Outcomes Following Depot Gonadotropin-Releasing Hormone Agonist Treatment in Children with Central Precocious Puberty: A Retrospective Analysis

Outcomes Following Depot Gonadotropin-Releasing Hormone Agonist Treatment in Children with Central Precocious Puberty: A Retrospective Analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Outcomes Following Depot Gonadotropin-Releasing Hormone Agonist Treatment in Children with Central Precocious Puberty: A Retrospective Analysis Elham Maleki, Maryam Razzaghy-Azar, Ali Talae, Saeedeh Saeedi This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8037280/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Gonadotropin-releasing hormone agonist (GnRHa) therapy is widely endorsed for Central Precocious Puberty (CPP). This longitudinal observational study aimed to assess the influence of GnRHa on anthropometric measures over a decade. Pre- and post-treatment clinical records of 196 patients (7 boys, 189 girls) who received GnRHa therapy were reviewed. The study showed that in girls, post-treatment final height exceeded pre-treatment predicted adult height (p < 0.001). BMI-SDS notably increased in treated girls (p < 0.001) contrasting with boys. GVI declined during therapy (p < 0.001) but rebounded post-therapy (p < 0.05), without reaching pre-treatment levels. Additionally, 43.7% of girls reported menarche 1.1 ± 0.7 years after therapy, but 50% experienced irregular cycles. Conclusion: GnRHa has positive effect on final height. Precocious puberty Gonadotropin-releasing hormone agonists Body Height Body Mass Index Growth and Development Figures Figure 1 Figure 2 Introduction Central precocious puberty (CPP) is due to the premature awakening of the hypothalamic Gonadotropin hormone-releasing hormone (GnRH) pulse generator with subsequent pulsatile gonadotropin secretion (Mul & Hughes, 2008 ). The disorder's clinical course is vastly different, ranging from transient to slowly progressive, alternating, or rapidly progressive (Fontoura et al., 1989 ; Heger et al., 1999 ; Palmert, Malin, et al., 1999; Pasquino et al., 1989 ). With significant contributions to the development of short stature due to the premature fusion of long bone epiphyseal growth plates, along with considerable psychosocial issues in the affected children and their families, the disorder should be managed promptly and appropriately (Sonis et al., 1985 ; Sorgo et al., 1987 ). GnRH agonists (GnRHa) and their depot formulations are the mainstay of treatment in CPP by reversibly suppressing the pituitary-gonadal axis (Hummelink et al., 1992 ; Manasco et al., 1988 ; Mul & Hughes, 2008 ; Oostdijk W, 1995; Roger et al., 1986 ). However, follow-up evaluations have demonstrated varying and controversial outcomes, especially regarding final height (FH), which ranged from near negligible changes to complete restoration of the desirable growth curves (Antoniazzi et al., 1994 ; Brauner et al., 1994 ; Galluzzi et al., 1998 ; Kauli et al., 1997 ; Kauli et al., 1990 ; Kletter & Kelch, 1994 ; Oerter et al., 1991 ; Oostdijk et al., 1996 ; Partsch et al., 1993 ; Pasquino et al., 2000 ; Paul et al., 1995 ; Stasiowska et al., 1994 ). Nevertheless, the continuous and complete suppression of the hypothalamic-pituitary-gonadal axis is still a prerequisite for achieving optimal height growth (Partsch et al., 1993 ). Moreover, the primary outcome investigated in most previous studies regarding growth deficiencies in CPP has been chiefly the FH rather than changes in weight and body composition following the suppression of the axis by GnRHa (Boot et al., 1998 ; Feuillan et al., 1999 ; Oostdijk et al., 1996 ). Objectives With a lack of relevant literature, investigating body composition changes due to GnRHa administration and the resulting gonadal sex steroid inhibition can help to provide invaluable insights into the physiology of growth in CPP (Boepple et al., 1986 ; Comite et al., 1981 ; Galluzzi et al., 1998 ; Jay et al., 1992 ; Manasco et al., 1988 ; Wierman et al., 1986 ). In addition, it can aid in the elaboration of whether or how obesity develops during GnRHa therapy or if it is simply from CPP alone (Feuillan et al., 1999 ). Therefore, the authors aimed to evaluate outcomes after long-term GnRHa therapy concerning FH, body mass index, and growth patterns in CPP. Methods Design and Location This longitudinal observational study was conducted in the Pediatric Endocrinology Department of Ali Asghar Children’s Hospital in Tehran, Iran, during 2015. Furthermore, our study protocol was approved by the local Institutional Review Board (IRB). In addition, written informed consent was obtained after informing the patient's legal guardians about the study's design and findings and assuring them of the confidentiality of their information. Finally, 496 patients were reviewed, and 196 cases (7 boys and 189 girls) were included. Population The population of interest included all those who were referred to the clinic of the Pediatric Endocrinology Department of Ali Asghar Children’s Hospital. The medical records of the patients who came due to the appearance of secondary sexual characteristics before the age of puberty in the preceding 10 