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      Increased final adult height by gonadotropin-releasing hormone agonist in girls with idiopathic central precocious puberty

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          Abstract

          Objective

          Gonadotropin-releasing hormone agonists (GnRHa) are the treatment of choice for central precocious puberty (CPP) and have been widely used for several decades. We determined the effect of GnRHa treatment on the auxological outcomes of girls with idiopathic CPP.

          Methods

          This study included 84 girls treated monthly with depot leuprolide acetate who had reached adult height. We compared their final adult height (FAH) with their initial predicted adult height (PAH). We performed a multivariate analysis of the factors associated with FAH on all girls diagnosed with CPP.

          Results

          We performed the final evaluations at a mean age of 14.1 ± 0.8 years after a mean treatment duration of 2.98 ± 0.73 years (ranging from 1.5–4.8 years). Menarche had occurred at 12.6 ± 0.6 years of age, which was 16.5 ± 6.1 months after discontinuation of GnRHa therapy. Mean FAH was 160.1 ± 5.0 cm, which was significantly higher than the initial PAH (156.1 ± 5.7 cm; P < 0.001). To investigate whether growth outcomes were influenced by the age at initial treatment, we divided all patients into two groups, those treated between 6 and 8 years (n = 23) and those treated after 8 years (n = 61); no significant differences were observed in FAH between the two groups. FAH was significantly and positively correlated with the height standard deviation score (SDS) at the end of treatment and with the target height, whereas the difference between bone age and chronological age at the start and end of treatment was negatively correlated with FAH.

          Conclusion

          FAH was significantly higher than the initial PAH in girls with CPP who were treated with GnRHa. Also, GnRHa treatment was still effective even after 8 years of age in girls with CPP.

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          Most cited references22

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          Tables for predicting adult height from skeletal age: revised for use with the Greulich-Pyle hand standards.

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            Growth pattern and final height after cessation of gonadotropin-suppressive therapy in girls with central sexual precocity.

            The objective of the study was to determine whether height gain after discontinuation of gonadotropin-suppressive (GnRHa) therapy differs in girls with sexual precocity diagnosed at various ages and assess its influence on final height (FHt) outcome. We compared data on post-GnRHa treatment course and FHt of 115 girls [22 diagnosed before chronological age of 6 yr; 38 between ages 6 and 8 yr; and 55 early fast puberty (EFP) between ages 8 and 9 yr] treated with GnRHa from Tanner stage 2-3 to chronological age 11-12 yr and bone age 12-12.5 yr. Despite comparable bone age at cessation of treatment, similar time to resumption of puberty (0.6 +/- 0.7, 0.5 +/- 0.7, and 0.5 +/- 0.7 yr), and age at menarche (12.6 +/- 0.5, 12.6 +/- 0.6, and 12.7 +/- 0.9 yr), height gain from cessation of therapy to FHt was greater and time to epiphyseal fusion was longer in the younger central precocious puberty (CPP) than in the older CPP (P < 0.05) and EFP (P < 0.001) groups. The percentage of residual growth predicted at discontinuation of treatment was achieved only by the younger CPP (6.6 +/- 1.6% vs. 6.7 +/- 1.6%), whereas in older CPP and EFP, it was significantly lower (6.2 +/- 1.6% vs. 4.6 +/- 2.7% and 6.3 +/- 1.5% vs. 3.6 +/- 1.5%, respectively). FHt of these two groups was compromised, compared with FHt predicted at discontinuation of treatment (P < 0.01 and P < 0.001, respectively). Girls with sexual precocity diagnosed after the age of 6 yr exhibit earlier epiphyseal fusion with diminished posttreatment height gain and compromised FHt. Because recovery of gonadal axis was similar in all girls, differences were probably due to pretreatment intrinsic changes in the growth plate. Prediction of residual growth at discontinuation of treatment is unreliable in these girls.
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              Increased final height in precocious puberty after long-term treatment with LHRH agonists: the National Institutes of Health experience.

