The urinary steroidome of treated children with classic 21-hydroxylase deficiency

https://doi.org/10.1016/j.jsbmb.2016.08.006Get rights and content

Highlights

  • Daily urinary steroid metabolite excretion of treated children with CAH are presented.

  • 11β-Hydroxyandrosterone was the dominant urinary adrenal-derived androgen metabolite.

  • Adrenarche is blunted in children with CAH under hydrocortisone treatment.

  • Cortisol metabolite excretion reflected supraphysiological hydrocortisone treatment dosage.

Abstract

Monitoring treatment of children with classic congenital adrenal hyperplasia (CAH) is difficult and biochemical targets are not well defined.

We retrospectively analysed 576 daily urinary steroid hormone metabolite profiles determined by gas chromatography–mass spectrometry of 150 children aged 3.0–17.9 years with classic 21-hydroxylase deficiency (21-OHD) on hydrocortisone and fludrocortisone treatment.

Daily urinary excretion of glucocorticoid-, 17α-hydroxyprogesterone (17-OHP)-, and androgen metabolites as well as growth and weight gain are presented. Children with classic CAH exhibited increased height velocity during prepubertal age, which was then followed by diminished growth velocity during pubertal age until final height was reached. Final height was clearly below the population mean. 11β-Hydroxyandrosterone was the dominant urinary adrenal-derived androgen metabolite in CAH children. Adrenarche is blunted in children with CAH under hydrocortisone treatment and androgen metabolites except 11β-hydroxyandrosterone were suppressed. Cortisol metabolite excretion reflected supraphysiological hydrocortisone treatment dosage, which resulted in higher body-mass-indices in children with CAH.

Reference values of daily urinary steroid metabolite excretions of treated children with CAH allow the clinician to adequately classify the individual patient regarding the androgen-, 17-OHP-, and glucocorticoid status in the context of the underlying disorder. Additionally, urinary 21-OHD-specific reference ranges will be important for research studies in children with CAH.

Introduction

21-Hydroxylase deficiency (21-OHD) is the most common form of congenital adrenal hyperplasia (CAH). 21-OHD is caused by mutations in CYP21A2, the gene encoding the adrenal steroid 21-hydroxylase enzyme (CYP21A2). Inefficient cortisol synthesis in patients with CAH leads to adrenal stimulation, but rather than cortisol, the adrenals produce excess androgen precursors that do not require 21-hydroxylation for their synthesis [1] (Fig. 1).

The aim of treatment of children with classic CAH with glucocorticoids consists in replacing the lack of cortisol and suppressing excess adrenal androgen production. Clinical management of classic CAH is a difficult balance between androgen and cortisol excess [2]. However, monitoring of treatment is difficult in CAH [3]. Laboratory data should indicate the need for dose adjustment. Serum or plasma concentrations of 17α-hydroxyprogesterone (17-OHP), androstenedione and testosterone are currently the most widely used indicators to monitor glucocorticoid treatment [2], [3]; however, biochemical targets of disease control are not well defined and random measurement of plasma concentrations of 17-OHP and androgens on a clinical visit is of only limited value in patients with CAH because it does not reflect a patient’s circadian pattern of adrenal steroid secretion [4], [5].

Analysis of urinary steroid hormone metabolites by gas chromatography–mass spectrometry (GC–MS) (urinary steroidomics) is a non-invasive diagnostic means and provides an overview of the whole spectrum of adrenal steroids in a CAH patient, including glucocorticoid, androgen and 17-OHP metabolites in parallel (Fig. 1). In contrast to the determination of single steroids in a single plasma sample 24-h urinary steroid profile analysis provides an assessment of daily steroid excretion rates [6], [7], [8].

The aim of our study was to analyse retrospectively 24-h urinary steroid metabolite excretion in a large cohort of children with classic CAH due to 21-OHD treated with hydrocortisone and fludrocortisone to characterize their daily excretion pattern of androgen-, 17-OHP-, and cortisol metabolites in the context of their growth and weight gain, and to provide 21-OHD specific reference values. 21-OHD specific reference values could help to classify the individual CAH patient’s urinary steroid metabolome on the basis of a large reference cohort and could be important for research studies in children with CAH.

Section snippets

Patients

Inclusion criteria for our retrospective analysis were: 1.) classic CAH due to 21-OHD. The diagnosis of classic 21-OHD was made on the basis of the characteristic urinary steroid metabolite profile determined by GC–MS analysis with highly elevated concentrations of 17-OHP and 21-deoxycortisol metabolites [8], [9], [10] and of requirement of mineralocorticoid (fludrocortisone) replacement therapy; 2.) oral hydrocortisone given in three divided doses, as the only glucocorticoid replacement

Results

The growth analysis of our CAH cohort demonstrated that the children with 21-OHD started at 3 years of age with a height similar to that of the healthy reference population (Fig. 2A + B; Table 2). Thereafter, children with CAH exhibited an increased height velocity during prepubertal age. This was much more pronounced in boys. Boys reached their maximum height-SDS at about 10 years and girls at about 6 years of age. The period of increased height gain was then followed by a substantial loss of

Discussion

This study characterizes the urinary steroid metabolome of children with classic CAH due to 21-OHD treated with oral hydrocortisone and fludrocortisone, including the daily urinary excretion of cortisol-, 17-OHP- and androgen metabolites in combination with their growth and weight development.

The growth of the children of our cohort indicated that children with CAH exhibit a prepubertal overgrowth, while the pubertal growth spurt is diminished, a finding reported by others as well [26], [27],

Disclosure

The authors have nothing to disclose.

Acknowledgements

We thank Dr. Adrian Sewell for correcting and reading the manuscript. We thank B. Wardega, C. Gregor and L. Hamann for their support in the laboratory. We are indebted to Prof. Dr. T. Remer and Dr. L Shi, Institute of Nutritional and Food Sciences, University of Bonn, for their analysis of the references of daily 11β-hydroxyandrosterone of healthy children.

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    1

    Both authors contributed equally to this work.

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