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Adrenarche and Puberty in Children with Classic Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency

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Adrenarche and Puberty in Children with Classic Congenital Adrenal Hyperplasia Due to 21-Hydroxylase Deficiency Original Paper HORMONE Horm Res Paediatr 2011;76:400–410 Received: July 4, 2011 RESEARCH IN DOI: 10.1159/000333696 Accepted: September 27, 2011 PÆDIATRIC S Published online: November 24, 2011 Adrenarche and Puberty in Children with Classic Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency a a a b Thomas M.K. Völkl Lisa Öhl Manfred Rauh Christof Schöfl a Helmuth G. Dörr a Division of Pediatric Endocrinology and Diabetology, Department of Pediatrics and Adolescent Medicine, and b Division of Endocrinology and Diabetology, First Department of Internal Medicine, Friedrich Alexander University of Erlangen-Nuremberg, Erlangen-Nuremberg , Germany Key Words was normal. Conclusions: Pubarche and adrenarche are dis- Congenital adrenal hyperplasia ؒ 21-Hydroxylase ؒ sociated in classic CAH: earlier pubarche, gonadarche and Adrenarche, puberty thelarche, respectively, in both sexes contrast with the ab- sence of typical adrenarche. Copyright © 2011 S. Karger AG, Basel Abstract There have been only a few studies on adrenarche in girls with classic congenital adrenal hyperplasia (CAH) showing Introduction that dehydroepiandrosterone sulfate (DHEAS) levels did not rise at the physiological age of adrenarche. Objective: Lon- Congenital adrenal hyperplasia (CAH) due to 21-hy- gitudinal analysis of serum DHEAS levels and Tanner stages droxylase deficiency is associated with abnormally low in CAH children. Design: We studied 98 CAH patients (52 fe- cortisol and low (salt wasting, SW-CAH) or normal aldo- males), aged between 1 month and 18.0 years. All patients sterone (simple virilizing, SV-CAH) production [1, 2] . had genetically proven classic CAH and received steroid sub- Due to an intact feedback system with activation of the stitution therapy. Results: Serum DHEAS levels did not differ CRH-ACTH axis, the production of androgens and ste- between CAH children and healthy children from the age of roid precursors prior to the enzyme defect is increased [1, 1 year until 5–6 years. Beginning at the age of 7–8 years, 2] . Adequate substitution therapy with glucocorticoids there was a continuous but blunted increase in DHEAS levels and mineralocorticoids is a prerequisite in order to avoid in CAH boys and girls compared to healthy children. There short-term and/or long-term complications such as elec- was no correlation of DHEAS levels with the genotype, glu- cocorticoid dosage, auxological data, or quality of metabol- ic control. Pubarche (PH2) as well as gonadarche (G2) and Parts of this study were presented at the 47th Annual Meeting of the thelarche (B2) occurred significantly earlier in CAH boys and European Society for Paediatric Endocrinology (ESPE), September girls than in the reference group, but timing of menarche 20–23, 2008, Istanbul, Turkey. © 2011 S. Karger AG, Basel Prof. Helmuth G. Dörr, MD, Division of Pediatric Endocrinology and Diabetology 1663–2818/11/0766–0400$38.00/0 Department of Pediatrics and Adolescent Medicine Fax +41 61 306 12 34 Friedrich Alexander University of Erlangen-Nuremberg E-Mail [email protected] Accessible online at: Loschgestrasse 15, DE–91054 Erlangen (Germany) www.karger.com www.karger.com/hrp Tel. +49 913 1853 3732, E-Mail helmuth-guenther.doerr @ uk-erlangen.de trolyte imbalances, addisonian crisis, accelerated bone the data with Tanner stages of puberty. We studied po- maturation, short stature, hirsutism and virilization, de- tential contributing factors like medication dosage, bone creased fertility, obesity, and hypertension [3–5] . age, height, and various laboratory parameters such as There are contradictory reports on the onset and serum 17-OHP levels and 24-hour urine PT excretion. course of puberty in CAH. Earlier data show that the on- set of puberty in treated patients is more or less normal [6–8] . However, these studies only report the onset of pu- M e t h o d s berty, i.e. Tanner stages B2 or G2, and not their follow-up Patients or pubic hair stages [6–8] . According to two recent pa- We included 98 Caucasian children and adolescents (46 males, pers, there is an earlier onset of pubarche and thelarche 52 females), who presented regularly at our outpatient endocrine in treated children with classic CAH [9, 10] , whereas tim- unit. All individuals had classic CAH with 21-hydroxylase defi- ing of menarche is normal [10] . ciency (salt wasting, SW: n = 79; simple virilizing, SV: n = 19). The phenotype classification was based on clinical and hormonal cri- The increase in the secretion of dehydroepiandros- teria, and the diagnosis was confirmed in all patients with molecu- terone (DHEA) and its sulfate ester (DHEAS) typically at lar genetic analyses by direct sequencing (after exclusion of dele- the age of 5–6 years reflects the development of the zona tions). The disease-causing mutations were divided into four muta- reticularis of the