Division of Nephrology and Hypertension, University Hospital of Berne, Switzerland. Email: bvogt{at}insel.ch
Sir,
We thank Dr M. N. Kerstens and colleagues for their constructive comments. They raise the important question of whether the urinary ratio of cortisol/cortisone metabolites in humans or corticosterone/dehydrocorticosterone metabolites in rodents are attributable to changes in the 11ß-hydroxysteroid dehydrogenase type 2 (11ßHSD2) activity in the kidney or in other parts of the body and/or to changes of the 11ßHSD1 activity.
The interconversion of cortisol and cortisone in humans or corticosterone and dehydrocorticosterone in rodents is attributable to two enzymes, 11ßHSD1 and 11ßHSD2. Therefore, the assessment of urinary steroid metabolites does not allow us to dissect unambiguously whether changes of these values are attributable to a change in the 11ßHSD1 or 11ßHSD2 enzyme. Nevertheless, there is evidence that the urinary ratio of tetrahydrocortisone (THF) plus 5-tetrahydrocortisone (5
THF) to tetrahydrocortisone (THE) [(THF + 5
THF)/THE] in humans or of tetrahydrocorticosterone (THB) plus 5
-tetrahydrocorticosterone (5
THB) to 11-dehydro-tetrahydrocorticosterone (THA) [(THB + 5
THB)/THA] in rodents reflect a diminished activity of 11ßHSD2 activity. First, in both humans and rodents with a loss of function mutation of the 11ßHSD2 enzyme, these ratios were found to be increased [13]. Secondly, in 11ßHSD1 knock-out mice, the urinary ratio of (THB + 5
THB)/THA does not appear to be changed significantly compared to the wild-type mice, suggesting that the urinary ratio of (THB + 5
THB)/THA represents 11ßHSD2 rather than 11ßHSD1 activity [3]. Thirdly, Ferrari et al. [4] showed recently that the F/E ratio is not more sensitive than (THF + 5
THF)/THE for the detection of a pharmacologically decreased 11ßHSD2 activity in normal volunteers.
Kerstens et al. mentioned the interesting observation of a functional defect of the cortisol metabolism in one subject by Jamieson et al. [5]. Since no genetic defect could be detected, it is unknown whether the observed changes in the urinary metabolites reflected a reduced activity of 11ßHSD1 or not and therefore the authors correctly entitled their observation an apparent cortisone reductase deficiency. Furthermore, in support of the superiority of the unreduced steroids excreted in urine as a measure of 11ßHSD activity the recent publication of Kasuya et al. is given [6]. In that publication two normal volunteers were administered cortisol-d5 and urine samples were collected for measuring the parent compound and its metabolites. In that study no subjects with a deficiency in either 11ßHSD1 or 11ßHSD2 were included and no attempt to modulate the activity of 11ßHSD by pharmacological means was performed. Thus, these results cannot be utilized to establish which measure best reflects the activity of 11ßHSD2.
Kerstens et al. [7] point to their abstract in which they describe eight proteinuric patients. In line with our previous observation in 28 patients they observed a tendency for increased urinary ratios of (THF + 5THF)/THE [7,8]. We do not know why at the same time their urinary cortisol to cortisone measurements declined in these subjects.
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