Endocrine Abstracts

Generalized Glucocorticoid Resistance (GR) is rare. Only about 30 patients and (asymptomatic) family members with GR have been described. The molecular basis of GR has been elucidated in nine patients and affected family members: mutations in the hormone binding domain of the glucocorticoid receptor gene were responsible for the clinical manifestations of GR, while in one individual a mutation in the DNA-binding domain was observed. Clinical presentation varied, including hypokalaemia, hypertension, acne, hirsutism and menstrual disorders. An initial biochemical approach shows: insufficient suppression to 1 mg dex, elevated cortisol production, a normal diurnal rhythm at an elevated level (midnight cortisol elevated) in patients without signs or symptoms of cortisol excess.

In the normal population there exists a (partly) genetically determined set-point of HPA-activity in healthy individuals, with highly variable sensitivity to dex. This variability is closely related to a number of frequently occurring polymorphisms in the glucocorticoid receptor gene. These polymorphisms are associated with changes in body composition, metabolic profile, atherosclerosis, dementia and longevity.

Apart from genetically determined generalized GC sensitivity, also transient and/or acquired tissue-specific changes in GC sensitivity occur. The mechanisms involved are at the post-genomic level, as alternative splicing of the glucocorticoid receptor pre-messenger RNA seems the biological basis for this. Either decreased (GR-beta) or increased (GR-delta) sensitivity in the tissues involved is of major clinical importance in immune diseases like asthma and ulcerative colitis and hemato-oncologic malignancies, like multiple myeloma.