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Copyright © 2002 by The Endocrine Society
Absence of Cushingoid Phenotype in a Patient with Cushing’s Disease due to Defective Cortisone to Cortisol ConversionJeremy W. Tomlinson, Nicole Draper, Joanna Mackie, Alan P. Johnson, Geoff Holder, Peter Wood and Paul M. StewartDivision of Medical Sciences (J.W.T., N.D., J.M., P.M.S.) and Department of Ear, Nose and Throat Surgery (A.J.), Queen Elizabeth Hospital, University of Birmingham, United Kingdom B15 2TH; Regional Endocrine Laboratory (G.H.), Department of Clinical Biochemistry, Selly Oak Hospital, Birmingham, United Kingdom B29 6JD; and Regional Endocrine Unit (P.W.), Southampton General Hospital, Southampton, United Kingdom SO16 0XW Address all correspondence and requests for reprints to: Prof. P. M. Stewart, M.D., F.R.C.P., F. Med. Sci., Division of Medical Sciences, University of Birmingham, Queen Elizabeth Hospital, Birmingham, United Kingdom B15 2TH. E-mail: P.M.Stewart{at}bham.ac.uk 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/m2), 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 11ß-hydroxysteroid dehydrogenase type 1 (11ß-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 11ß-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 11ß-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. Abbreviations: 11ß-HSD, 11ß-Hydroxysteroid dehydrogenase; ACRD, apparent cortisone reductase deficiency; AME, apparent mineralocorticoid excess; BMI, body mass index; E, cortisone; F, cortisol; GR, glucocorticoid receptor; MR, mineralocorticoid receptor; THE, tetrahydrocortisone; THF, tetrahydrocortisol; UFE, urinary free cortisone; UFF, urinary free cortisol. This article has been cited by other articles:
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