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      Restoration of Height after 11 Years of Letrozole Treatment in 11β-Hydroxylase Deficiency

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          Abstract

          11β-hydroxylase deficiency (11β-OHD) is the second most common form of congenital adrenal hyperplasia (CAH). Males with 11β-OHD CAH are often diagnosed late with a significantly advanced bone age leading to a poor height prognosis due to early closure of epiphysis. Delaying epiphyseal fusion by treatment of aromatase inhibitors (AIs) might be a useful strategy in patients with very advanced bone ages. However, there are limited data regarding the effect on final height and long-term safety of this approach. We report our experience with 11 years of letrozole treatment and 17 years of follow-up in a boy with 11β-OHD. He presented at 2 years and 11 months of age with a bone age of 13 years (predicted adult height, PAH, 129.5 cm). Letrozole was added after 1 year of glucocorticoid treatment due to no improvement in height prognosis (130 cm), and continued until the age of 14 years and 11 months. He also received GnRH analog treatment at 10 years and 3 months of age for 2.5 years due to central activation of puberty. He reached a final height of 165.2 cm (35.2 cm above his PAH). This long-term treatment with letrozole was associated with changes in vertebral morphology such as vertebral body end-plate changes, Schmorl nodes, and mild protrusions in the intervertebral discs. Testicular volumes, gonadotropins, testosterone, and anti-Müllerian hormone were normal at age 20 years. A spermiogram showed a normal count but impaired sperm motility and morphology. This unique case represents the longest duration of AI treatment reported in CAH and the first case in which letrozole was started before puberty with the final height reported. We conclude that AIs may restore height in selected patients with CAH with very advanced bone age and severely compromised height prognosis.

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          Most cited references 23

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          Reduced final height outcome in congenital adrenal hyperplasia under prednisone treatment: deceleration of growth velocity during puberty.

          Normal to decreased final height (FH) has been reported in patients with congenital adrenal hyperplasia (CAH). The objective was to determine FH outcome and influences of steroid treatment. The effects of glucocorticoid treatment for classical CAH were retrospectively studied in 125 patients (77 females). Growth pattern, FH, and pubertal development were recorded. Corrected FH was in the lower range of genetic potential [females with simple virilizing (SV)-CAH, -0.6 +/- 1.0 sd score (SDS) vs. females with salt-wasting (SW)-CAH, -0.6 +/- 0.9 SDS; males with SV-CAH, -1.1 +/- 0.9 SDS vs. males with SW-CAH, -0.9 +/- 0.9 SDS]. Total pubertal growth was significantly reduced in comparison with a reference population (females with SV-CAH, 11.9 +/- 6.5 cm, and females with SW-CAH, 13.8 +/- 7.6 cm vs. reference 20.3 +/- 6.8 cm, P < 0.01; and males with SV-CAH, 15.4 +/- 6.6 cm, and males with SW-CAH, 18.5 +/- 6.9 cm vs. reference 28.2 +/- 8.2 cm, P < 0.01). Thirty-three patients had been treated with prednisone, which resulted in reduced FH compared with patients (n = 92) treated with hydrocortisone (-1.0 +/- 0.9 SDS vs.-0.6 +/- 0.9 SDS; P < 0.05). FH correlated negatively with hydrocortisone dose given at the start of puberty (r = -0.3; P < 0.05). Pubertal development started early in boys [9.8 +/- 2.3 yr (SV) and 10.6 +/- 1.9 yr (SW)] and was timely in girls [9.8 +/- 1.9 yr (SV) and 10.3 +/- 1.5 yr (SW), menarche at 13.3 +/- 1.7 yr (SV) and 13.7 +/- 1.5 yr (SV)]. Patients with CAH are able to achieve adequate FH with conventional therapy. Total pubertal growth is significantly decreased, and treatment with prednisone results in decreased FH. In addition to biochemical analysis, treatment should be adjusted to normal growth velocity, especially during puberty.
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            Inhibition of estrogen biosynthesis with a potent aromatase inhibitor increases predicted adult height in boys with idiopathic short stature: a randomized controlled trial.

