Primary Generalized Glucocorticoid Resistance Workup

Updated: Dec 21, 2021
  • Author: Nicolas Nicolaides, MD, PhD; Chief Editor: Robert P Hoffman, MD  more...
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Laboratory Studies

Endocrinologic evaluation

The concentrations of plasma corticotropin, plasma renin activity (recumbent and upright), and aldosterone, as well as those of serum cortisol, testosterone, androstenedione, DHEA, DHEAS, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and fasting glucose and insulin should be recorded in the morning. [45]

Determination of the 24-hour urinary free cortisol (UFC) excretion on 2 or 3 consecutive days is central to the diagnosis, given that patients with Chrousos syndrome demonstrate increased 24-hour UFC excretion in the absence of clinical manifestations suggestive of hypercortisolism. In patients with Chrousos syndrome, the rise in serum cortisol and androgen concentrations, as well as in the 24-hour UFC excretion, varies considerably depending on the severity of impairment of glucocorticoid signal transduction. In most severe cases, serum cortisol and 24-hour UFC concentrations may be, respectively, up to 7- and 50-fold higher than the upper limit of normal range. [45]

Plasma corticotropin concentrations may be normal or high in patients with Chrousos syndrome.

The responsiveness of the HPA axis to exogenous glucocorticoids should also be tested with dexamethasone in patients suspected of having Chrousos syndrome. Increasing doses of dexamethasone (0.3 mg, 0.6 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg) should be given orally at midnight every other day, and a serum sample should be drawn at 8:00 am the following morning for determination of serum cortisol and dexamethasone concentrations. The concurrent measurement of serum dexamethasone concentrations is suggested in order to exclude the possibility of nonadherence to treatment, increased metabolic clearance, or decreased absorption of this medication. Affected subjects demonstrate resistance of the HPA axis to dexamethasone suppression, which varies depending on the severity of the condition. The dose of dexamethasone required to suppress serum cortisol concentrations by 50% may be up to 7.5-fold higher than that required to achieve the same degree of HPA axis suppression in healthy subjects. [45]

Molecular studies

Thymidine incorporation assays and dexamethasone-binding assays on peripheral blood mononuclear cells in association with sequencing of the hGR gene are necessary to confirm the diagnosis. [28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39] In Chrousos syndrome, the thymidine incorporation assays reveal resistance to dexamethasone-induced suppression of phytohemagglutinin-stimulated thymidine incorporation, while the dexamethasone-binding assays often show decreased affinity of the hGR receptor for the ligand compared with control subjects. [22, 27]

Sequencing of the coding region of the hGR gene, including the intron/exon junctions, reveals mutations or deletions in most but not all patients with Chrousos syndrome. [27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 41, 42, 43, 44] Once a structural defect is determined, it is suggested that functional characterization of the mutant receptor should be undertaken in order to determine the molecular mechanisms through which the mutant hGR impairs glucocorticoid signal transduction.

In a study that included 100 patients with bilateral adrenal hyperplasia, increased arterial pressure, and/or hypercortisolism, but no stigmata of Cushing syndrome, Vitellius et al found that 5 of the patients (5%) had novel heterozygous NR3C1 mutations. [46, 47] Thus, Sanger sequencing of the NR3C1 gene is recommended in patients who have clinical features that suggest primary generalized glucocorticoid resistance, or Chrousos syndrome. [47, 48]