Altered Cortisol Metabolism In Obesity

Cortisol Metabolism in Primary Obesity

Relatively small case-control studies, almost exclusively in women, showed that obesity, particularly of predominantly abdominal distribution, is associated with increased urinary free cortisol excretion (160-162). However, as detailed above, urinary free cortisol forms a very small fraction of total cortisol metabolite excretion. More convicingly, recent large studies confirm that total cortisol production rate is somewhat enhanced in obesity in men as well as women (131,163,164). This is further supported by evidence of enhanced responsiveness of the hy-pothalamic-pituitary-adrenal axis to ACTH and CRH (161,165). However, in obesity plasma cortisol levels are not consistently elevated. Indeed, peak plasma cortisol levels in the morning are low (166-169). The combination of increased secretion with low morning plasma levels suggests either that diurnal variation of cortisol secretion is disrupted, or that peripheral metabolism of cortisol is enhanced.

Previous studies using radioisotope tracers showed that metabolic clearance rate for cortisol is indeed enhanced in obesity (170). Very recent studies have identified which specific pathways of cortisol metabolism are involved. In a study of 68 men and women, we reported elevated ratios of cortisol/ cortisone metabolites in obese men and elevated excretion of 5a-reduced metabolites in obese men and women (Figure 18.10) (163). Our finding of enhanced 5a-reduced metabolites in obesity has been confirmed in a further independent study of nearly 500 men and women (164) and in our own unpublished observations in an additional 300 subjects. It is likely that the same change explains the observation of increased 5a-reduced cortisol metabolites in polycystic ovary syndrome (171). We have also observed increased hepatic 5a-reductase type 1 activity in liver of leptin-resistant, obese Zucker rats (72).

However, cortisol/cortisone metabolite ratios have proved less consistent in further studies. Stewart and colleagues (131) studied 36 men and women and reported that the obese group (n = 12) had impaired conversion of oral cortisone to cortisol in peripheral plasma—suggesting impaired hepatic 110-reductase activity (Figure 18.4). This was associated with lower ratios of cortisol/corti-sone metabolites, and relatively impaired inactiva-tion of cortisol by 5a-reductase (Figure 18.2). By contrast, Katz et al. examined arteriovenous differences in cortisol/cortisone ratio across subcutaneous abdominal fat and found a trend towards increased 110-HSD1 activity in obesity (57). A likely explanation for these discrepancies is that there are tissue-specific differences in the activity of 110-HSD type 1 in obesity (72), with impaired conversion of cortisone to cortisol in liver but normal or enhanced conversion in adipose tissue and perhaps other sites. The sum may frequently be no overall change in urinary metabolites. Indeed, we have evidence in favour of such tissue-specific changes in 110-HSD 1 activity from leptin-resistant obese Zucker rats (72).

We have therefore proposed that in obesity enhanced cortisol clearance by 5a-reductase may lower plasma cortisol levels, thereby reducing negative feedback and providing a key stimulus to the hypothalamic-pituitary-adrenal axis. Such enhanced cortisol clearance will be exacerbated by impaired regeneration of cortisol from cortisone by reduced 110-HSD1 in liver. However, this results in an elevated pool of cortisol metabolites, including cortisone, available for potential reactivation. In tissues where 110-HSD 1 activity is maintained or even enhanced (e.g. adipose tissue), the local cortisol levels may be elevated in the face of overall increased metabolic clearance rate (Figure 18.11).

At present we can only speculate on the mechanism of altered cortisol metabolism in obesity. The regulation of relevant enzymes by hormones which are disturbed in obesity is clearly relevant (Table 18.4), but none of these have yet been manipulated in obese subjects to assess reversibility of the dys-regulation of cortisol metabolism.

Cortisol Metabolism and Growth Hormone Deficiency

Adult growth hormone deficiency is associated with a syndrome which includes lethargy, dyslipidaemia and central obesity. The mechanisms whereby growth hormone and insulin-like growth factor 1 (IGF-1) influence body fat distribution are poorly characterized, and may be mediated indirectly by changes in glucocorticoid receptor activation. In growth-hormone deficient rats, female pattern (continuous administration) growth hormone replacement potently downregulates hepatic 11ft-HSD1 expression (172). By contrast, male pattern (pulsatile) growth hormone does not affect enzyme activity. Similar effects of growth hormone and IGF-1 have been reported in human adipose stromal cells in primary culture. In humans, evidence is restricted to interpretation of urinary cortisol metabolites, and studies in hypopituitary patients are confounded by the effect of oral cortisol replacement therapy. However, it appears that continuous (daily subcutaneous injection) growth hormone replacement inhibits 11ft-HSD1 on the basis that cortisol/ cortisone metabolite ratios are lower and urinary free cortisol/cortisone ratios either unchanged or elevated (173-175). Thus, growth hormone deficiency may well be associated with enhanced adipose 11ft-HSD1 and higher intra-adipose cortisol concentrations. It is an intriguing speculation that many of the benefits of growth hormone replacement in adult hypopituitary patients—reduced central adiposity, normalization of dyslipidaemia, and