adrenal cortex and is called adrenarche tion groups (0, A, B, and D) as previously described by Speiser et [11] . The mechanisms that initiate adrenarche are not al. [20] (online suppl. material 1, for all online suppl. material, see www.karger.com/doi/10.1159/000333696). All patients received known in detail to date. However, the increase in 17,20-ly- glucocorticoid substitution/androgen-suppressive therapy with ase activity, IGF-1, and insulin concentrations, and the hydrocortisone (HC), prednisone (PR) or dexamethasone (DX). nutritional status play a role besides CRH and ACTH [11, HC was given three times daily ( ϳ 50% of the daily dosage in the 12] . Pubarche, the development of pubic hair, is the clini- early morning, 25% at noon, and 25% in the evening); PR was giv- cal sign of adrenarche. Both terms, pubarche and adren- en twice and DX once daily in the morning. 96 patients addition- ally received fludrocortisone (twice daily) due to mineralocorti- arche, are usually used as synonyms, but a dissociation coid insufficiency diagnosed based on elevated renin concentra- between pubarche and biochemical markers of adren- tions. The quality of therapy was monitored during follow-up visits arche can occur, e.g. in girls with Turner syndrome [13] . every 3–6 months by clinical presentation, bone age (BA) accelera- The dichotomy whether DHEAS levels can serve as a tion and laboratory measurements according to current guidelines measure of disease control or as a target for suppression [21] . None of the patients included in this study showed signs of severe under- or overtreatment such as Cushing’s syndrome, severe by glucocorticoid therapy can be neglected, since in clin- hirsutism, increasing clitoris length, or growth failure. ical practice, DHEAS levels are not used to measure dis- ease control [1, 2] . CAH children with poor metabolic Study Design control have for example high serum 17-hydroxyproges- The longitudinal data of all patients were retrospectively as- terone (17-OHP) and urine pregnanetriol (PT) levels but certained from patient charts and the digital in-house CAH data- base. Based on the 98 patients, data from a total of 1,047 patient- normal or low serum DHEAS levels. years were available (males 433 years, females 614 years). The Only a few studies on adrenarche in children with average available follow-up interval was 10.7 years 8 5.05 SD, classic CAH have found low serum DHEAS levels in well- median 10 years, range 1–18 years (males 9.41 8 5.29 years, fe- controlled patients [14–17] . Despite blunted adrenarche, males 11.8 8 4.59 years). The study was approved by our institu- the onset of pubarche (PH2) in children with classic CAH tional review board. All subjects and parents gave their written informed consent/assent. was found to be earlier in females and males with both Standardized physical examination in our department includ- clinical forms than in controls with a significantly earlier ed the measurement of height (Harpenden stadiometer), weight onset in SV-CAH than in SW-CAH [10] . (without clothes, except underwear), and the assessment of puber- Besides the known hormonal effects as an androgen, tal status (Tanner stages). Height standard deviation scores (SDS) recent studies show positive effects of DHEA on well-be- were calculated using German references [22] . Pubarche was de- fined as the appearance of pubic hair (PH2), whereas puberty was ing and sexuality in adult females with adrenal insuffi- defined as Tanner stage B2 in girls (by inspection and palpation) ciency [18] . Binder et al. [19] reported that atrichia pubis and testicular sizes 1 3 ml (G2) in boys, respectively. vanishes and psychological well-being improves signifi- Equivalent HC dosages (eHC) were calculated for PR and DX cantly by daily replacement with 25 mg DHEA orally in (factors 4 and 30, respectively) [23] . BA was assessed by an expe- adolescent girls with central adrenal insufficiency. rienced observer using the atlas method of Greulich & Pyle, which has been found to be reliable for Central European children [24] . Hence, the aim of this retrospective, single-center, lon- For the evaluation of the current status of skeletal maturation, we gitudinal study was to measure serum DHEAS levels in a calculated the difference between BA and chronological age (CA) large cohort of patients with classic CAH and to correlate (BA delay, ⌬ BA = BA – CA in years) [4, 23] . Adrenarche and Puberty in CAH Horm Res Paediatr 2011;76:400–410 401 Children Table 1. Detailed clinical and laboratory cohort data of the chil- measured with the new established LC-MS/MS method. Intra- dren with classic CAH and interassay CV were below 10%; the limit of detection was 0.05 ng/ml. The reliability of both assays was investigated and pub- Males, n = 46 F emales, n = 52 p lished elsewhere [25] . The conversion factor from ng/ml to nmol/l is 3.03. Levels of PT in specimens of urine collected during 24 h 8 8 male vs. mean SD mean SD were simultaneously determined by isotope dilution/gas chroma- median [quartiles] median [quartiles] female tography-mass spectrometry procedure.
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