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      Effect of Treatment with Cyproterone Acetate on Uterine Bleeding at the Beginning of GnRH Analogue Therapy in Girls with Idiopathic Central Precocious Puberty

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          Abstract

          Background: The flare-up effect of GnRH analogues may cause transient uterine bleeding in girls affected with idiopathic central precocious puberty (ICPP). Aims: To assess the incidence of endometrial bleeding and verify whether pretreatment with cyproterone acetate could counteract it. Methods: Fifty-four girls affected by ICPP were divided into 2 groups. The first group (30 girls) was treated with triptorelin (3.75 mg, i.m. injection) every 28 days. The second group (24 girls) was treated with cyproterone acetate and triptorelin: cyproterone acetate (50 mg/m<sup>2</sup>) was administered every day for 8 weeks, and triptorelin (3.75 mg) was commenced 4 weeks after starting the cyproterone, then the intramuscular injection of triptorelin was repeated every 28 days. Results: Eight of 54 girls (15%) had mild withdrawal bleeding. There were no differences in incidence between groups 1 and 2. Girls with pubertal uterus at pelvic ultrasound had a higher incidence of uterine bleeding than girls with infantile uterus (25 vs. 7%), but this difference was not significant. Conclusion: Co-administration of cyproterone acetate and GnRH analogues does not significantly decrease the incidence of uterine bleeding.

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          The use of GnRH agonists in precocious puberty.

          In this review several aspects of gonadotrophin releasing hormone agonists (GnRHa) treatment in central precocious puberty (CPP) are highlighted. These include issues of the definition of precocity, assessment of CPP and thelarche variants. Indications for treatment with GnRH agonists are discussed, not only in CPP but also in children with other reasons to suppress central activation, e.g. adopted or developmental retardation. Finally, outcome data are summarized, both on growth and psychosocial parameters.
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            Treatment of central precocious puberty by subcutaneous injections of leuprorelin 3-month depot (11.25 mg).

            Depot GnRH agonists are widely used for the treatment of precocious puberty. Leuprorelin 3-month depot is currently used in adults but has not been evaluated in children. We evaluated the efficacy of this new formulation (11.25 mg every 3 months), for the suppression of gonadotropic activation and pubertal signs in children with central precocious puberty. We included 44 children (40 girls) with early-onset pubertal development in a 6-month open trial. The inclusion criteria were clinical pubertal development before the age of 8 (girls) or 10 (boys), advanced bone age, enlarged uterus (>36 mm), testosterone more than 1.7 nmol/liter (boys), and pubertal response of LH to GnRH (peak >5 IU/liter). The principal criterion for efficacy assessment, GnRH-stimulated LH peak less than 3 IU/liter, was met in 81 of 85 (95%) of the tests performed at months 3 and 6. The remaining four values were slightly above the threshold. The levels of sex steroids were also significantly reduced and clinical pubertal development was arrested. Plasma leuprorelin levels, measured every 30 d, were essentially stable after d 60. Local intolerance was noted after 10 of 86 injections (12%), and was mild in four cases, moderate in five cases, and severe in one. Among these 10 events, 4 consisted in local pain at injection's site. In conclusion, leuprorelin 3-month depot efficiently inhibits the gonadotropic axis in 95% of children with central precocious puberty studied for a 6-month period. This regimen allows the reduction of the number of yearly injections from 12 to 4.
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              Three-month sustained-release triptorelin (11.25 mg) in the treatment of central precocious puberty.

              Depot GnRH agonists are commonly used in the treatment of central precocious puberty (CPP). The triptorelin 11.25 mg 3-month depot, currently used in adult indications, had not previously been evaluated in CPP. This was a multicenter, open-label, 12 month trial conducted in 64 CPP children (54 girls and 10 boys), treated quarterly. Children with a clinical onset of pubertal development before the age of 8 years (girls) or 9 years (boys), pubertal response of LH to GnRH > or = 7 IU/l, advanced bone age > 1 year, enlarged uterus (> or = 36 mm) and testosterone level > or = 0.5 ng/ml (boys), were included. Suppression of gonadotropic activation, as determined from serum LH, FSH, estradiol or testosterone, and pubertal signs were assessed at Months 3, 6 and 12. GnRH-stimulated peak LH < or = 3 IU/l, the main efficacy criterion, was met in 53 out of 62 (85%), 60 out of 62 (97%) and 56 out of 59 (95%) of the children at Months 3, 6 and 12 respectively. Serum FSH and sex steroids were also significantly reduced, while pubertal development regressed in most patients. Mean residual triptorelin levels were stable from Month 3 through to Month 12. The triptorelin 3-month depot was well tolerated. Severe injection pain was experienced in only one instance. Five girls experienced mild-to-moderate or severe (one girl) withdrawal bleeding. The triptorelin 3-month depot efficiently suppresses the pituitary-gonadal axis and pubertal development in children with CPP. This formulation allows a 3-fold reduction, over the once-a-month depot, in the number of i.m. injections required each year.
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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
                2010
                April 2010
                14 April 2010
                : 73
                : 5
                : 386-389
                Affiliations
                Paediatric Endocrinology Unit, Department of Paediatrics, University of Florence, AOU Meyer, Florence, Italy
                Article
                308172 Horm Res Paediatr 2010;73:386–389
                10.1159/000308172
                20389110
                6b131a16-ef15-4926-849a-0ed294c2add4
                © 2010 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.

                History
                : 16 April 2009
                : 31 July 2009
                Page count
                Tables: 4, References: 18, Pages: 4
                Categories
                Original Paper

                Endocrinology & Diabetes,Neurology,Nutrition & Dietetics,Sexual medicine,Internal medicine,Pharmacology & Pharmaceutical medicine
                Cyproterone acetate,GnRH analogue,Precocious puberty, females,Flare-up effect

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