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Endocrine Care: Vania Tonetto-Fernandes, Sofia H. V. Lemos-Marini, Hilton Kuperman, Luciane M. Ribeiro-Neto, Ieda T. N. Verreschi, Claudio E. Kater and the Brazilian Congenital Adrenal Hyperplasia Multicenter Study Group Serum 21-Deoxycortisol, 17-Hydroxyprogesterone, and 11-Deoxycortisol in Classic Congenital Adrenal Hyperplasia: Clinical and Hormonal Correlations and Identification of Patients with 11ß-Hydroxylase Deficiency among a Large Group with Alleged 21-Hydroxylase Deficiency J Clin Endocrinol Metab 2006; 91: 2179-2184 [Abstract] [Full text] [PDF]

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Vania Tonetto-Fernandes   (13 March 2007)

Elevated 17-Hydroxyprogesterone Concentrations In Pubertal Patients with Classic CAH

Evangelia Charmandari   (7 September 2006)

Response to E-Letter 13 March 2007
Vania Tonetto-Fernandes, MD Universidade Federal de Sao Paulo Send letter to journal: Re: Response to E-Letter vaniatonetto{at}uol.com.br Vania Tonetto-Fernandes	We thank Dr. E. Charmandari for her important comments on our paper (1) and for the opportunity to reply expressing our views on the matter. The subgroup of patients mentioned by Dr. Charmandari is, indeed, an enigma. Surprisingly, their 08:00h serum levels of testosterone were not different from prepubertal patients (114 ± 121 vs 116 ± 115 ng/dl, respectively), and did not correlate with 17OHP levels. Unfortunately, we did not determine either ACTH or androstenedione levels in these subjects. The extremely elevated levels of 17OHP uncontrolled with glucocorticoid in nearly pharmacological doses could have several explanations. The most simplistic is poor adherence to treatment and the contribution of an extra-adrenal source of steroids typical of puberty. We agree that the pharmacokinetic changes in cortisol metabolism due or related to the endocrine milieu characteristic of puberty (increased cortisol clearance and shorter half-life of free cortisol) could be involved. Dr. Charmandari's group has shed light on this question (2). While shortening the intervals between doses in the adolescent might be pharmacokinetically appropriate, in our opinion, this would jeopardize adherence. Alternatively one could switch replacement therapy to synthetic glucocorticoids with longer half-lives in appropriate bioequivalent doses (3). Dr. Charmandari's supposition regarding alterations in the GH/IGF-1 axis, insulin concentration and sensitivity, and their possible implications in subsequent hypocortisolism and hyperandrogenism is very interesting. Although we did not investigate these issues in detail, we concur that they may play an important role in the failure to suppress ACTH appropriately in the adolescent patient with 21-hydroxylase deficiency. Also, in none of our patients was an adrenalectomy erformed nor an adrenal rest tumor or ACTH-secreting pituitary tumor suspected or detected. Finally, for the past three years we have therapeutically managed these and even younger patients with a single morning dose of prednisolone (2.5-4 mg/m2 BSA) without observing any significant side- effects, as increase in body mass index (Z score for BMI) or decrease in growth velocity (Z score for GV) (3). References 1. Tonetto-Fernandes V, Lemos-Marini SH, Kuperman H, Ribeiro-Neto LM, Verreschi IT, Kater CE 2006. Serum 21-Deoxycortisol, 17-Hydroxyprogesterone, and 11-deoxycortisol in classic congenital adrenal hyperplasia: clinical and hormonal correlations and identification of patients with 11β-hydroxylase deficiency among a large group with alleged 21-hydroxylase deficiency. J Clin Endocrinol Metab 91:2179-2184 2. Charmandari E, Hindmarsh PC, Johnston A, Brook CG. 2001. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: alterations in cortisol pharmacokinetics at puberty. J Clin Endocrinol Metab 86:2701-2708 3. Caldato MCF, Fernandes VT, Kater CE 2004. One-year clinical evaluation of single morning dose prednisolone therapy for 21-hydroxylase deficiency. Arq Bras Endocrinol Metab 48:705-712
Elevated 17-Hydroxyprogesterone Concentrations In Pubertal Patients with Classic CAH 7 September 2006
