In peripheral tissues, corticosteroid hormone action is determined, in part, through the activity of 11β-hydroxysteroid dehydrogenases (11β-HSD), two isozymes of which interconvert hormonally active cortisol (F) and inactive cortisone (E). 11β-HSD type 2 (11β-HSD2) inactivates F to E in the kidney, whilst 11β-HSD type 1 (11β-HSD1) principally performs the reverse reaction activating F from E in the liver and adipose tissue. Alteration in expression of these 11β-HSD isozymes in peripheral tissues modifies corticosteroid action: loss of 11β-HSD2 activity in the kidney results in cortisol-induced mineralocorticoid excess, and loss of hepatic 11β-HSD1 activity improves insulin sensitivity through a reduction in cortisol-induced gluconeogenesis and hepatic glucose output. Conversely, overexpression of 11β-HSD1 in omental adipose tissue can stimulate glucocorticoid-induced adipocyte differentiation which may lead to central obesity. Patients with hypopituitarism have many clinical features in common with patients with Cushing’s syndrome – notably visceral obesity, insulin resistance, osteoporosis and increased vascular mortality. Our hypothesis was that many of these features may be explained by an effect of growth hormone (GH) on the 11β-HSD isozymes. As assessed by urinary free cortisol/urinary free cortisone ratios and endorsed through in vitro studies, neither GH nor insulin-like growth factor (IGF)-I affect 11β-HSD2 activity. Patients with acromegaly show a reduction in hepatic-derived metabolites of cortisol/cortisone – levels return to normal when GH concentrations are normalized. Conversely, patients with GH deficiency in the setting of hypopituitarism demonstrate an increased cortisol/cortisone metabolite ratio and reduction in circulating cortisol concentrations in patients on hydrocortisone replacement. Treatment with low-dose GH replacement reverses these abnormalities. These clinical data suggest that GH (and/or IGF-I) inhibits 11β-HSD1 (i.e. E to F conversion) (parallel in vitro studies suggest that IGF-I and not GH inhibits 11β-HSD1). These findings have important clinical ramifications. Firstly, the GH-mediated increase in cortisol metabolism (mediated via reduced E to F conversion) may precipitate adrenal insufficiency in hypopituitary patients with partial adrenocorticotropic hormone deficiency commencing GH therapy. Secondly, many of the phenotypic features of hypopituitarism can be explained by an alteration in 11β-HSD1 activity: GH deficiency effectively increases cortisol production in key target tissues including liver and adipose tissue, promoting insulin resistance and visceral adiposity. Thirdly, the reported beneficial effects of GH on cardiovascular risk factors in patients with hypopituitarism may be an indirect effect via alterations in cortisol metabolism. Finally, the GH/IGF-I modulation of cortisol metabolism may underpin the pathogenesis of common diseases such as central obesity and idiopathic osteoporosis. Patients with central obesity but with no evidence of hypopituitarism have relative GH deficiency and it is exciting to speculate that low-dose GH treatment in this group, by inhibiting cortisol generation within omental fat, may offer a novel therapeutic approach.

Journal Section:
Paper
Keywords:
Growth hormone, Cortisol, 11β-Hydroxysteroid dehydrogenase, Obesity
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