Mechanism of action

1. Glucocorticoids bind to the ligand binding domain of the glucocorticoid receptor (GR)
2. The steroid-bound GR regulates the transcription of genes
3. As a dimer, the GC-bound GR activates transcription while it represses transcription as a monomer
4. The DNA sequence of a glucocorticoid response element (GRE) in the promoter dictates activation vs repression of a target gene
   1. If +GRE sequence favours GR dimer formation → target gene expression induced
   2. If nGRE sequence suppresses GR dimer formation → target gene expression repressed by GR as a monomer or by GR tethering other transcription factors, especially NFkappaB

Influence of genetic polymorphisms

• Mutations/polymorphisms can cause reduced sensitivity to glucocorticoids by altering the protein structure of the GR
• This results in a compensatory elevation of circulating cortisol and ACTH (but no clinical evidence of hypercortisolism)
• Excess ACTH → increased adrenal steriod production with increased mineralocorticoid and/or android receptor activation
• Possible clinical features:
  • Mineralocorticoid excess e.g. hypertension and hypokalaemic alkalosis
  • Androgen excess e.g. precocoius puberty, acne, hirsutism and infertility, male-pattern hair loss, menstrual irregularities and oligo-anovulation in females
  • Clinical spectrum broad - many subjects asymptomatic

Glucocorticoids and mineralocorticoid receptors

• Glucocorticoids also activate the mineralocorticoid (aldosterone) receptor
• Cutaneous adverse effects of glucocorticoids (skin atrophy and delayed wound healing) may be partially triggered by glucocorticoids acting on the mineralocorticoid receptor
• Co-administration of anti-mineralocorticoids can inhibit glucocorticoid-induced delay in wound healing and glucocorticoid-induced skin atrophy