years (2005–2015) were reviewed. Patients who received Triptoreline SR for more than two years were included. Moreover, these individuals must have had their onset of sexual characteristics before turning 8 (girls) or 9 (boys) years, respectively, and had demonstrated rapidly progressive signs during their disease's clinical course, along with the pubertal response of LH and FSH to GnRH test (LH > 15 IU/L and LH/FSH ratio > 0.66; determined via radioimmunoassay) (Razzaghy-Azar et al., 2011 ), high 08:00 hr testosterone levels (> 20 ng/dL) (Razzaghi Azar et al., 2006 ), and bone age (BA) that was at least one year above their chronological age (CA). In addition, if clinically rapidly progressive signs were seen without some of the hormonal or radiological criteria mentioned above, they still were included. However, suffering from any concomitant impactful disorders (e.g., Polycystic Ovarian Syndrome, Turner syndrome, Prader-Willi syndrome, or any other condition affecting pubertal progression, Peripheral precocious puberty, including McCune-Albright syndrome or adrenal disorders, Thyroid disorders, Uncontrolled metabolic disorders, including Diabetes Mellitus or obesity-related hormonal imbalances) led to the exclusion of the patients. Exposure The Triptoreline SR (Dipherelin, Ipsen-Biotech, Paris, France) dose was 3.75 mg in children > 20 kg and 1.87 mg in children < 20 kg intramuscularly every 28 days (Bertelloni et al., 2018 ). Furthermore, therapeutic sufficiency was considered as Luteinizing hormone levels below 6.6 IU/L 2 hours after the injection of Triptoreline (Brito et al., 2004 ). However, when clinical manifestations persisted, the period between two injections decreased to 21 days. The decision to discontinue treatment was also based primarily on the height, CA reaching the healthy children's mean age-onset of puberty, BA, and the caretakers' preferences. The cases were followed every three months for height, weight, and the signs of puberty. If growth velocity became less than 4 cm/year after 6 months, follow-up growth hormone was added to the treatment regimen (Antoniazzi et al., 2000 ). Outcomes and measures The outcomes included clinical investigations at each follow-up visit every three months. At each visit, the patients' height (Centimeters; Stadiometer, SECA, Germany) and weight (Kilograms; SECA scale, Germany) were measured. The body mass index (BMI) was also calculated with the method previously described by Rolland-Cachera et al. (Rolland-Cachera et al., 1991 ). In addition, the standard deviation score (SDS) for height and body mass index was calculated using the age-appropriate CDC 2000 curves and tables (Kuczmarski, 2000 ). The sex-adjusted target and predicted height were also determined from the mean height of parents and based on the Bayley-Pinneau calculations (Tanner et al., 1970 ; Zachmann et al., 1978 ). FH was recorded when the BA was at age 15 in girls and 16 in boys, while the height growth velocity was also less than 2.5 cm/year, obtained from several measurements at least 3 months apart (Kleign, 2012 ). Sexual maturity was assessed according to the Tanner scaling, and BA was estimated based on separate and mean scoring of the bones on the wrist and hand radiographs based on the atlas of Greulich and Pyle (Greulich WW, 1959 ; Marshall & Tanner, 1969 , 1970 ; Zachmann et al., 1974 ). In addition, the Growth velocity index (GVI) was calculated as the ratio of growth velocity to the average height growth velocity of age and sex-specific 50th percentile, then multiplied by 100. Ultimately, the onset of menarche and respective menstrual patterns after the discontinuation of treatment were evaluated via semi-structured interviews. Statistical analysis The 19th version of the SPSS statistical software package (SPSS Inc., IBM, USA) was used to analyze the data. Furthermore, categorical and continuous variables were described as Frequency (%) and mean ± SD, respectively. In addition, paired t-tests and repeated measures for the analysis of variance were used to analyze the variables of interest. p < 0.05 was considered statistically significant. Results Case selection The medical records of 496 patients were reviewed, which led to the exclusion of 264 cases, including 111 (22.4%) with premature adrenarche, 59 (11.9%) with premature thelarche, 9 (1.8%) with premature menarche, 10 (2%) with McCune-Albright syndrome, 5 (1%) with Testotoxicosis, 12 (2.4%) with congenital adrenal hyperplasia, 14 (2.8%) with 21 hydroxylase deficiency, and 44 (8.9%) with Arrested or regressed precocious puberty. Therefore, 232 (43.6%) had central precocious puberty and were considered. However, among these, 2 had arrested puberty, and 34 had received treatment for less than two years and, therefore, were excluded. Ultimately, 196 cases (7 boys and 189 girls) were included. In addition, 7 girls (3%) had disorders in the brain (3 cases had astrocytoma and 4 cases, each one suffering from hamartoma, pinealoma, pineal cyst, and prolactinoma), and 3 (30%) boys had brain lesions (each 1 case suffering from hamartoma, temporal cyst, or brain atrophy). (Table 1) [Table 1] The patients were evaluated for 1.1 ± 0.94 years