Cushing's syndrome invariably presents with a classical phenotype comprising central adiposity, prominence of dorsal, supraclavicular and temporal fat pads, bruising, abdominal striae, proximal
myopathy, and
hypertension. We report the case of a 20-yr-old student with pituitary-dependent
Cushing's syndrome who was spared this classical phenotype because of a defect in the peripheral conversion of
cortisone to
cortisol. She presented to her general practitioner with secondary
amenorrhea. Clinical examination revealed normal fat distribution (body mass index, 20.9 kg/m(2)), absence of
hirsutism,
myopathy, or bruising; her blood pressure ranged from 115/70 to 122/82 mm Hg. She was investigated for biochemical hypercortisolemia because of a mildly elevated random circulating
cortisol (serum
cortisol, 661 nmol/liter).
Cushing's syndrome was confirmed on the basis of repeatedly elevated urinary free cortisols (831-1049; reference range, <350 nmol/24 h), failure of low-dose
dexamethasone suppression (611 nmol/liter) and loss of circadian
cortisol secretion. Investigations suggested
Cushing's disease; there was suppression after high-dose
dexamethasone (<20 nmol/liter) and a 950% increase in
ACTH after stimulation with CRH. Pituitary magnetic resonance imaging revealed a 3-mm
adenoma within the pituitary gland. Urinary
corticosteroid metabolites were analyzed by gas chromatography-mass spectrometry and demonstrated a decreased THF+allo-THF/THE ratio of 0.66 (mean +/- SE in
Cushing's disease, 1.74 +/- 0.24) suggesting a defect in
11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), an
enzyme that converts the inactive
glucocorticoid cortisone to active
cortisol. Transphenoidal microadenomectomy was performed, and histology confirmed the diagnosis of a
corticotroph adenoma. Postoperatively, serum
cortisol was undetectable and replacement
therapy was commenced. Subsequent investigations revealed a significantly impaired ability to convert an oral dose of
cortisone acetate (25 mg) to
cortisol, reduced serum
cortisol to
cortisone ratios, and a reduced serum half-life for
cortisol (57.3 min). These results provide strong evidence for a partial defect in
11beta-HSD1 activity and concomitant increase in
cortisol clearance rate. We have described a case of
Cushing's disease that failed to present with a classical phenotype, and we postulate that this is due to a partial defect of
11beta-HSD1 activity, the defect in
cortisone to
cortisol conversion increasing
cortisol clearance and thus protecting the patient from the effects of
cortisol excess. This observation may help to explain individual susceptibility to the adverse effects of
glucocorticoids.