What is the Origin of Glucocorticoid Receptor Resistance?

The term is composed of 'glucocorticoid receptor,' referring to the specific intracellular protein that binds cortisol, and 'resistance,' denoting a diminished biological response to the hormone. This pathology stems from germline or somatic mutations in the gene encoding the glucocorticoid receptor (NR3C1), which impair its ability to bind the hormone or translocate to the nucleus for gene regulation. Understanding this resistance is vital for interpreting complex HPA axis dysregulation and guiding appropriate therapeutic strategies.

What is the Mechanism of Glucocorticoid Receptor Resistance?

The core mechanism involves a defect in the glucocorticoid receptor's structure or function, leading to impaired downstream signaling and a failure to modulate gene transcription effectively. The dysfunctional receptor cannot efficiently bind cortisol or, once bound, cannot properly translocate to the nucleus to regulate the transcription of glucocorticoid-responsive genes. This reduced transcriptional activity leads to a failure in the negative feedback loop on the HPA axis, driving compensatory overproduction of ACTH and cortisol from the pituitary and adrenal glands, respectively, to overcome the tissue insensitivity.

Glucocorticoid Receptor Resistance

Meaning

Glucocorticoid Receptor Resistance (GRR), also known as primary or generalized glucocorticoid resistance, is a rare endocrine disorder characterized by a reduced sensitivity of target tissues to cortisol and other glucocorticoid hormones. This condition necessitates chronically elevated circulating cortisol and ACTH levels to maintain normal physiological function, as the cellular receptors fail to respond adequately to the hormonal signal. Clinically, it often presents with signs of mineralocorticoid excess, such as hypertension and hypokalemia, despite high or normal cortisol levels, complicating diagnosis.