before therapy started. Moreover, the therapy lasted for 3.2 ± 1.3 years and 2.7 ± 1.3 years in girls and boys, respectively, discontinuing at mean ages of 10.1 ± 1 and 11.1± 1.1 years in girls and boys. Bone age at the time of therapy discontinuation in girls and boys was 11.7 ± 1 and 13.7 ± 0.8 years, respectively. Furthermore, the analyses revealed that treatment significantly decreased BA-CA differences (p < 0.001). Final Height Due to the low number of boys in our study, only 3 reached their final respective height, and, therefore, they were not included in our analyses. Girls' mean final height was significantly higher than the target height (p < 0.001) but significantly lower than the predicted height at the end of treatment (p = 0.011). Moreover, the mean predicted height at the end of treatment was significantly higher than that of pre-treatment (p = 0.016). Furthermore, the final height SDS was significantly better than the target height SDS (p < 0.001) and worse than the pre-treatment height SDS (p < 0.001). In addition, the mean Height SDS at the end of treatment was significantly lower than the pre-treatment height SDS (p 0.05). However, after treatment, in the girls, BMI SDS significantly increased (1.2 ± 1.0 vs. 1.3 ±0.9, p = 0.033). (Table 2) [Table 2] Growth velocity index (GVI) It has been found that even though GVI in the first year since the initiation of therapy was not significantly different compared to pre-treatment (115.1 ± 25.9 vs. 119 ± 37.7, P = NS), it significantly declined in the second and third years of treatment (103.6 ± 31.4 and 87.6 ± 29.6, with a mean difference of 5.7 ± 1.7 and 5.1 ± 1.5, respectively, p < 0.05). In addition, 1-year post-treatment GVI was significantly higher than GVI during the last year of therapy (96.8 ± 33.6 vs. 84 ± 40.1, p = 0.003), although it was significantly lower than pre-treatment GVI (p = 0.02). Furthermore, the index progressively declined in the second (74.2 ± 41.4) and third (58.2 ± 45.6) post-treatment years. (Tables 3 and 4 and Figures 1 and 2) [Table 3] [Table 4] [Figure 1] [Figure 2] Menarche It took 1.1 ± 0.7 (range 0.1-6) years following the last dose of triptorelin for the girls to experience menarche (occurring in 43.6%), 50% of whom had irregular cycles. Discussion Although depot GnRH analogs have been used to treat precocious puberty for many years, few studies have assessed their effects on anthropometric parameters other than height or bone age, such as weight, BMI, and overall growth. Moreover, some have stated that FH as an outcome can be compounded by several factors (e.g., age and bone age on initiation of therapy and therapy duration), impacting its accuracy and relevance (Mul & Hughes, 2008 ). Furthermore, many studies have solely relied on height predictions rather than the final achieved height, limiting its reliability (Bertelloni & Mul, 2008 ). Therefore, our study aimed to assess other anthropometric parameters mentioned above, revealing that FH in girls who received GnRHa exceeded target height but was similar to the pre-treatment predicted adult height and significantly lower than post-treatment predicted height. GVI declined progressively throughout the years of therapy. In addition, even though BMI did not change during therapy in boys, it considerably increased in girls. Regarding the final height (FH), girls achieved outcomes comparable to those predicted by their pre-treatment adult heights and even exceeded their target height. This finding was similar to the reports already demonstrated (Carel et al., 1999 ; Heger et al., 1999 ; Oostdijk et al., 1996 ). Although FH exceeded the pre-treatment predicted height in some studies, it failed to surpass the target height (although it fell within the genetically acceptable range) (Mul et al., 2000 ; Tanaka et al., 2005 ; Traggiai et al., 2005 ). However, an increase in the predicted height during treatment was noted, which led to a higher post-treatment predicted height, similar to previous studies (Klein et al., 2001 ; Oostdijk et al., 1991 ; Oostdijk et al., 1996 ). Consequently, FH was significantly lower than the post-treatment predicted height. The Growth velocity (GV) during the first year of therapy was similar to before, yet it progressively declined throughout the study, reaching its nadir at about 11 years. In addition, the Height velocity (HV) increased briefly after the discontinuation of therapy but decreased afterward. This finding means that patients will not experience a post-treatment growth spurt. Some studies have shown that GV decreases by about 60% during the first year of therapy, with more significant decreases found in those with the most advanced bone age and relatively taller. However, GV is usually appropriate for the respective bone age from the second year onward (Carel et al., 1999 ; Mouat et al., 2009 ; Sklar et al., 1991 ; Weise et al., 2004 ). Moreover, one study has also reported that even though HV stabilized after three years of therapy, it increased over the first six months after the discontinuation of therapy and continued to remain higher than its pre-treatment values in the second 6 months. However, the 2nd year following therapy