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Research Papers Efficacy of Combined Treatment with Growth Hormone and Gonadotropin Releasing Hormone Analogue in Children with Poor Prognosis of Adult Height M. Toumba, I. Bacopoulou*, S.C. Savva and
Research Papers Efficacy of Combined Treatment with Growth Hormone and Gonadotropin Releasing Hormone Analogue in Children with Poor Prognosis of Adult Height M. Toumba, I. Bacopoulou*, S.C. Savva and N. Skordis From the Pediatric Endocrine Unit, Makarios Hospital, Nicosia, Cyprus and *Research and Education Institute of Child Health, Cyprus. Correspondence to: M Toumba, Pediatric Endocrine Unit, Makarios Hospital, Nicosia 1474, Cyprus. Manuscript received: May 25, 2006; Initial review completed: August 18, 2006; Revision accepted: February 13, Objective: This study was conducted to study the role of combination therapy of growth hormone and Gonadotropin-releasing hormone (GnRH) analogues in girls with idiopathic central precocious puberty (CPP) or idiopathic short stature (ISS). Methods: Five girls with CPP (median age 9.1 y, pubertal stage 2-3) (3 of them previously treated with GnRH analogue (GnRHa) for 16.2 ± 0.3 months) and 8 girls with ISS (median age 11.4 y, pubertal stage 2-3) (previously treated with GH for ± 1.42 months), were treated with recombinant human GH (0.33mg/kg/week) and GnRHa (3.75 mg/28 days) for 22 months. Results: Height of girls with CPP improved from 1.3 to 0.2 SDS and height for BA from 2.1 to 0.6 SDS (P = 0.042). Predicted adult height (PAH) improved from 3.1 to 0.6 SDS (P = 0.042). In girls with ISS only PAH improved from 3.0 to 1.5 SDS (P = 0.025). Conclusion: Combined treatment improves height and PAH in CPP. Height in ISS is also improved however not significantly. Key words: Central precocious puberty (CPP), Gonadotropin-releasing hormone analogue (GnRHa), Growth hormone (GH), Idiopathic short stature (ISS). GO N A D O T R O P I N-releasing hormone analogues (GnRHa) are used in the treatment of central precocious puberty (CPP) to increase final height with controversial results(1,2) The combination of GnRH analogue with growth hormone (GH) may lead to more satisfactory results by improving the final height in children with precocious puberty and attenuated growth(3,4). Pubertal growth represents approximately 15-20% of adult height and precedes the fusion of growth plates. Before puberty, growth rate declines with age. This deceleration is compensated by the pubertal growth spurt(5). Nevertheless in girls with precocious puberty, growth acceleration and fusion of the growth plates may be advanced even before the onset of breast development, resulting in impaired adult height(5). When puberty is suppressed with GnRHa, the rate of epiphyseal maturation is decreased as are the GH pulse amplitude and growth rate(2,5). It is against this background that combined treatment with GnRHa and GH may benefit children with poor adult height potential. The addition of GH to GnRHa treatment may increase the growth velocity and improve the final height in children with CPP. Children with idiopathic short stature (188) and relatively early puberty may also benefit from the combination; by interrupting puberty in order to delay epiphyseal maturation with the hope to gain some centimetres in height. Subjects and Methods The study participants consisted of 13 children who were treated with the combination of GH and GnRHa. Five girls were diagnosed with idiopathic CPP and 8 girls with ISS and normal puberty. All children were born full-term appropriate for gestational age and were followed in the Pediatric Endocrine Unit in our hospital. Height, weight and pubertal development were evaluated every INDIAN PEDIATRICS 497 VOLUME 44 JULY 17, 2007 3-6 months. Heights of children and their parents were recorded to the nearest 0.1 cm by a wallmounted stadiometer with standard counter (Harpenden Stadiometer) at the standing position. CDC charts were used. Subsequent measurements of height were converted into SDS scores using the current CDC reference values as there are no growth charts representing the Cypriot population. Bone age (BA) was determined according to the method of Greulich and Pyle and adult height was predicted according to the Bayley-Pinneau method. Target height (TH) was calculated according to the method of Tanner(6). Predicted adult height (PAH), height for BA and TH were also converted to SDS. Pubertal development was assessed according to Tanner stages by the same persons (IB, NS) and the initiation of puberty