            In males as well as in females, estrogen is an essential regulator of bone maturation, growth plate fusion, and cessation of longitudinal growth. Therefore, an increase in predicted adult height (PAH) may be achieved in short boys by blocking estrogen biosynthesis. We tested the hypothesis that a decrease in the rate of bone maturation and an increase in PAH can be achieved in boys with idiopathic short stature (ISS) by the method of blocking estrogen biosynthesis with an aromatase inhibitor. Secondarily, we investigated the effects of aromatase inhibition on bone mineralization. This was a prospective, double-blind, randomized, placebo (Pl)-controlled clinical study. The study was performed at a university hospital out-patient clinic. Thirty-one boys, aged 9.0-14.5 yr, with ISS were studied. The boys were treated with the aromatase inhibitor letrozole (Lz; 2.5 mg/d) or Pl for 2 yr. The main outcome measure was the change in PAH after 24 months of treatment. PAH increased by 5.9 cm (P < 0.0001), and height SD score for bone age increased by 0.7 SD score (P < 0.0001) in the Lz-treated boys, whereas no changes occurred in the respective measures in Pl-treated boys. Areal bone mineral density of the lumbar spine and femoral neck, assessed by dual-energy x-ray absorptiometry, increased in a similar fashion in both groups during the treatment, whereas bone mineral apparent density increased only in those taking Lz (median increase, 4.3%; P = 0.009). Treatment with the aromatase inhibitor Lz delays bone maturation and improves PAH in boys with ISS. No adverse effects on bone mineralization were evident after 2 yr of treatment.
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              A specific aromatase inhibitor and potential increase in adult height in boys with delayed puberty: a randomised controlled trial.

              The role of oestrogens in the closure of growth plates in both sexes is unequivocal. We postulated that inhibition of oestrogen synthesis in boys with delayed puberty would delay maturation of the growth plates and ultimately result in increased adult height. We did a randomised, double-blind, placebo-controlled study in which we treated boys with constitutional delay of puberty with testosterone and placebo, or testosterone and letrozole. Boys who decided to wait for the spontaneous progression of puberty without medical intervention composed the untreated group. Letrozole effectively inhibited oestrogen synthesis and delayed bone maturation. Progression of bone maturation was slower in the letrozole group than in the placebo group. In 18 months, bone age had advanced 1.1 (SD 0.8) years in the untreated group and 1.7 (0.9) years in the group treated with testosterone and placebo, but only 0.9 (0.6) years in the letrozole group (p=0.03 between the treatment groups). Predicted adult height did not change significantly in the untreated group and in the placebo group, whereas in the group treated with letrozole the increase was 5.1 (3.7) cm (p=0.004). Our findings suggest that if oestrogen action is inhibited in growing adolescents, adult height will increase. This finding provides a rationale for studies that aim to delay bone maturation in several growth disorders.
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                Author and article information

                Journal
                HRP
                Horm Res Paediatr
                10.1159/issn.1663-2818
                Hormone Research in Paediatrics
                S. Karger AG
                1663-2818
                1663-2826
                2019
                February 2020
                27 August 2019
                : 92
                : 3
                : 203-208
                Affiliations
                aDepartment of Pediatric Endocrinology and Diabetes, Marmara University, Istanbul, Turkey
                bDepartment of Radiology, Marmara University, Istanbul, Turkey
                cDepartment of Pediatric Endocrinology, Medipol University, Istanbul, Turkey
                Author notes
                *Dr. Zeynep Atay, Fevzi Cakmak, Mh. Mimar Sinan Cad. No. 41 Pendik, TR–34692 Istanbul (Turkey), E-Mail atay.zeynep@yahoo.com
                Article
                501456 Horm Res Paediatr 2019;92:203–208
                10.1159/000501456
                31454824
                © 2019 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 2, Tables: 1, Pages: 6
                Categories
                Novel Insights from Clinical Practice / Case Report

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