discontinuation coincided with a decrease in HV (Oostdijk et al., 1991 ). This study used BMI as an indirect body fat index, and BMI data were expressed with age and sex-appropriate normative values. In boys, the mean BMI SDS changes during GnRHa therapy were insignificant. However, BMI SDS in girls was significantly higher at the end of therapy. Unfortunately, the few available literature regarding the effects of GnRHa therapy on body composition are controversial, with some having emphasized that obesity is a frequent finding among children with CPP and not related to GnRHa therapy, indicating that it seldom fosters the development of obesity (Heger et al., 1999 ; Traggiai et al., 2005 ). However, some have also reported that GnRHa therapy induces a reduction in BMI, especially in girls (Arrigo et al., 2004 ). Nevertheless, several studies have also indicated that BMI does increase during therapy, and its trend persists even after its discontinuation, while some report that the higher baseline values of BMI predict the onward trend after therapy cessation (Oostdijk et al., 1996 ; Palmert, Mansfield, et al., 1999 ; Unal et al., 2003 ). Therefore, future studies should compare such changes with anthropometrically similar control groups. Regarding the onset of menarche following CPP treatment, there is some evidence that when treatment is discontinued even after long-term therapy, it reverses the gonadal suppression within a few weeks to months, leading to a rise in the concentrations of plasma gonadal steroids, the progression of sexual maturation, and the appearance menstrual cycles (Feuillan et al., 1999 ; Heger et al., 1999 ; Manasco et al., 1988 ). In those who experienced menarche in our study (less than 50%), the phenomenon occurred within 1-1.5 years following the discontinuation of therapy, which aligns with previous studies (Heger et al., 1999 ; Jay et al., 1992 ; Oostdijk et al., 1996 ; SHLOMO MELMED, 2011). However, it has also been demonstrated that more than 90% of girls experience menarche within two years, which can also be true in our study sample, but the data regarding it is lacking (Antoniazzi et al., 2000 ; SHLOMO MELMED, 2011). Therefore, future studies should extend their follow-up period to at least two years after therapy cessation to make conclusions more accurate and reliable. In girls with precocious puberty who received GnRHa, the final height was higher than the target height. In girls, BMI-SDS after treatment increased, so prevention of obesity by an appropriate diet and follow-up is recommended. Growth velocity should be followed during therapy; if it is lower than 4 cm/year, growth hormone should be added. Treatment significantly decreased bone age advancement to chronological age. Declarations Acknowledgements: The authors would like to acknowledge the assistance of the Pediatric Endocrinology staff at Aliasghar Children’s Hospital for their guidance and support throughout this project. Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work, and approve this version to be published. Author Contribution: M.R. led the clinical section and writing of the paper. A.T. and E.M. conceived the project, did the clinical assessments, and oversaw the project's progress. E.M. performed statistical analyses. A.T., S.S., and E.M. were equally responsible for the preparation of data as well as the collection of statistics. E.M. wrote the main manuscript text, and S.S. prepared figures. All authors reviewed the manuscript. Competing interests: None. Ethics approval: The study received approval from the Ethics Committee of Iran University of Medical Sciences (TUMS), and the participants and their legal guardians provided written informed consent . Moreover, it followed the guidelines provided in the Declaration of Helsinki. (The grant number has not been allocated according to the university policy.) Availability of supporting data: The dataset supporting the conclusions of this article is available upon request to the corresponding author. Funding: None. No grant was taken from the Iran University of Medical Sciences or any other organization. References Antoniazzi, F., Arrigo, T., Cisternino, M., Galluzzi, F., Bertelloni, S., Pasquino, A. M., Borrelli, P., Osio, D., Mengarda, F., De Luca, F., & Tato, L. (2000). End results in central precocious puberty with GnRH analog treatment: the data of the Italian Study Group for Physiopathology of Puberty. J Pediatr Endocrinol Metab , 13 Suppl 1 , 773-780. 