The aim of treatment in
congenital adrenal hyperplasia is to suppress excess adrenal
androgens while achieving physiological
glucocorticoid replacement. However, current
glucocorticoid replacement regimes are inadequate because doses sufficient to suppress excess
androgens almost invariably induce adverse metabolic effects. Although both
cortisol and
corticosterone are
glucocorticoids that circulate in human plasma, any physiological role for
corticosterone has been neglected. In the brain, the
adenosine 5'-triphosphate-binding cassette transporter ABCB1 exports
cortisol but not
corticosterone. Conversely, ABCC1 exports
corticosterone but not
cortisol. We show that ABCC1, but not ABCB1, is expressed in human adipose and that ABCC1 inhibition increases intracellular
corticosterone, but not
cortisol, and induces
glucocorticoid-responsive gene transcription in human adipocytes. Both C57Bl/6 mice treated with the ABCC1 inhibitor
probenecid and FVB mice with deletion of Abcc1 accumulated more
corticosterone than
cortisol in adipose after
adrenalectomy and
corticosteroid infusion. This accumulation was sufficient to increase
glucocorticoid-responsive adipose transcript expression. In human adipose tissue, tissue
corticosterone concentrations were consistently low, and ABCC1
mRNA was up-regulated in
obesity. To test the hypothesis that
corticosterone effectively suppresses
adrenocorticotropic hormone (
ACTH) without the metabolic adverse effects of
cortisol, we infused
cortisol or
corticosterone in patients with
Addison's disease.
ACTH suppression was similar, but subcutaneous adipose transcripts of
glucocorticoid-responsive genes were higher after infusion with
cortisol rather than with
corticosterone. These data indicate that
corticosterone may be a metabolically favorable alternative to
cortisol for
glucocorticoid replacement
therapy when
ACTH suppression is desirable, as in
congenital adrenal hyperplasia, and justify development of a pharmaceutical preparation.