was confirmed by the LH predominant response to LH-releasing hormone (LHRH) stimulation test. Girls with idiopathic CPP entered puberty before the age of 8 years with breast development at stage 2-3 and pubertal response to LHRH stimulation test. BA was accelerated by two years compared to the chronological age (CA). Pelvic ultrasound showed pubertal findings (increased ovarian volume, number and volume of ovarian follicles and size of uterus) in all girls. MRI of the brain did not reveal any hypothalamic or pituitary abnormality. The criteria used for the girls with ISS (n = 8) were: (1) short stature with height below 2 SDS, (2) PAH lower than their TH, (3) exclusion of GH deficiency based on normal response to two stimulation tests; glucagon and oral clonidine with peak GH levels 10 ng/ml and (4) exclusion of other conditions such as psychosocial deprivation syndrome. skeletal dysplasias and systematic diseases. All girls with ISS entered puberty at a normal age. All patients were treated with recombinant human GH at a dose of 0.33 mg/kg/week and GnRHa (triptorelin) 3.75 mg every 28 days. This study was approved by our institution s ethical committee and informed consent was obtained from the parents of all the girls participating in the study. Statistical Analysis Wilcoxon signed rank test with two-relatedsamples for pre-and post-treatment variables was used for comparing means. P 0.05 was considered statistically significant. Results The auxological characteristics of the five girls with idiopathic CPP are shown in Table I. Before adding GH, three of the patients were treated with GnRHa alone for a mean duration of 16.2 ± 0.3 months. Patients 3, 4 and 5 were on Tanner stage 3 and started GnRHa treatment at ages 7.5, 9.8 and 3.8 years respectively. Their heights did not improve significantly after 16.2 ± 0.3 months of GnRHa treatment alone (1.1 to 1 SDS, 1.4 to 1.1 SDS and +3.9 to 3.4 SDS respectively). Additionally their bone ages were advanced despite the GnRHa treatment worsening the PAH (10 to 10.8 years, 11 to 11.5 years, 10 to 11 years). Patients 1 and 2 started GnRHa and GH together because of their rapid progression of puberty with advanced BA and very poor PAH. At the start of combined treatment, the median chronological age was 9.1 years and the median height was 1.3 SDS. The patients median TH was calculated as 0.6 SDS. All females with idiopathic CPP were treated with both GH and GnRHa for a period of 22.8 ± 2.8 months. At the median age of 11.3 years, the median height increased from 1.3 to 0.2 SDS. The median BA advanced by only 0.7 years compared to the CA (median DBA = 2.2). The median height for BA improved significantly from 2.1 SDS to 0.6 SDS (P = 0.043). PAH (median) also improved significantly from 3.1 SDS to 0.6 SDS (P = 0.042), resulting in a gain of approximately 9 cm (Table I). The auxological characteristics of the girls with ISS are shown in Table II. The mean duration of the combined treatment was ± 6.36 months. Patients 3, 5, and 8 were on GH treatment before adding GnRHa for mean duration of ± 1.42 months. They were started on GH at ages 9.8, 10.6, and 7.3 years respectively (Tanner stage 1). Their heights had slightly improved (from 3.5 to 3.0 SDS, 3.0 to 2.7 SDS, and 5.8 to 5.3 SDS respectively) while on GH therapy alone. GnRHa was added when they entered puberty in order to INDIAN PEDIATRICS 498 VOLUME 44 JULY 17, 2007 TABLE I Auxological Characteristics of Patients with Idiopathic CPP Before and After Combined Treatment with GnRH Analogue and GH Pateint CA on BA on start Height on Height for Breast PAH on CA after BA after Height Height for Breast PAH after TH (SDS) no./ start (years) start (SDS) BA on stage start (years) (years) after BA stage (SDS) sex (years) start (SDS) (SDS) after (SDS) (SDS) 1/F /F /F /F 10, /F Median (range) (6.5, 10.1) (10.5, 11.0) ( 1.8, 0.8) ( 2.8, 0.4) ( 3.3, 1-1) (8.7, 11.6) (11.0, 13.0) ( 2.8,0.9) ( 1.8,0.9) ( 1.8, 0.3) ( 1.8, 0.3) CA: Chronological age; BA: bone age; PAH: predicted adult height; TH: target height TABLE II Auxological Characteristics of Patients with ISS Before and After Combined Treatment with GnRH Analogue and GH Pateint CA on BA on start Height on Height for Breast PAH on CA after BA after Height Height for Breast PAH after TH (SDS) no./ start (years) start (SDS) BA on stage start (years) (years) after BA stage (SDS) sex (years) start (SDS) (SDS) after (SDS) (SDS) 1/F /F /F /F /F /F /F /F Median (range) (8.3, 11.8) (6.8, 12.0) ( 5.3, 2.0) ( 3.3, 0.2) ( 4.4, 0.3) (11.9, 14.6) (10.0, 13.0)( 3.4, 