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Adult height in short normal girls treated with gonadotropin-releasing hormone analogs and growth hormone. J Clin Endocrinol Metab , 85 (2), 619-622. Paul, D., Conte, F. A., Grumbach, M. M., & Kaplan, S. L. (1995). Long-term effect of gonadotropin-releasing hormone agonist therapy on final and near-final height in 26 children with true precocious puberty treated at a median age of less than 5 years. J Clin Endocrinol Metab , 80 (2), 546-551. Razzaghi Azar, M., Moghimi, A., Sadigh, N., Montazer, M., Golnari, P., Zahedi Shulami, L., Van Buuren, S., Mohammad Sadeghi, H., Zanganeh Kazemi, A., & Fereshtehnejad, S. (2006). Age at the onset of puberty and menarche in Iranian girls and boys. Razi Journal of Medical Sciences , 13 (50), 71-82. Razzaghy‐Azar, M., Ghasemi, F., Hallaji, F., Ghasemi, A., & Ghasemi, M. (2011). Sonographic measurement of uterus and ovaries in premenarcheal healthy girls between 6 and 13 years old: correlation with age and pubertal status. Journal of Clinical ultrasound , 39 (2), 64-73. Roger, M., Chaussain, J. L., Berlier, P., Bost, M., Canlorbe, P., Colle, M., Francois, R., Garandeau, P., Lahlou, N., Morel, Y., & et al. (1986). Long term treatment of male and female precocious puberty by periodic administration of a long-acting preparation of D-Trp6-luteinizing hormone-releasing hormone microcapsules. J Clin Endocrinol Metab , 62 (4), 670-677. Rolland-Cachera, M. F., Cole, T. J., Sempe, M., Tichet, J., Rossignol, C., & Charraud, A. (1991). Body Mass Index variations: centiles from birth to 87 years. Eur J Clin Nutr , 45 (1), 13-21. SHLOMO MELMED, K. S. P., P. REED LARSEN,et al. (2011). Puberty:Ontogeny,Neuroendocrinology,Physiology,and Disorders. In WilliamsTextbook of ENDOCRINOLOGY (12th ed., pp. 1054-1202). SAUNDERS ELSEVIER. Sklar, C. A., Rothenberg, S., Blumberg, D., Oberfield, S. E., Levine, L. S., & David, R. (1991). Suppression of the pituitary-gonadal axis in children with central precocious puberty: effects on growth, growth hormone, insulin-like growth factor-I, and prolactin secretion. J Clin Endocrinol Metab , 73 (4), 734-738. Sonis, W. A., Comite, F., Blue, J., Pescovitz, O. H., Rahn, C. W., Hench, K. D., Cutler, G. B., Jr., Loriaux, D. L., & Klein, R. P. (1985). Behavior problems and social competence in girls with true precocious puberty. J Pediatr , 106 (1), 156-160. Sorgo, W., Kiraly, E., Homoki, J., Heinze, E., Teller, W. M., Bierich, J. R., Moeller, H., Ranke, M. B., Butenandt, O., & Knorr, D. (1987). The effects of cyproterone acetate on statural growth in children with precocious puberty. Acta Endocrinol (Copenh) , 115 (1), 44-56. Stasiowska, B., Vannelli, S., & Benso, L. (1994). Final height in sexually precocious girls after therapy with an intranasal analogue of gonadotrophin-releasing hormone (buserelin). Horm Res , 42 (3), 81-85. Tanaka, T., Niimi, H., Matsuo, N., Fujieda, K., Tachibana, K., Ohyama, K., Satoh, M., & Kugu, K. (2005). Results of long-term follow-up after treatment of central precocious puberty with leuprorelin acetate: evaluation of effectiveness of treatment and recovery of gonadal function. The TAP-144-SR Japanese Study Group on Central Precocious Puberty. J Clin Endocrinol Metab , 90 (3), 1371-1376. https://doi.org/10.1210/jc.2004-1863 Tanner, J. M., Goldstein, H., & Whitehouse, R. H. (1970). Standards for children's height at ages 2-9 years allowing for heights of parents. Arch Dis Child , 45 (244), 755-762. Traggiai, C., Perucchin, P. P., Zerbini, K., Gastaldi, R., De Biasio, P., & Lorini, R. (2005). Outcome after depot gonadotrophin-releasing hormone agonist treatment for central precocious puberty: effects on body mass index and final height. Eur J Endocrinol , 153 (3), 463-464. https://doi.org/10.1530/eje.1.01975 Unal, O., Berberoglu, M., Evliyaoglu, O., Adiyaman, P., Aycan, Z., & Ocal, G. (2003). Effects on bone mineral density of gonadotropin releasing hormone analogs used in the treatment of central precocious puberty. J Pediatr Endocrinol Metab , 16 (3), 407-411. Weise, M., Flor, A., Barnes, K. M., Cutler, G. B., Jr., & Baron, J. (2004). Determinants of growth during gonadotropin-releasing hormone analog therapy for precocious puberty. J Clin Endocrinol Metab , 89 (1), 103-107. Wierman, M. E., Beardsworth, D. E., Crawford, J. D., Crigler, J. F., Jr., Mansfield, M. J., Bode, H. H., Boepple, P. A., Kushner, D. C., & Crowley, W. F., Jr. (1986). Adrenarche and skeletal maturation during luteinizing hormone releasing hormone analogue suppression of gonadarche. J Clin Invest , 77 (1), 121-126. https://doi.org/10.1172/jci112265 Zachmann, M., Prader, A., Kind, H. P., Hafliger, H., & Budliger, H. (1974). Testicular volume during adolescence. Cross-sectional and longitudinal studies. Helv Paediatr Acta , 29 (1), 61-72. Zachmann, M., Sobradillo, B., Frank, M., Frisch, H., & Prader, A. (1978). Bayley-Pinneau, Roche-Wainer-Thissen, and Tanner height predictions in normal children and in patients with various pathologic conditions. J Pediatr , 93 (5), 749-755. Tables Table 1. Baseline Characteristics of Participants Characteristic Girls (n = 189) Mean ± SD (Min-Max) Boys (n = 7) Mean ± SD (Min-Max) Age-onset of clinical signs (years) 6.7 ± 1.4 (0.33 - 8) 7.9 ± 0.9 (6.75 - 8.9) Duration of evaluation before therapy (years) 0.98 ± 0.95 (0.33 - 5.4) 0.80 ± 0.67 (0.34 - 1.58) Age at initiation of therapy (years) 7.7 ± 1.2 (2.33 - 10) 9.0 ± 1.0 (7.0 - 9.8) Age at discontinuation of therapy (years) 11.1 ± 0.9 (8.7 - 14.2) 12.3 ± 0.5 (11.7 - 13.2) Therapy duration (years) 3.4 ± 1.2 (2 - 8.8) 3.2 ± 1 (2.4 - 4.8) Abbreviations: SD, standard deviation Table 2. Height, Body mass index, and bone-chronological age differences during the study Characteristic Mean ± SD (Min-Max) (BA - CA), pre- treatment 1.5 ± 1.3 (-1.95 - 5) (BA - CA), post-treatment 0.7 ± 1.1 (-2.16 - 3.25) Height Final 161.4 ± 4.2 (149.5 -173) Target 