A patient with congenital adrenal hyperplasia (21-hydroxylase deficiency) is on hydrocortisone for glucocorticoid replacement. The dose is titrated to suppress ACTH-driven androgen excess. Which glucocorticoid receptor signaling mechanism explains the therapeutic anti-inflammatory and HPA-suppressive effect?

• A Transrepression: GR-ligand complex inhibits NF-kB and AP-1 transcription factors without DNA binding, suppressing inflammatory gene expression and CRH/ACTH production ✓
• B Transactivation: GR-ligand complex binds GRE and activates cytokine synthesis genes
• C Non-genomic: rapid membrane receptor activation producing second messengers that immediately suppress corticotrophs
• D Upregulation of beta-2 adrenoceptors on bronchial smooth muscle by direct GR-GRE binding

Explanation

Glucocorticoid receptor (GR) signaling has two distinct molecular pathways: (1) Transactivation — the GR-ligand complex enters the nucleus, binds glucocorticoid response elements (GREs), and activates anti-inflammatory genes (e.g., lipocortin-1/annexin A1, IL-10). (2) Transrepression — the GR-ligand complex directly interacts with (tethers to) pro-inflammatory transcription factors NF-kB and AP-1, inhibiting their target genes (TNF-alpha, IL-6, IL-1beta) and also suppressing CRH/ACTH transcription at the hypothalamic-pituitary level. The therapeutic HPA suppression in CAH and most anti-inflammatory effects are largely mediated by transrepression, while the metabolic side effects (hyperglycemia, osteoporosis) are predominantly transactivation-mediated — this distinction is the basis for developing selective GR agonists (SEGRAs).

Reference: KD Tripathi, Essentials of Medical Pharmacology, 8th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.