Endocrine Abstracts

In Cushing's Syndrome, elevated circulating cortisol levels are responsible for the association of central obesity, hypertension, insulin resistance, hyperglycaemia, and dyslipidaemia. Recent evidence suggests that there are subtle elevations in circulating cortisol concentrations amongst patients with hypertension and insulin resistance, and these are predicted by low birthweight suggesting that they may be programmed by events occurring in early life. In addition, there is evidence of altered tissue responsiveness to glucocorticoids in patients with cardiovascular risk factors, including obesity. Patients with salt sensitive hypertension may have subtle defects in 11bHSD2, and hence impaired protection of corticosteroid receptors in the distal nephron, and perhaps in the blood vessel wall, from cortisol. In obesity, there is upregulation of 11bHSD1 in adipose tissue, and hence increased intra-adipose cortisol concentrations which may exacerbate the obesity and its metabolic complications. Finally, there is evidence that glucocorticoid receptor expression is increased in peripheral target tissues in patients with insulin resistance.

Understanding these multiple disturbances of cortisol signalling may allow novel therapies to be developed. Therapy which lowers circulating cortisol concentration almost inevitably risks impaired cortisol response to stress. A more productive approach might be to manipulate tissue responsiveness to glucocorticoids. Inhibition of 11bHSD type 1 may lower cortisol concentrations in liver and adipose tissue and hence improve the metabolic profile. Alteration in glucocorticoid receptor signalling may also be possible. Crucially, these interventions, if targeted to specific tissues, may improve features of the metabolic syndrome without the adverse effects of cortisol insufficiency.