Defective 11ß-HSD Reductase Activity in a Patient with Congenital Adrenal Hyperplasia

Anna Nordenstrom, Claude Marcus, Magnus Axelson, Anna Wedell and Martin Ritzén

Department of Pediatrics (A.N., C.M.), Huddinge University Hospital, Karolinska Institutet, S-141 86 Stockholm; and Departments of Clinical Chemistry (M.A.), Molecular Medicine (A.W.), and Woman and Child (M.R.) Karolinska Hospital, Karolinska Institutet S-171 76 Stockholm, Sweden

To the editor:

As pointed out by Dr. Phillipov, our patient with congenital adrenal hyperplasia (CAH) and an apparent 11-ß hydroxysteroid dehydrogenase (11-ß HSD) type 1 deficiency (1) seems to differ from the patients (without CAH) described by Phillipov et al. (2, 3) and Taylor et al. (4). In contrast to these patients, our patient did not rapidly deactivate all administered hydrocortisone (conversion to cortisone) and could, therefore, be successfully treated with hydrocortisone at a dose of 14 mg/m2. This dose is commonly used for treatment of other CAH patients, consistent with a normal inactivation and excretion rate of cortisol. However, although the ratio of cortisone to cortisol metabolites was markedly reduced when changing the treatment from cortisone acetate to hydrocortisone (25 to 3), it was higher than we have seen for other CAH patients (3 vs. 1–2). This is consistent with a low reactivation rate of cortisone to cortisol (11-ß HSD type I deficiency). In addition, our patient may have a low deactivation rate of cortisol. We would like to emphasize that the metabolites included in our calculations were all cortisol (THF, allo-THF, and cortols) as well as all cortisone (THE and cortolones) metabolites. Thus, altered rates of 5{alpha}- or 5ß-reduction would not make any difference.

Prednisolone at the common dose of 2.5 mg per day was also effective in suppressing the adrenals during a 4-month period. However, the effect of a two-day treatment (illustrated in Fig. 1 of our report) seems to be small, possibly due to the short period of treatment.

We agree that it would have been interesting to look at the plasma cortisol concentrations after administration of cortisone acetate vs. hydrocortisone, although it would be difficult to interpret during glucocorticoid treatment. However, the very poor adrenal suppression during the long period of treatment with cortisone acetate strongly indicates that cortisol levels in blood were low during this period.

We suggested that the unusual steroid metabolism seen in our patient could be due to a deficiency of hepatic 11-ß HSD (type 1), but we could not identify any mutations in the corresponding gene. This was also the case in the patients described by others (5, 6).

Insufficient effect of treatment with cortisone acetate has been reported for patients with CAH (7, 8). Among CAH patients in Sweden, we have found four children with an incomplete effect of treatment by cortisone acetate, displayed as a minimal reduction in 17-OHP and androgen levels despite extremely high treatment doses. Our patient (1) is, to our knowledge, the first with CAH in whom a congenital 11-ß HSD type 1 deficiency has been described.

Several differences exist in the presentation of our patient and those previously reported to have an apparent 11ß-HSD deficiency. One obvious difference is that our patient has CAH and was treated with glucocorticoids, while the others have endogenous cortisol production. The other patients described (3, 4, 5) seem to have a high rate of excretion and possibly deactivation of cortisol. In none of the published cases, however, has a specific underlying cause of the observed findings been pinpointed, such as a genetic defect or an exogenous regulating factor of a specific enzyme. Thus, the exact clinical presentation of a putative human liver 11-ß HSD deficiency remains to be determined. The possibility remains that there are several reasons for apparent 11-ß HSD deficiency. It is not inconceivable that a putative additional enzyme deficiency in glucocorticoid metabolism would present differently in combination with CAH than when present in individuals with otherwise normal adrenal steroid production.

Cortisone acetate has been widely used for replacement therapy in both children and adults with adrenal insufficiency. We acknowledge that idiosyncrasies may well exist for several of the enzymes involved in steroid metabolism, which may affect the response to treatment with different compounds used for glucocorticoid replacement, as is the case for many other drugs. We agree that exact definitions of the nature of these clinically relevant syndromes awaits additional studies.

Received December 18, 2000.

References

  1. Nordenstrom A, Marcus C, Axelson M, Ritzén M. 1999 Failure of cortisone acetate treatment in congenital adrenal hyperplasia because of defective 11ß-hydroxysteroid dehydrogenase reductase activity. J Clin Endocrinol Metab. 84:1210–1213.[Abstract/Free Full Text]
  2. Phillipov G, Higgins BA. 1985 A new defect in the periferal conversion of cortisone to cortisol. J Steroid Biochem. 22:435–436.[CrossRef][Medline]
  3. Phillipov G, Palermo M, Shackleton CHL. 1996 Apparent cortisone reductase deficiency a unique form of hypercortisolemia. J Clin Endocrinol Metab. 81:3855–3860.[Abstract]
  4. Taylor NF, Bartlett WA, Dawson DJ, Enoch BA. 1984 Cortisone reductase deficiency: evidence for a new inborn error in metabolism of adrenal steroids. J Endocrinol. 102:S90.
  5. Jamieson A, Wallace AM, Andrew R, et al. 1999 Apparent cortisone reductase deficiency: a functional defect in 11ß-hydroxysteroid dehydrogenase type 1. J Clin Endocrinol Metab. 84:3570–3574.[Abstract/Free Full Text]
  6. Nikkilä H, Tannin GM, New MI, et al. 1993 Defects in the HSD11 gene encoding 11ß-hydroxysteroid dehydrogenase are not found in patients with apparent mineralocorticoid excess or 11-oxoreductase deficiency. J Clin Endocrinol Metab. 77:687–691.[Abstract]
  7. Hansen JW, Loriaux DL. 1976 Variable efficacy of glucocorticoids in congenital adrenal hyperplasia. Pediatrics. 57:942–947.[Abstract]
  8. Whorwood CB, Warne GL. 1991 A possible defect in the inter-conversion between cortisone and cortisol in prepubertal patients with congenital adrenal hyperplasia receiving cortisone acetate therapy. J Steroid Biochem Mol Biol. 139:461–470.[CrossRef]




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