Height Velocity Defined Metabolic Control in Children With Congenital Adrenal Hyperplasia Using Urinary Steroid GC-MS Analysis.

BACKGROUND: Treatment of children with classic congenital adrenal hyperplasia (CAH) with glucocorticoids is a difficult balance between hypercortisolism and hyperandrogenism. Biochemical monitoring of treatment is not well defined. Achievement of a normal growth rate is the most important therapeutic goal. METHODS: We retrospectively evaluated 123 24-hour gas chromatography-mass spectrometry urinary steroid metabolome analyses together with their corresponding 1-year height velocity (HV) z scores in 63 prepubertal children aged 7.2 ± 1.6 years with classic CAH due to 21-hydroxylase deficiency treated with hydrocortisone and fludrocortisone. RESULTS: Multivariate linear mixed effects model analysis revealed a positive influence of CAH-specific z scores of summed urinary androgen metabolites (B = 0.97 ± 0.20, t = 4.87, P < 0.0001) and a negative influence of the cortisol metabolite tetrahydrocortisol (B = -1.75 ± 0.79, t = -2.20, P = 0.03) on HV z scores. Receiver operating characteristic analysis demonstrated that adrenal androgen excess, defined as HV >1.5 z, was best determined by a z score of all urinary androgen metabolites of >0.512 [accuracy, 66.2%; sensitivity, 57.1%; specificity, 74.4%; positive prediction value (PPV), 66.7%; negative prediction value (NPV), 65.9%]. Tetrahydrocortisol excretion >1480 µg/m2 BSA/d in conjunction with suppressed urinary androgen metabolites <0.163 z indicated overtreatment, defined as HV < -1.5 z (accuracy, 79.6%; sensitivity, 40.0%; specificity, 94.9%; PPV, 75.0%; NPV, 80.4%). CONCLUSION: We established target values for urinary steroid metabolite excretions in children with CAH based on their growth rate. Urinary steroid metabolome analysis represents a highly suitable method for monitoring metabolic control in children with CAH.

Androgen excess is due to elevated 11-oxygenated androgens in treated children with congenital adrenal hyperplasia.

Adrenal androgen excess is the hallmark of classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. Recently, 11-oxygenated C19 steroids, a class of highly active adrenal-derived androgens, have been described in patients with CAH. The aim of our study was to elucidate the significance of 11-oxygenated androgens in children with CAH. We retrospectively analysed 190 daily urinary excretion rates of glucocorticoid-, 17α-hydroxyprogesterone (17OHP)-, and androgen metabolites determined by gas chromatography-mass spectrometry of 99 children aged 3.0-10.9 years with classic CAH on hydrocortisone and fludrocortisone treatment. Daily urinary steroid metabolite excretions were transformed into z-scores using references of healthy children. Androgen metabolite z-scores were separately calculated for androsterone (AN), the major urinary metabolite of androstenedione (A4), testosterone and 5α-dihydrotestosterone, for urinary metabolites of dehydroepiandrosterone (DHEA), and for 11ß-hydroxyandrosterone (11OHAN), the major urinary metabolite of adrenal-derived 11-oxygenated androgens. Multivariate regression analysis was applied to analyse the precursors of 11OHAN synthesis. 11OHAN, cortisol-, and 17OHP metabolite z-scores were elevated in treated children with CAH, whereas AN- and DHEA metabolite z-scores were normalized or suppressed. Multivariate regression analysis revealed that 11OHAN excretion was strongest associated with 21-deoxycortisol (ß = 0.379; P =.0006), followed by A4 (ß = 0.280; P = .0008)) and 17OHP (ß = 0.243; P = .04) metabolite excretion. Androgen excess in treated children with CAH is solely due to elevated 11-oxygenated androgens that derive in addition to the known conversion from A4 also by direct conversion from 21-deoxycortisol. 11-Oxygenated androgens may represent better biomarkers of adrenal androgen status and treatment response than conventional androgens.

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

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. 11ß-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 11ß-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.