Cortisol resistance (CR) is a
rare disease characterized by a generalized reduced sensitivity of end-organs to the actions of
glucocorticoids (GCs). GC effects are mediated by the GC receptor (GR). The molecular alterations in CR described thus far were located in the
hormone-binding domain of the GR gene. Recent reports of a considerable prevalence of abnormalities in the GR in patients attending the endocrine clinic prompted us to carry out further investigations with respect to GR
protein and GR gene in patients attending the endocrine clinic for a broad spectrum of complaints and biochemical evidence suggesting a CR. In the present study, we describe five patients with biochemical and clinical CR. All patients showed a diurnal rhythm of serum
cortisol concentrations (albeit at a high level), an insufficient suppression of serum
cortisol concentration in reaction to 1 mg
dexamethasone (DEX), and variable degrees of
androgen overproduction, in the absence of clinical signs and symptoms of
Cushing's syndrome. Three of the four female patients presented with complaints of
androgen overproduction, two of them in combination with
fatigue. The other female patient had severe
steroid-resistant
asthma. The only male patient and his son were asymptomatic. In four patients, we investigated receptor
protein characteristics on mononuclear leukocytes in a whole cell DEX binding assay and studied the ability of DEX to inhibit
mitogen-induced cell proliferation in mononuclear leukocytes in vitro. In all patients investigated, we found alterations in receptor number or
ligand affinity and/or the ability of DEX to inhibit
mitogen-induced cell proliferation. To investigate the molecular defects leading to the clinical and biochemical pictures in these patients, we screened the GR gene using PCR/single-strand conformational polymorphism/sequence analysis. No GR gene alterations were found in these patients. In conclusion, the five patients described had clinical and biochemical evidence of CR, but no abnormalities were demonstrated in the GR gene. Probably, as yet undefined alterations somewhere in the cascade of events starting with
ligand binding to the GR
protein, and finally resulting in the regulation of the expression of GC responsive genes, or postreceptor defects or interactions with other nuclear factors form the pathophysiologic basis of CR in these patients.