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Failure of Cortisone Acetate Treatment in Congenital Adrenal Hyperplasia because of Defective 11ß-Hydroxysteroid Dehydrogenase Reductase Activity*

Department of Pediatrics (A.N., C.M.), Huddinge University Hospital, Karolinska Institutet, S-141 86 Huddinge, Sweden; Department of Clinical Chemistry (M.A.), Karolinska Hospital, Karolinska Institutet, S-171 76 Stockholm, Sweden; Department of Molecular Medicine (A.W.), CMM:02, Karolinska Hospital, Stockholm, Sweden; and Department of Woman and Child Health (E.M.R.), Karolinska Hospital, Karolinska Institutet, S-171 76 Stockholm, Sweden

Address all correspondence and requests for reprints to: Dr. Claude Marcus, Department of Pediatrics, Huddinge University Hospital, Karolinska Institutet, S-141 86 Huddinge, Sweden.

	Abstract

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Congenital adrenal hyperplasia in children is often treated with cortisone acetate and fludrocortisone. It is known that certain patients with congenital adrenal hyperplasia require very high substitution doses of cortisone acetate, and a few patients do not respond to this treatment at all.

A patient with 21-hydroxylase deficiency, for whom elevated pregnanetriol (P3) levels in urine were not suppressed during treatment with cortisone acetate (65 mg/m²·day), was examined. The activation of cortisone to cortisol was assessed by measuring urinary metabolites of cortisone and cortisol.

The patient’s inability to respond to treatment with cortisone acetate was found to be caused by a low conversion of cortisone to cortisol, assumed to be secondary to low 11ß-hydroxysteroid dehydrogenase activity (11-oxoreductase deficiency). All exons and exon/intron junctions of the 11ß-hydroxysteroid dehydrogenase type1 gene (HSD11L) were sequenced without finding any mutations, but a genetic lesion in the promoter or other regulatory regions cannot be ruled out. The deficient 11-oxoreductase activity seems to have been congenital, in this case, but can possibly be attributable to a down-regulation of the enzyme activity. The results support the use of hydrocortisone, rather than cortisone acetate, for substitution therapy in adrenal insufficiency.

	Introduction

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The enzyme 11ß-hydroxysteroid dehydrogenase (11ß-HSD) catalyzes the interconversion of cortisol and cortisone (1, 2). It is present in at least two isoforms. The renal isoenzyme is nicotinamide adenine dinucleotide (NAD)-dependent and favors the conversion of cortisol to cortisone, thereby protecting the kidneys from excessive mineralocorticoid activity of cortisol (3). The hepatic isoenzyme, expressed to some extent also in other tissues (4, 5), is NAD phosphate-dependent (NADP) and has both dehydrogenase and 11-oxoreductase activity. It has a low affinity for the substrate cortisol, which favors the conversion of cortisone to cortisol (3). In cell systems, it has been shown to exert reductase activity only (6, 7, 8). It has been suggested that 11ß-HSD might play a role in modulating cortisol availability at the glucocorticoid receptor (9) and thereby influence insulin sensitivity (10). Defects in hepatic 11ß-HSD have been postulated to play a role in essential hypertension and polycystic ovary syndrome (5, 11).

Congenital adrenal hyperplasia (CAH) is a recessively inherited disease. In more than 95% of the cases, it is caused by a deficiency of 21-hydroxylase in the adrenals. All symptoms can be explained by the decreased synthesis of cortisol and aldosterone and an excessive production of androgens. The manifestations of the disease range from the severe neonatal form (with virilization and salt loss) to milder forms (with symptoms of excessive androgen production only later in life) (12, 13). It has been shown that, with few exceptions, there is a correlation between genotype and clinical manifestations (14, 15).

A substitution therapy often used in pre- and peripubertal children with adrenal insufficiency is cortisone acetate and fludrocortisone with NaCl supplementation during the first 2 yr of life. The mean bioavailability of cortisone given orally was about 80% of that of hydrocortisone (16); and clinical observations indicate that, calculated by weight, cortisone acetate has about two-thirds the potency of cortisol (16, 17). In another study, the bioavailability of oral hydrocortisone averaged 96%, compared with iv administration (18). Despite a wide interindividual variability in bioavailability for oral cortisone and cortisol, there is a close correlation of the serum cortisol response in each individual after oral administration of the drugs, indicating that the factors controlling the bioavailability are common for both drugs. Large individual variations in response to treatment have been observed, however. The inability of two patients with CAH to respond to treatment with cortisone acetate has been reported (19).