              We report 98 children who have reached final adult height in a long-term trial of LHRH agonist treatment. These children were 5.3 +/- 2.1 yr old at the start of treatment and were treated with either deslorelin (4 microg/kg.d sc) or histrelin (4-10 microg/kg.d) for an average of 6.1 +/- 2.5 yr. Final height averaged 159.8 +/- 7.6 cm in the 80 girls, which was significantly greater than pretreatment predicted height (149.3 +/- 9.6 cm) but still significantly less than midparental height (MPH) (163.7 +/- 5.6). Final height averaged 171.1 +/- 8.7 cm in the 18 boys, which was significantly greater than pretreatment predicted height (156.1 +/- 14.2 cm) but still significantly less than MPH (178.3 +/- 5.2 cm). However, the average adult height of the 54 children who had less than a 2-yr delay in the onset of treatment was not significantly different from their MPH, and 21 children exceeded MPH. Final height SD score correlated positively with duration of treatment (P < 0.01), midparental height (P < 0.001), predicted height at the start of treatment (P < 0.001), and growth velocity during the last year of treatment (P < 0.001) and correlated inversely with delay in the onset of treatment (P < 0.001), age at the start of treatment (P < 0.001), bone age at the start of treatment (P < 0.001), bone age at the end of treatment (P < 0.001), breast stage at the start of treatment (P = 0.02), and bone age minus chronological age at the start of treatment (P = 0.001). We conclude that LHRH agonist treatment improves the final height for children with rapidly progressing precocious puberty treated before the age of 8 yr for girls or 9 yr for boys. Less delay in the onset of treatment, longer duration of treatment, and lower chronological and bone age at the onset of treatment all lead to greater final height. All children with onset of pubertal symptoms before age 8 in girls and age 9 in boys should be evaluated for possible treatment. Treatment is appropriate in children with rapidly progressing puberty, accelerated bone maturation, and compromise of adult height prediction, regardless of bone age or chronological age at time of evaluation. However, once treatment is considered appropriate, it should be initiated quickly, because longer delays lead to shorter final height. In addition, the longer the treatment is continued, the greater is the final height outcome.
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                Author and article information

                Contributors
                Role: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: ValidationRole: Writing – original draft
                Role: Data curationRole: Methodology
                Role: Data curation
                Role: ConceptualizationRole: SupervisionRole: Validation
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                22 August 2018
                2018
                : 13
                : 8
                : e0201906
                Affiliations
                [001]Department of Pediatrics, Ajou University School of Medicine, Ajou University Hospital, Suwon, Korea
                Florida International University, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-9684-4042
                http://orcid.org/0000-0003-2331-1680
                http://orcid.org/0000-0002-2666-3801
                Article
                PONE-D-18-09181
                10.1371/journal.pone.0201906
                6104939
                30133462
                d51872d0-010d-415c-94dd-b0a3d03165dd
                © 2018 Lee et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 26 March 2018
                : 24 July 2018
                Page count
                Figures: 0, Tables: 3, Pages: 8
                Funding
                Funded by: New faculty Research Fund from Ajou University School of Medicine.
                Award Recipient :
                This study was supported by the 2016 new faculty Research Fund from Ajou University School of Medicine, URL: http://medicine.ajou.ac.kr/, Grant number M-2016-C0460-00033. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Medicine and Health Sciences
                Endocrinology
                Endocrine Physiology
                Puberty
                Biology and Life Sciences
                Physiology
                Endocrine Physiology
                Puberty
                Medicine and Health Sciences
                Physiology
                Endocrine Physiology
                Puberty
                Medicine and Health Sciences
                Endocrinology
                Pediatric Endocrinology
                Medicine and Health Sciences
                Pediatrics
                Pediatric Endocrinology
                Medicine and health sciences
                Pharmacology
                Pharmacologic-based diagnostics
                GnRH stimulation test
                Biology and Life Sciences
                Physiology
                Physiological Parameters
                Body Weight
                Body Mass Index
                Medicine and Health Sciences
                Physiology
                Physiological Parameters
                Body Weight
                Body Mass Index
                Medicine and Health Sciences
                Endocrinology
                Endocrine Physiology
                Menstrual Cycle
                Menarche
                Biology and Life Sciences
                Physiology
                Endocrine Physiology
                Menstrual Cycle
                Menarche
                Medicine and Health Sciences
                Physiology
                Endocrine Physiology
                Menstrual Cycle
                Menarche
                Biology and Life Sciences
                Physiology
                Reproductive Physiology
                Menstrual Cycle
                Menarche
                Medicine and Health Sciences
                Physiology
                Reproductive Physiology
                Menstrual Cycle
                Menarche
                Medicine and Health Sciences
                Pediatrics
                Research and Analysis Methods
                Immunologic Techniques
                Immunoassays
                Radioimmunoassays
                Immunoradiometric Assay
                Research and Analysis Methods
                Mathematical and Statistical Techniques
                Statistical Methods
                Regression Analysis
                Physical Sciences
                Mathematics
                Statistics (Mathematics)
                Statistical Methods
                Regression Analysis
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