What are the manifestations and management of Glucocorticoid (corticosteroid) resistance syndrome?

Glucocorticoid Resistance Syndrome: Manifestations and Management

Clinical Manifestations

Glucocorticoid resistance syndrome (GRS) presents with a paradoxical combination of elevated cortisol levels without Cushingoid features, accompanied by signs of mineralocorticoid and androgen excess due to compensatory HPA axis hyperactivity. 1, 2, 3

Cardinal Features by System

Cardiovascular manifestations:

• Hypertension (often severe, potentially leading to hypertensive encephalopathy as the first presentation) 1
• Hypokalemic alkalosis from excess mineralocorticoid activity 2, 3
• Microinfarcts in basal ganglia, thalamus, and pons from uncontrolled hypertension 1

Reproductive/androgenic manifestations in females:

• Hirsutism and male-pattern baldness 2, 3
• Menstrual irregularities and oligoanovulation 3, 4
• Acne and infertility 3, 4

Reproductive manifestations in males:

• Infertility from androgen excess 3, 4

Pediatric manifestations:

• Precocious puberty 3, 4
• Hypertensive seizures with hypoglycemia 1

Neuropsychiatric manifestations:

• Chronic fatigue (potentially from CNS glucocorticoid deficiency) 3
• Hypoglycemic seizures 1

Biochemical Hallmarks

Laboratory findings include:

• Markedly elevated ACTH and cortisol without diurnal variation 2, 3
• Elevated adrenal androgens (DHEA, DHEA-S, androstenedione) 3, 4
• Elevated adrenal steroid biosynthesis intermediates with salt-retaining activity 3, 4
• Hypokalemia with metabolic alkalosis 2, 3

Molecular Basis

The underlying defect involves mutations in the NR3C1 gene encoding the glucocorticoid receptor, with both novel and previously described mutations identified. 1, 2

Specific molecular mechanisms include:

• Point mutations in the ligand-binding domain causing receptor dysfunction 5
• Transdominant negative activity where mutant receptors inhibit wild-type receptors even in heterozygous states 5
• Cytoplasmic retention of wild-type receptors by mutant proteins 5
• Defective interaction between receptor AF2 region and coactivator LXXLL motifs 5

Diagnostic Approach

Begin with measurement of morning ACTH and cortisol levels; paradoxically elevated levels without Cushingoid features in the presence of hypertension and/or hyperandrogenism suggest GRS. 2, 3

Essential diagnostic workup:

• Morning ACTH and cortisol (expect both markedly elevated) 2, 3
• Serum potassium and bicarbonate (expect hypokalemic alkalosis) 2, 3
• Adrenal androgens: DHEA-S, androstenedione, testosterone 3, 4
• 24-hour urinary free cortisol (elevated without suppression) 2
• Dexamethasone suppression test (resistance to suppression) 2
• Genetic testing for NR3C1 mutations 1, 2

Imaging considerations:

• Brain MRI if hypertensive encephalopathy suspected (look for punctate microinfarcts in basal ganglia, thalamus, pons) 1

Management Strategy

High-dose dexamethasone is the cornerstone of treatment, as it can overcome receptor resistance and suppress the hyperactive HPA axis, thereby reducing mineralocorticoid and androgen excess. 1, 2

Glucocorticoid Therapy

Initiate dexamethasone at 2-4 mg daily in divided doses, titrating upward based on blood pressure control and suppression of ACTH/cortisol. 1, 2

• Some patients require extremely high doses (up to 14 mg/day) for adequate symptom control 1
• Dexamethasone is preferred over prednisone because it has minimal mineralocorticoid activity and greater receptor-binding affinity 1, 2
• Monitor for adequate suppression by tracking ACTH, cortisol, blood pressure, and potassium levels 2

Antihypertensive Management

Initiate antihypertensive therapy immediately in all patients with elevated blood pressure, as hypertensive complications can be life-threatening. 1

• Mineralocorticoid receptor antagonists (spironolactone 50-200 mg daily) directly counteract excess mineralocorticoid activity 2
• Add additional antihypertensives (ACE inhibitors, calcium channel blockers) as needed for blood pressure control 1
• Target blood pressure <130/80 mmHg to prevent end-organ damage 1

Management of Hyperandrogenism

In females with significant hirsutism or menstrual irregularities, add antiandrogen therapy once blood pressure is controlled. 2, 3

• Spironolactone serves dual purpose as both antihypertensive and antiandrogen 2
• Combined oral contraceptives can regulate menses and reduce androgen effects 3
• Cosmetic treatments (laser hair removal, topical eflornithine) for persistent hirsutism 3

Monitoring Protocol

Follow patients every 2-4 weeks initially, then every 3 months once stable, checking:

• Blood pressure and heart rate 1
• Serum potassium and bicarbonate 2
• Morning ACTH and cortisol levels 2
• Androgen levels in symptomatic patients 3
• Bone density annually (glucocorticoid therapy increases osteoporosis risk) 6, 7

Critical Pitfalls to Avoid

Never mistake GRS for Cushing syndrome—patients lack Cushingoid features despite elevated cortisol, and treatment with dexamethasone is therapeutic rather than diagnostic. 2, 3

Do not withhold high-dose dexamethasone due to concerns about glucocorticoid side effects—the paradox of GRS is that these patients are glucocorticoid-resistant and require supraphysiologic doses to achieve therapeutic effects. 1, 2

Recognize that hypertensive encephalopathy can be the presenting manifestation in children, requiring immediate aggressive blood pressure management and high-dose dexamethasone. 1

Avoid using prednisone or hydrocortisone as primary therapy—these have significant mineralocorticoid activity that worsens hypertension and hypokalemia. 1, 2

Do not delay genetic testing—identifying specific NR3C1 mutations confirms diagnosis, guides family counseling, and may predict treatment response. 1, 2