Evangelia Charmandari, Consultant Pediatric Endocrinologist St. James University Hospital & Leeds General Infirmary, Leeds, LS2 9NS, United Kingdom Send letter to journal: Re: Elevated 17-Hydroxyprogesterone Concentrations In Pubertal Patients with Classic CAH charmane{at}mail.nih.gov Evangelia Charmandari	I read with great interest the extremely important article entitled ‘Serum 21- deoxycortisol, 17-hydroxyprogesterone, and 11-deoxycortisol in classic congenital adrenal hyperplasia: Clinical and hormonal correlations and identification of patients with 11beta-hydroxylase deficiency among a large group with alleged 21-hydroxylase deficiency’ by Tonetto-Fernandes et al. (1). However, the markedly elevated 17-hydroxyprogesterone (17-OHP) concentrations in patients receiving hydrocortisone doses of 20-30+ mg/m2/day are notable. Interestingly, 80% of these subjects were pubertal (median age: 12.5 years) and their 17-OHP concentrations (11,020 ng/dL) were higher than those observed (9,000 ng/dL) in the untreated group of patients with classic CAH. It would be interesting to know the 08:00h plasma adrenocorticotropic hormone (ACTH) and serum androgen concentrations in these subjects. In addition to lack of adherence to medical therapy, the elevated 17-OHP concentrations in this group of patients may be due to physiologic alterations in the endocrine milieu at puberty, which result in increased cortisol clearance and shorter half life of free cortisol (2). Alterations in the GH/IGF-I axis, insulin sensitivity and the activity of enzymes participating in cortisol metabolism (11beta-hydroxysteroid dehydrogenase) and adrenal steroidogenesis (17alpha-hydroxylase and 3beta-hydroxysteroid dehydrogenase) may account for the documented hypocortisolism and hyperandrogenism, and may explain the difficulty in achieving and maintaining adrenocortical suppression in pubertal patients with classic CAH (2). Furthermore, pubertal patients with classic 21-hydroxylase deficiency have significantly higher serum insulin concentrations than those expected to arise as a result of the pubertal process itself, and a higher insulin resistance index than their normal counterparts (ref. 3 and unpublished data). Insulin stimulates primarily adrenal and to a lesser extent ovarian steroidogenesis, and constitutes an important component of the pathogenetic mechanism of hyperandrogenism, which predisposes female subjects to the development of polycystic ovarian syndrome. Both hypocortisolism and hyperandrogenism lead to increased secretion of ACTH, which may further amplify hypocortisolism by increasing the metabolic clearance rate of cortisol. Finally, insulin inhibits basal and/or glucocorticoid-induced transcription of genes (gluconeogenic genes) by targeting the ligand-binding domain of the glucocorticoid receptor or a cofactor interacting with this domain (4). Although there are no data to support a similar effect of insulin on the transcription of other glucocorticoid-induced target genes, it is likely that insulin inhibits normal glucocorticoid signal transduction, inducing a state of glucocorticoid resistance. Other rare causes of markedly elevated 17-OHP concentrations in pubertal patients with classic CAH include ACTH-induced activation of ovarian or testicular adrenal rests following chronic ACTH hypersecretion and/or the development of an ACTH-secreting adenoma. The latter may be due to the longstanding presumed corticotropin-releasing hormone (CRH), arginine vasopressin (AVP) and/or other ACTH secretagogue hypersecretion, and might resemble the development of pituitary tumors secondary to primary target gland insufficiency, such as those described in Addison’s disease, glucocorticoid resistance or untreated/undertreated CAH (5). I would be interested in having the authors’ views on the above comments. I would also be interested to know whether these patients have had any further investigations to determine the cause(s) of suboptimal control of their condition. References 1. Tonetto-Fernandes V, Lemos-Marini SH, Kuperman H, Ribeiro-Neto LM, Verreschi IT, Kater CE. 2006. Serum 21-Deoxycortisol, 17-Hydroxyprogesterone, and 11-deoxycortisol in classic congenital adrenal hyperplasia: clinical and hormonal correlations and identification of patients with 11beta- hydroxylase deficiency among a large group with alleged 21-hydroxylase deficiency. J Clin Endocrinol Metab 91:2179-2184. 2. Charmandari E, Hindmarsh PC, Johnston A, Brook CG. 2001. Congenital adrenal hyperplasia due to 21-hydroxylase deficiency: alterations in cortisol pharmacokinetics at puberty. J Clin Endocrinol Metab 86:2701-2708. 3. Charmandari E, Weise M, Bornstein SR, Eisenhofer G, Keil MF, Chrousos GP, Merke DP. 2002. Children with classic congenital adrenal hyperplasia have elevated serum leptin concentrations and insulin resistance: potential clinical implications. J Clin Endocrinol Metab 87:2114-2120. 4. Pierreux CE, Urso B, De Meyts P, Rousseau GG, Lemaigre FP. 1998. Inhibition by insulin of glucocorticoid-induced gene transcription: involvement of the ligand-binding domain of the glucocorticoid receptor and independence from the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways. Mol Endocrinol 12:1343-1354. 5. Charmandari E, Chrousos GP, Merke DP. 2005. Adrenocorticotropin hypersecretion and pituitary microadenoma following bilateral adrenalectomy in a patient with classic 21-hydroxylase deficiency. J Pediatr Endocrinol Metab 18:97-101.