157.9 ± 4.8 (147.5 -174) Predicted, pre-treatment 160.4 ± 7.4 (138.6 -178.7) Predicted, post-treatment 162 ± 6 (140.7 - 175) SDS final -0.28± 0.66 (-2.13 - 1.49) SDS target -0.8 ± 0.7 (-2.44 -1.64) SDS, pre-treatment 0.9 ± 1 (-2.8 - 3.2) SDS, post-treatment 0.7 ± 1.1 (-3 - 3.5) BMI SDS, pre-treatment 1.2 ± 1 (-0.49 - 5.95) SDS, post-treatment 1.3 ± 0.9 (-0.29 - 4.1) Abbreviations: SD, standard deviation; SDS, Standard deviation score; BMI, Body mass index Table 3. Growth velocity index measurements in follow-up sessions during GnRHa therapy and after its discontinuation GVI Mean ± SD (Min-Max) During therapy 1 st year 116.6 ± 24.7 (11.5 - 211.4) 2 nd year 104.7 ± 22.2 (27.75 - 173.63) 3 rd year 86.2 ± 26.5 (0 - 149.85) 4th year 77.4 ± 25.4 (21.06 - 119.42) Post-treatment 1 st year 117.6 ± 39.6 (9.05 - 232.48) 2 nd year 102 ± 30.3 (29.98 - 173.07) 3 rd year 72.7 ± 36.4 (0 - 174.76) Table 4. Statistical analysis of changes in Growth velocity index during GnRHa therapy and after its discontinuation (described in P-values) Follow-up session During therapy Post-treatment 2 nd year 3 rd year 4 th year Last year 1 st year 2 nd year 3 rd year During therapy 1 st year <0.001 <0.001 <0.001 0.05 0.001 <0.001 2 nd year - <0.001 <0.001 0.05 <0.001 3 rd year - - <0.001 <0.001 0.05 4 th year - - - 0.01 0.015 0.001 > 0.05 Last year - - - - <0.001 0.05 Post-treatment 1 st year - - - - - 0.026 0.001 2 nd year - - - - - - <0.001 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8037280","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":545878298,"identity":"6f0e741c-cff5-4f1f-a0bd-65d1be3723e2","order_by":0,"name":"Elham Maleki","email":"","orcid":"","institution":"Kerman University of Medical Sciences","correspondingAuthor":false,"prefix":"","firstName":"Elham","middleName":"","lastName":"Maleki","suffix":""},{"id":545878299,"identity":"a547e757-bd19-4b8d-a16e-0463f968ba80","order_by":1,"name":"Maryam 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1","display":"","copyAsset":false,"role":"figure","size":40163,"visible":true,"origin":"","legend":"\u003cp\u003eGrowth velocity index in years with GnRHa administration (no growth hormone). The follow-up sessions occurred in years 1, 2, 3, and 4.\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8037280/v1/ff7bf1b0c27d2821c94c8469.jpeg"},{"id":96555515,"identity":"33e7d53f-b280-494b-8c78-41da1b66e59a","added_by":"auto","created_at":"2025-11-23 11:38:42","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":45566,"visible":true,"origin":"","legend":"\u003cp\u003eGrowth velocity index in years with GnRHa administration (adjunctive growth hormone administration). The follow-up sessions occurred before the start of Growth hormone (GH) and years 1 and 2 after it.\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8037280/v1/be39200c4c25b69955d2849c.jpeg"},{"id":96919738,"identity":"50f7d960-2757-4a7b-9b44-557dde6e1413","added_by":"auto","created_at":"2025-11-27 14:14:25","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":848672,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8037280/v1/6c742318-b697-4cb6-8c5c-fd2256fc420a.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Outcomes Following Depot Gonadotropin-Releasing Hormone Agonist Treatment in Children with Central Precocious Puberty: A Retrospective Analysis","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCentral precocious puberty (CPP) is due to the premature awakening of the hypothalamic Gonadotropin hormone-releasing hormone (GnRH) pulse generator with subsequent pulsatile gonadotropin secretion (Mul \u0026amp; Hughes, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2008\u003c/span\u003e). The disorder's clinical course is vastly different, ranging from transient to slowly progressive, alternating, or rapidly progressive (Fontoura et al., \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e1989\u003c/span\u003e; Heger et al., \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e1999\u003c/span\u003e; Palmert, Malin, et al., 1999; Pasquino et al., \u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e1989\u003c/span\u003e). With significant contributions to the development of short stature due to the premature fusion of long bone epiphyseal growth plates, along with considerable psychosocial issues in the affected children and their families, the disorder should be managed promptly and appropriately (Sonis et al., \u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e1985\u003c/span\u003e; Sorgo et al., \u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e1987\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eGnRH agonists (GnRHa) and their depot formulations are the mainstay of treatment in CPP by reversibly suppressing the pituitary-gonadal axis (Hummelink et al., \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e1992\u003c/span\u003e; Manasco et al., \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e1988\u003c/span\u003e; Mul \u0026amp; Hughes, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2008\u003c/span\u003e; Oostdijk W, 1995; Roger et al., \u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e1986\u003c/span\u003e). However, follow-up evaluations have