| dc.description.abstract | Both cortisol and corticosterone circulate in human plasma however corticosterone has
been relatively neglected in human research to date. There is evidence of distinct
regulation within different tissues with the transmembrane transporter ABCB1, highly
expressed in the brain, exporting cortisol but not corticosterone. This may account for
the relative accumulation of corticosterone in the CNS. In contrast, ABCC1, highly
expressed in adipose tissue and skeletal muscle, exports corticosterone but not cortisol,
suggesting cortisol is the principal glucocorticoid acting in these tissues.
We tested the hypotheses that: (i) corticosterone physiology in humans is different to
that of cortisol; (ii) inhibition of ABCC1 increases binding of corticosterone to
corticosteroid receptors in adipose tissue and skeletal muscle but has no central CNS
effect; and (iii) corticosterone is superior to cortisol as a basis for glucocorticoid
replacement therapy with fewer metabolic side effects.
We compared paired salivary and plasma samples from 10 healthy individuals. Plasma
corticosterone showed a similar diurnal variation to cortisol but salivary corticosterone
was low and did not correlate with plasma concentrations.
A placebo-controlled randomised crossover study was carried out in 14 healthy
individuals comparing receptor occupancy of glucocorticoids centrally and
peripherally with and without ABCC1 inhibition. Receptor occupancy was assessed
through displacement with MR and GR antagonists potassium canrenoate and
mifepristone. Centrally, ABCC1 inhibition caused increased activation of the HPA
axis after MR and GR antagonism. Peripherally, we were unable to show displacement
from adipose tissue or skeletal muscle.
A further placebo-controlled randomised crossover study is still ongoing in 16 patients
with congenital adrenal hyperplasia, comparing metabolic effects of placebo, cortisol
and corticosterone infusions over 6 hours. We present interim data for n=8. ACTH and
17-OHP were suppressed with corticosterone. Metabolic parameters were similar
between placebo, cortisol and corticosterone phases.
These data suggest corticosterone physiology is distinct compared with cortisol in
humans. We have shown ABCC1 inhibition alters the HPA axis after receptor
antagonism which suggests ABCC1 may play more of a key role centrally than
previously thought. Corticosterone suppresses ACTH and 17-OHP in the short term in
congenital adrenal hyperplasia, highlighting the possibility of its use as an alternative
glucocorticoid replacement therapy in the future. | en |