1.4) ( 2.2,0.8) ( 3.4, 0.3) ( 2.8, 0.3) CA: Chronological age; BA: bone age; PAH: predicted adult height; TH: target height INDIAN PEDIATRICS 499 VOLUME 44 JULY 17, 2007 avoid BA progression and height deterioration. Just before starting the combined treatment, the median age of all girls with ISS was 11.4 years and their median height was 2.6 SDS. Median TH was 1.4 SDS. After about 20 months of combined treatment (at median age 13.4 years), there was a significant improvement in PAH from 3.0 to 1.5 SDS (P = 0.025) which resulted in a height gain of about 5 cm. Height for BA improved from 2.2 to 1.2 SDS, although this is not a significant improvement (P = 0.238). Discussion Our study is a preliminary short-term study based on predicted adult heights in children with two different conditions treated with combination of GnRHa and GH. Predicted height is an important factor which strongly correlates with bone age and can influence final height. Adult height is also affected by other factors such as target height, bone age advancement, the time of onset of puberty and the duration of treatment(2,5). Target height reflects the genetic influence on height, irrespective of pubertal development. The limited effect of GnRHa on final height led to the attempt of using GH as an additional treatment, especially in girls with poor growth prognosis. Similarly, with the hope that the suppression of puberty leads to improvement of final height, GnRH was used as an additional treatment in children currently taking GH for ISS. Our results show that combined treatment improves PAH in patients with CPP or ISS with poor height potential. PAH improved by 9 cm and 5 cm in CPP and ISS respectively which is a remarkable height gain. Table III shows the effect on height with combination therapy with GH and GnRHa in different studies(7-19). Majority of the earlier studies using combined treatment in girls with idiopathic CPP, showed encouraging results on the height prognosis as reported in our study(7-10). However only a few published studies were completed until final height was reached, with advantageous results(9,10). On the contrary others found no significant increase in final heights despite the previous increase in predicted heights(11,12). Some studies showed beneficial effect in girls with early puberty(13,14). Controversial results were also observed on children with ISS treated with GnRHa and GH. Combined treatment increases predicted adult heights in short girls without GH TABLE III-Different Studies(7-10) for the Use of Combined Treatment in Patients with Central Precocious Puberty and Idiopathic Short Stature Reference Diagnosis No of Duration of Height gain Patients treatment (years) (cm) Job, Horm Res 1994 CPP/EP Saggese, Acta Pediatr 1995 CPP/GHD ± 0.2 Pasquino, JCEM 1999 CPP ± 1.1 Tuvemo, Acta Pediatr 1999 CPP/EP Pucarelli, JPEM 2003 CPP ± 4.8 Mul, Clin Endocrinol 2005 EP ± 3.7 Volta, J Endocrinol lnv 1993 ISS Saggese, J Pediatr 1995 ISS ± ± 1.2 Tanaka, JPEM 1997 ISS Lanes, Clin Endocrinol 1998 ISS ± 2 Pasquino, JCEM 2000 ISS/EP ± ± 2.9 Balducci, JCEM 2001 ISS Kamp, JCEM 2001 ISS CPP = Central precocious puberty, EP = Early Puberty, ISS = idiopathic short stature, GHD = Growth hormone deficiency INDIAN PEDIATRICS 500 VOLUME 44 JULY 17, 2007 What is Already Known Combined treatment with GH and GnRH analogue in girls with idiopathic CPP and ISS may have satisfactory results on the height prognosis. What this Study Adds Combined treatment improves PAH in patients with CPP and ISS with poor height potential improving PAH by 9 cm and 5 cm respectively. deficiency, entering puberty at a normal age(15). Other studies showed improvement on PAH in children with ISS or IUGR(16) while some others found no or minor effect on PAH in patients with ISS and normal puberty(17-19). The limited number of the patients and the lack of randomized blinded prospective trials do not allow a thorough analysis of the results but the available evidence suggests a beneficial effect of combined treatment on PAH. The majority of patients were treated for a short period of time (less than 3 years) and some of them started late or treated with either GH or GnRHa at the first place depending on the growth disorder they had. PAH may improve with early initiation and longer duration of therapy. Definite conclusions will arise after the patients reach their final heights. However we should always consider the economical and ethical cost of such therapies, which must be limited to very short subjects with very poor growth