretation is in excellent agreement with the endocrine subgrouping of the metabolic syndrome as discussed above.
In summary, these findings suggest the possibility
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