Endocrine Abstracts

Pharmacological treatment with synthetic glucocorticoids, which are widely prescribed for the treatment of numerous inflammatory and autoimmune diseases, can also affect the way the adrenal gland produces cortisol. Indeed, patients undergoing synthetic glucocorticoid treatment can develop adrenal insufficiency. This condition is characterised by reduced responsiveness of the adrenal to ACTH stimulation, and adrenal crisis/shock can occur in response to acute physiological stress (e.g. surgical or inflammatory stress). Here we have investigated the effects of prolonged treatment with the synthetic glucocorticoid methylprednisolone on HPA axis dynamics and on the adrenal steroidogenic pathway. We have found that 5 days of treatment with methylprednisolone not only suppresses basal ACTH and corticosterone secretion, as well as corticosterone secretion in response to a high dose of ACTH, but also down-regulates key genes in the adrenal steroidogenic pathway, including StAR, MRAP, CYP11A1 and CYP11B1. Importantly, 5 days after withdrawal of the treatment, ACTH levels are restored, yet basal levels of corticosterone, as well as some key steroidogenic genes, including StAR and HSL, remain down regulated. In addition to affecting the steroidogenic pathway, prolonged exposure with methylprednisolone also increases the expression of pro-inflammatory cytokines and their receptors. Our data suggest that the steroidogenic pathway is directly affected by synthetic glucocorticoid treatment in the long-term, presumably via a mechanism involving activation of the glucocorticoid receptor. Our data also suggest that prolonged treatment with syntetic glucocorticids increases adrenal responsiveness to inflammatory stress.