prognosis. Acknowledgements We would like to thank T. Apsiotou (ND), T. Georgiou (ND) and S. Stavrou (ND) for their technical contribution in this study. Contributors: MT concept and design, acquisition of data; IB acquisition of data; SCS analysis and interpretation of data; and NS drafting the article, revising it critically for important intellectual content and final approval. Funding: None. Competing interests: None stated. REFERENCES 1. Klein KO, Barnes KM, Jones JV, Feuillan PP, Cutler GBJ. Increased final height in precocious puberty after long-term treatment with LHRH agonists: The National Institutes of Health experience. J Clin Endocrinol Metab 2001; 86: Carel JC, Roger M, Ispas S, Tondu F, Lahlou N, Blumberg J, et al. Final height after long-term treatment with triptorelin slow-release for central precocious puberty: importance of statural growth after interruption of treatment. J Clin Endocrinol Metab 1999; 84: Carel JC. Management of short stature with GnRH agonist and co-treatment with growth hormone: A controversial issue. Mol Cell Endocrinol 2006; 25: : Walvoord EC, Pescovitz OH. Combined use of growth hormone and Gonadotropin-releasing hormone analogues in precocious puberty: theoretic and practical considerations. Pediatrics 1999; 104: Stanhope R, Preece MA, Grant DB, Brook CG. New concepts of the growth spurt of puberty. Acta Paediatr Scand (Suppl) 1988; 347: Tanner JM, Goldstein H, Whitehouse RH. Standards for children s height at ages 2-9 allowing for height of parents. Arch Dis Child 1970; 45: Saggese G, Pasquino AM, Bertelloni S, Baroncelli GI, Battini R, Pucarelli I, et al. Effect of combined treatment with gonadotrophin -releasing hormone analogue and growth hormone in patients with central precocious puberty who had subnormal growth velocity and impaired height prognosis. Acta Paediatr 1995; 84: Pasquino AM, Pucarelli I, Roggini M, Segni M. Adult height in short normal girls treated with gonadotropin-releasing hormone analogs and growth hormone. J Clin Endocrinol Metab 2000; 85: Pasquino AM, Municchi G, Pucarelli I, Segni M, Mancini MA. Combined treatment with gonadotropin-releasing hormone analogue and growth hormone in central precocious puberty. J Clin Endocrinol Metab 1996; 81: INDIAN PEDIATRICS 501 VOLUME 44 JULY 17, 2007 10. Pucarelli I, Segni M, Ortore M, Arcadi E, Pasquino AM. Effects of combined gonadotropin-releasing hormone agonist and growth hormone therapy on adult height in precocious puberty: A further contribution. J Paediatr Endocrinol Metab 2003; 16: Balducci R, Toscano V, Mangiantini A, Municchi G, Vaccaro F, Picone S, et al. Adult height in short normal adolescent girls treated with gonadotropinreleasing hormone analogue and growth hormone. J Clin Endocrinol Metab 1995; 80: Lanes R, Gunczler P. Final height after combined growth hormone and gonadotropin releasing analogue treatment in short healthy children entering into normally timed puberty. Clin Endocrinol (Oxf) 1998; 49: Tuvemo T, Gustafsson J, Proos LA. Growth hormone treatment during suppression of early puberty in adopted girls. Swedish Growth Hormone Advisory Group. Acta Pediatr 1999; 88: Mul D, Oostdijk W, Waelkens JJ, Schulpen TW, Drop SL. Gonadotropin releasing hormone agonist treatment with or without recombinant human GH in adopted children with early puberty. Clin Endocrinol (Oxf) 2005; 55: Saggese G, Cesaretti G, Barsanti S, Rossi A. Combination treatment with growth hormone and gonadotropin-releasing hormone analogues in short normal girls. J Pediatr 1995; 126: Kamp GA, Mul D, Waelkens JJ, Jansen M, Delemarre-Van De Waal HA, Verhoeven-Wind l, et al. A randomized controlled trial of three years growth hormone and gonadotropin-releasing hormone analogues in children with idiopathic short stature and intrauterine growth retardation. J Clin Endocrinol Metab 2001; 86: Volta C, Bernasconi S, Tondi P, Salvioli V, Ghizzoni l, Baldini A, et al. Combined treatment with growth hormone and luteinizing hormone releasing hormone-analogue (LHRHa) of pubertal children with familial short stature. J Endocrinol lnvest 1993; 16: Job JC, Toublanc JE, Landier F. Growth of short normal children in puberty treated for 3 years with growth hormone alone or in association with gonadotropin-releasing hormone agonist. Horm Res 1994; 41: Tanaka T, Satoh M, Yasunaga T, Horikawa R, Tanae A, Hibi I. GH and GnRH analog treatment in children who enter puberty at short stature. J Clin Endocrinol Metab 1997; 10: INDIAN PEDIATRICS 502 VOLUME 44 JULY 17, 2007
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