Figure 18.11 A model of consequences of tissue-specific changes in cortisol metabolism in obesity

Figure 18.12 Interaction of increasing plasma cortisol and obesity in predicting blood pressure. Data are from 226 otherwise healthy men and women from the MONICA cross-sectional cohort study in northern Sweden. Obesity in this population is associated with lower 0900 h plasma cortisol concentrations, but both obesity and higher plasma cortisol are independently associated with higher blood pressure. This emphasizes that the mechanisms underlying elevated cortisol concentrations in hypertension are likely to be different from those in obesity, and it is those obese subjects who fail to show a characteristic fall in plasma cortisol levels who may be subject to the greatest metabolic complications. Adapted from Walker et al. (167)

Figure 18.12 Interaction of increasing plasma cortisol and obesity in predicting blood pressure. Data are from 226 otherwise healthy men and women from the MONICA cross-sectional cohort study in northern Sweden. Obesity in this population is associated with lower 0900 h plasma cortisol concentrations, but both obesity and higher plasma cortisol are independently associated with higher blood pressure. This emphasizes that the mechanisms underlying elevated cortisol concentrations in hypertension are likely to be different from those in obesity, and it is those obese subjects who fail to show a characteristic fall in plasma cortisol levels who may be subject to the greatest metabolic complications. Adapted from Walker et al. (167)

enhanced insulin sensitivity—might perhaps be achieved at no cost by lowering the replacement dose of oral hydrocortisone!

Interactions Between Cortisol, Obesity and Other Cardiovascular Risk Factors

Cushing's syndrome is characterized not only by central obesity, but also by hypertension, dys-lipidaemia, insulin resistance, and glucose intolerance. This cluster of clinical features bears remarkably similarity to the cluster which occurs in the metabolic syndrome (Reaven's syndrome X; the insulin resistance syndrome). It is possible that a more subtle increase in cortisol action explains the association between these features of the metabolic syndrome and obesity.

In case-control and cross-sectional studies, high blood pressure is associated with elevated cortisol concentrations (in blood, saliva or urine) (164,168,176-179), impaired peripheral inactivation of cortisol by 11£-HSD2 (127,151), and enhanced tissue sensitivity to glucocorticoids as measured by the intensity of dermal vasoconstriction following topical application of beclomethasone (179,180). Similarly, insulin resistance and glucose intolerance are associated with higher circulating cortisol levels (169) and increased dermal vasoconstrictor sensitivity to beclomethasone (179,180). Higher morning plasma cortisol concentrations and increased responsiveness to ACTH also occur in adults with the additional cardiovascular risk factor of low birth-weight (169,181). However, all of these associations between cortisol activity and hypertension/insulin resistance are independent of obesity. Obesity is associated with lower (not higher) plasma cortisol, no change in 11^-HSD2 (rather, alterations in 11^-HSD1; see above), and no difference in dermal responses to glucocorticoids.

From these observational studies it is not possible to dissect causality but they do not favour a proposed unifying hypothesis (182) which ascribes the associations between obesity and other features of the metabolic syndrome X to enhanced cortisol secretion. Rather, there may be a primary increase in hypothalamic-pituitary-adrenal axis activity and tissue sensitivity to glucocorticoids in subjects with hypertension/insulin resistance which does not directly predispose to obesity. However, if these individuals become obese, then perhaps acquired changes in 5a-reductase and 11^-HSD1 activities result in higher local glucocorticoid concentrations and amplification of hypertension and insulin resistance. In support of this concept of 'amplification' by obesity, the highest blood pressure in cross-sectional studies occurs amongst relatively rare individuals who are most obese but who have the highest morning plasma cortisol (167,169) (Figure 18.12).

Therapeutic Opportunities

No matter whether the changes in cortisol metab olism are primary or secondary to obesity and/or its associated neurohumoral disturbances, their influence on the hypothalamic-pituitary-adrenal axis and glucocorticoid receptor activation may be a key step in the cascade leading to adverse metabolic consequences of obesity. Therefore, therapeutic intervention to reverse the tissue-specific alterations in cortisol metabolism in obesity may be extremely useful. The results of experiments with 11/-HSD1 and 5a-reductase inhibitors in obesity are awaited with interest.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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