We report on a patient with 21-hydroxylase deficiency who, despite very high doses of cortisone and fludrocortisone, produced large amounts of androgens. The cause was found to be a congenital inability to convert cortisone to cortisol, probably because of reduced 11ß-HSD reductase activity.

	Case Report

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The girl was born at full term after normal gestation, with a birth weight of 3730 g and a length of 51 cm. Her genitalia were found to be ambiguous at birth, corresponding to Prader score 3–4 (20).

In the neonatal period, she had a tendency to lose salt despite treatment with cortisone acetate and fludrocortisone. For this reason, the patient was also given iv cortisol on two occasions. The child was discharged from the hospital at the age of 3 weeks. Mutation analysis of the 21-hydroxylase gene (14) showed a complete deletion on one chromosome and six point mutations in the other allele, rendering both alleles silent. Initially, the girl was treated with cortisone acetate and fludrocortisone, with addition of sodium chloride during the first 3 yr. In spite of this treatment, androgens and 17-OHP in serum, as well as urine P3, remained high. In an effort to suppress the adrenal androgens, the dose of cortisone acetate was drastically increased, to 65 mg/m²·day, the recommended dose being 15–20 mg hydrocortisone per m²/day (12). Nevertheless, the androgens and androgen precursors were elevated (Table 1). Her bone age was +2 SD at 1 yr of age and +4 SD at 4.3 yr of age. Despite the acceleration of bone age, the girl showed no acceleration of growth rate.

After 4 months of treatment with prednisolone, the girl was readmitted for a follow-up investigation. The treatment was changed back to cortisone acetate, in a dose equivalent to 50 mg/m²·day, divided into 3 daily doses for 5 days; and the effect was monitored with daily 17-OHP measurements. On the 1st, 3rd, and 5th days of treatment, the levels of 17-OHP, androstenedione, and testosterone in serum, as well as of plasma renin, were measured. On the 5th day, a 24-h urine sample was collected, and cortisone/cortisol metabolites and P3 were analyzed. The patient then received prednisolone (2.5 mg, twice a day, for 2 days). The following week, treatment was changed to hydrocortisone (20 mg per day, divided into three doses; 10 + 5+5), and the effect was followed (see Fig. 1).

View larger version (20K): [in this window] [in a new window]   Figure 1. The effect of different treatments [cortisone acetate (Cortisone-Ac) and prednisolone (Pred) hydrocortisone] on the serum levels of 17-OHP, androstendione (A4), and testosterone (test).

The 17-OHP was determined by RIA (CIS-Bio International, Gis-sur-yvette, Cedex, France). Serum estradiol and testosterone were determined by RIA (Diagnostic Products Corporation, Los Angeles, CA). Androstenedione was analyzed by RIA after ether extraction (21, 22). Plasma renin was determined as active renin (IRMA, Nichols Institute Diagnostics, San Juan Capistrano, CA). The urinary steroid metabolites, including P3, were determined by gas chromatography and gas chromatography-mass spectrometry (23). For bone age determination, Tanner-Whitehouse-2 RUS was used (24). The blood volume was determined with labeled iodinated albumin.

Genomic DNA was prepared from peripheral leukocytes. All exons, including exon/intron junctions of the HSD11L, were PCR amplified using sets of primers flanking each exon. Sequencing was performed using the Big Dye Primer Cycle Sequencing Ready Reaction kit and the ABI Prism 377 DNA sequencer (Perkin-Elmer Corp. PE Applied Biosystems, Foster City, CA)

	Results

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During the 5 days of treatment with cortisone acetate (50 mg/m²·day), the 17-OHP level increased from 70 to 500 nmol/L on the 5th day. A substantial amount of cortisone metabolites was detected in urine, showing that removal of the acetate group from cortisone had occurred. However, virtually no 11ß-hydroxylated cortisol metabolites were found, the ratio of cortisone to cortisol metabolites being 25:1. When the patient received hydrocortisone (30 mg/m²·day), the levels of 17-OHP, as well as other metabolites derived from cortisol precursors, decreased rapidly (see Fig. 1). As expected, the composition of steroid metabolites in the 24-h urine sample collected on the 5th day of the 2nd week (during treatment with hydrocortisone) was very different from that of the previous samples. The excretion of P3 was much lower (12 µmol/L), and the ratio of cortisone to cortisol metabolites was 3:1. Patients with CAH under good control, on cortisone acetate treatment, were reported to have ratios of 3.73 ± 0.96 (25).

The steroid metabolites have been reexamined retrospectively in urine specimens collected from the 2nd month of age and onward, and the ratio of cortisone to cortisol metabolites has been calculated. It was high at all times, also during periods with lower doses of cortisone acetate, the mean being 13.6 (range, 7–24).

