Additional value of measurement of urinary cortisone and unconjugated cortisol metabolites in assessing the activity of 11β‐hydroxysteroid dehydrogenase in vivo

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Abstract
OBJECTIVE It has been shown recently that 11β‐hydroxysteroid dehydrogenase (11β‐HSD) is expressed as at least 2 isozymes. In the liver, 11β‐HSD1 converts cortisone to cortisol; in the kidney, 11β‐HSD2 converts cortisol to cortisone. Conventional assessment of 11β‐HSD activity in vivo has relied on gas chromatographic measurement of the ratios of conjugated cortisol and cortisone metabolites. However, these do not permit distinction between the tissue‐specific activities of the enzymes and do not reflect all forms of 11β‐HSD deficiency. In this report, we have assessed the usefulness of measuring unconjugated cortisol metabolites and free cortisol and cortisone in urine as indices of renal 11β‐HSD activity in man. DESIGN Six healthy male subjects established in sodium balance were given either glycyrrhetinic acid (170 mg t.d.s., to inhibit 11β‐HSD2), carbenoxolone (100 mg t.d.s., to inhibit both 11β‐HSD1 and 11β‐HSD2) or both inhibitors in combination. MEASUREMENTS Urinary electrolytes were measured and the concentrations of total and unconjugated urinary cortisol and its metabolites were determined by gas chromatography mass spectrometry. RESULTS Glycyrrhetinic acid and carbenoxolone inhibited renal 11β‐HSD2 to a similar degree, as judged by similar sodium retention. As previously reported, conventional measurement of ratios of total cortisol to cortisone metabolites were influenced to a greater extent by glycyrrhetinic acid (100–200% increase in ratio from baseline) than by carbenoxolone (< 30% increase). However, the effect of carbenoxolone was readily detected by measurement of urinary unconjugated cortisol/cortisone (130–480% increase of ratio from baseline) and also by measurement of ratios of unconjugated cortisol metabolites (60–130% increase). CONCLUSIONS Measurement of free cortisol and cortisone in urine provides the most sensitive index of renal 11β‐HSD activity. Measurement of total and conjugated urinary steroids is insensitive in circumstances where 11β‐HSD activity in liver or elsewhere may be abnormal.

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