demonstrated varying and controversial outcomes, especially regarding final height (FH), which ranged from near negligible changes to complete restoration of the desirable growth curves (Antoniazzi et al., \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e1994\u003c/span\u003e; Brauner et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e1994\u003c/span\u003e; Galluzzi et al., \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e1998\u003c/span\u003e; Kauli et al., \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e1997\u003c/span\u003e; Kauli et al., \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e1990\u003c/span\u003e; Kletter \u0026amp; Kelch, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e1994\u003c/span\u003e; Oerter et al., \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e1991\u003c/span\u003e; Oostdijk et al., \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e1996\u003c/span\u003e; Partsch et al., \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e1993\u003c/span\u003e; Pasquino et al., \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e2000\u003c/span\u003e; Paul et al., \u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e1995\u003c/span\u003e; Stasiowska et al., \u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e1994\u003c/span\u003e). Nevertheless, the continuous and complete suppression of the hypothalamic-pituitary-gonadal axis is still a prerequisite for achieving optimal height growth (Partsch et al., \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e1993\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eMoreover, the primary outcome investigated in most previous studies regarding growth deficiencies in CPP has been chiefly the FH rather than changes in weight and body composition following the suppression of the axis by GnRHa (Boot et al., \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e1998\u003c/span\u003e; Feuillan et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e1999\u003c/span\u003e; Oostdijk et al., \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e1996\u003c/span\u003e).\u003c/p\u003e\n\u003ch3\u003eObjectives\u003c/h3\u003e\n\u003cp\u003eWith a lack of relevant literature, investigating body composition changes due to GnRHa administration and the resulting gonadal sex steroid inhibition can help to provide invaluable insights into the physiology of growth in CPP (Boepple et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e1986\u003c/span\u003e; Comite et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e1981\u003c/span\u003e; Galluzzi et al., \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e1998\u003c/span\u003e; Jay et al., \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e1992\u003c/span\u003e; Manasco et al., \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e1988\u003c/span\u003e; Wierman et al., \u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e1986\u003c/span\u003e). In addition, it can aid in the elaboration of whether or how obesity develops during GnRHa therapy or if it is simply from CPP alone (Feuillan et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e1999\u003c/span\u003e). Therefore, the authors aimed to evaluate outcomes after long-term GnRHa therapy concerning FH, body mass index, and growth patterns in CPP.\u003c/p\u003e\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003cdiv id=\"Sec4\" class=\"Section3\"\u003e\u003c/div\u003e\u003c/div\u003e"},{"header":"Methods","content":"\u003ch2\u003eDesign and Location\u003c/h2\u003e\u003cp\u003eThis longitudinal observational study was conducted in the Pediatric Endocrinology Department of Ali Asghar Children’s Hospital in Tehran, Iran, during 2015. Furthermore, our study protocol was approved by the local Institutional Review Board (IRB). In addition, written informed consent was obtained after informing the patient's legal guardians about the study's design and findings and assuring them of the confidentiality of their information. Finally, 496 patients were reviewed, and 196 cases (7 boys and 189 girls) were included.\u003c/p\u003e\n\u003ch3\u003ePopulation\u003c/h3\u003e\n\u003cp\u003eThe population of interest included all those who were referred to the clinic of the Pediatric Endocrinology Department of Ali Asghar Children\u0026rsquo;s Hospital. The medical records of the patients who came due to the appearance of secondary sexual characteristics before the age of puberty in the preceding 10 years (2005\u0026ndash;2015) were reviewed.