After 1 yr of treatment with hydrocortisone, most of the laboratory parameters remained normal: 17-OHP, 3.8–28.6 nmol/L; androstenedione, 0.9 nmol/L; and P3, less than 1 µmol/24 h. The acceleration of bone age had stopped. The doses of hydrocortisone were 5 + 2.5 + 5 mg (which is equivalent to 14 mg cortisol/m²·day); and of fludrocortisone, 0.15 mg/day. The plasma renin levels remained high (256–1100 ng/L, reference < 35 ng/L). The blood volume was 84% of the expected value despite the relatively high dose of mineralocorticoids.

DNA sequence determination did not reveal any deviations within the exon/intron junctions of the HSD11L, as compared with the published reference sequence (4).

	Discussion

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In this patient, cortisone acetate treatment had little or no effect. The girl responded well, however, to long-term treatment with prednisolone or hydrocortisone. If inefficient acetate group removal from cortisone was the only cause, this would result in low urinary excretion of cortisone metabolites and a normal urinary cortisone-to-cortisol ratio, because the rate-limiting step would occur before this conversion. Hyperplasia of the adrenals, secondary to a long period of inadequate treatment, is known to cause therapeutic problems, and sometimes very high doses of glucocorticoids are required to suppress androgen synthesis. In this case, the inability to suppress excess androgen with cortisone treatment persisted, even after 4 months of good control of the disease with prednisolone, which rules out adrenal hyperplasia as the cause. Thus, our results indicate that the girl has had a lack of 11ß-HSD activity since birth, because the cortisone-to-cortisol ratios were very high at all times.

The most probable explanation for the resistance to cortisone therapy is that the conversion of cortisone to cortisol did not occur; and thus, the active substance was not formed. This was confirmed by the analysis of urinary metabolites of cortisone and cortisol. For normal subjects, the ratio has been reported to be 1.79 ± 0.20 (25). Thus, this patient had never had cortisone-to-cortisol ratios in the previously reported range. The deficient reduction of the oxo-group is assumed to be caused by a lack of 11-oxoreductase activity of the liver isoform of the enzyme 11ß-HSD. Sequence analysis of all coding regions and exon/intron junctions of the HSD11L failed to detect any genetic abnormalities. However, this does not rule out the possibility of a genetic lesion in the promoter or other regulatory regions of the gene. Alternatively, the patient may have a different, trans-acting genetic defect, affecting the expression of the HSD11L gene. The expression of the genes encoding both isoforms of 11ß-HSD is known to be highly regulated by both metabolic and hormonal factors, although the exact molecular mechanisms behind this regulation have not yet been determined (26, 27, 28).

The importance of 11ß-HSD has not been understood until recently; and, to the best of our knowledge, this is the first patient reported with an inability to convert cortisone to cortisol. The defect may be of considerable clinical importance, however. At least one of the previously reported patients with a reduced response to cortisone acetate treatment (19) might have had a similar reduction in enzyme activity. It has been reported that patients with CAH have significantly higher ratios of cortisone to cortisol metabolites during periods of poor therapeutic control (often during puberty) than during periods of good control, 6.56 ± 2.51 vs. 3.73 ± .0.96 (25). It has been shown, in the rat, that the hepatic isoform of 11ß-HSD is down-regulated by estradiol (29, 30, 31). Thus, it is possible that, for our patient, the situation has become progressively worse with time, i.e. that insufficient 11ß-HSD reductase activity was further down-regulated when the metabolic situation resulted in high levels of testosterone and estradiol.

The blood volume of the patient remained low also after treatment with hydrocortisone; and probably secondary to this, the renin levels in plasma were still elevated (32). High renin levels have been reported in patients with adrenal insufficiency despite high fludrocortisone substitution doses (33).

Cortisone acetate is approved worldwide for substitution therapy. However, our findings, as well as previous reports, raise the question of whether cortisone acetate should be used for treatment in children. This study has shown that treatment with cortisone acetate should be questioned when a patient requires high doses. In contrast to cortisone, hydrocortisone possesses an 11ß-hydroxyl group and does not require activation by the enzyme 11ß-HSD. This is also the case with the synthetic and extremely potent glucocorticoids, dexamethasone, and prednisolone. These can not, however, be used for substitution therapy in children, because of their growth suppressive effect, as well as the increased risk for other adverse effects, such as osteoporosis. Because there are few, if any, advantages with cortisone acetate, compared with hydrocortisone, hydrocortisone should be the drug of choice for substitution therapy in children with adrenal insufficiency.

Received June 11, 1998.

Revised January 4, 1999.

Accepted January 4, 1999.

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