\u003c/p\u003e\u003cp\u003ePatients who received Triptoreline SR for more than two years were included. Moreover, these individuals must have had their onset of sexual characteristics before turning 8 (girls) or 9 (boys) years, respectively, and had demonstrated rapidly progressive signs during their disease's clinical course, along with the pubertal response of LH and FSH to GnRH test (LH\u0026thinsp;\u0026gt;\u0026thinsp;15 IU/L and LH/FSH ratio\u0026thinsp;\u0026gt;\u0026thinsp;0.66; determined via radioimmunoassay) (Razzaghy-Azar et al., \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e2011\u003c/span\u003e), high 08:00 hr testosterone levels (\u0026gt;\u0026thinsp;20 ng/dL) (Razzaghi Azar et al., \u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e2006\u003c/span\u003e), and bone age (BA) that was at least one year above their chronological age (CA). In addition, if clinically rapidly progressive signs were seen without some of the hormonal or radiological criteria mentioned above, they still were included. However, suffering from any concomitant impactful disorders (e.g., Polycystic Ovarian Syndrome, Turner syndrome, Prader-Willi syndrome, or any other condition affecting pubertal progression, Peripheral precocious puberty, including McCune-Albright syndrome or adrenal disorders, Thyroid disorders, Uncontrolled metabolic disorders, including Diabetes Mellitus or obesity-related hormonal imbalances) led to the exclusion of the patients.\u003c/p\u003e\n\u003ch3\u003eExposure\u003c/h3\u003e\n\u003cp\u003eThe Triptoreline SR (Dipherelin, Ipsen-Biotech, Paris, France) dose was 3.75 mg in children\u0026thinsp;\u0026gt;\u0026thinsp;20 kg and 1.87 mg in children\u0026thinsp;\u0026lt;\u0026thinsp;20 kg intramuscularly every 28 days (Bertelloni et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2018\u003c/span\u003e). Furthermore, therapeutic sufficiency was considered as Luteinizing hormone levels below 6.6 IU/L 2 hours after the injection of Triptoreline (Brito et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2004\u003c/span\u003e). However, when clinical manifestations persisted, the period between two injections decreased to 21 days. The decision to discontinue treatment was also based primarily on the height, CA reaching the healthy children's mean age-onset of puberty, BA, and the caretakers' preferences. The cases were followed every three months for height, weight, and the signs of puberty. If growth velocity became less than 4 cm/year after 6 months, follow-up growth hormone was added to the treatment regimen (Antoniazzi et al., \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2000\u003c/span\u003e).\u003c/p\u003e\n\u003ch3\u003eOutcomes and measures\u003c/h3\u003e\n\u003cp\u003eThe outcomes included clinical investigations at each follow-up visit every three months.\u003c/p\u003e\u003cp\u003eAt each visit, the patients' height (Centimeters; Stadiometer, SECA, Germany) and weight (Kilograms; SECA scale, Germany) were measured. The body mass index (BMI) was also calculated with the method previously described by Rolland-Cachera et al. (Rolland-Cachera et al., \u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e1991\u003c/span\u003e). In addition, the standard deviation score (SDS) for height and body mass index was calculated using the age-appropriate CDC 2000 curves and tables (Kuczmarski, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e2000\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe sex-adjusted target and predicted height were also determined from the mean height of parents and based on the Bayley-Pinneau calculations (Tanner et al., \u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e1970\u003c/span\u003e; Zachmann et al., \u003cspan citationid=\"CR57\" class=\"CitationRef\"\u003e1978\u003c/span\u003e). FH was recorded when the BA was at age 15 in girls and 16 in boys, while the height growth velocity was also less than 2.5 cm/year, obtained from several measurements at least 3 months apart (Kleign, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e2012\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eSexual maturity was assessed according to the Tanner scaling, and BA was estimated based on separate and mean scoring of the bones on the wrist and hand radiographs based on the atlas of Greulich and Pyle (Greulich WW, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e1959\u003c/span\u003e; Marshall \u0026amp; Tanner, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e1969\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e1970\u003c/span\u003e; Zachmann et al., \u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e1974\u003c/span\u003e). In addition, the Growth velocity index (GVI) was calculated as the ratio of growth velocity to the average height growth velocity of age and sex-specific 50th percentile, then multiplied by 100.\u003c/p\u003e\u003cp\u003eUltimately, the onset of menarche and respective menstrual patterns after the discontinuation of treatment were evaluated via semi-structured interviews.\u003c/p\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eThe 19th version of the SPSS statistical software package (SPSS Inc., IBM, USA) was used to analyze the data. Furthermore, categorical and continuous variables were described as Frequency (%) and mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD, respectively. In addition, paired t-tests and repeated measures for the analysis of variance were used to analyze the variables of interest. p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eCase selection\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe medical records of 496 patients were reviewed, which led to the exclusion of 264 cases, including\u0026nbsp;111 (22.4%) with premature adrenarche, 59 (11.9%) with premature thelarche, 9 (1.8%) with premature menarche, 10 (2%) with McCune-Albright syndrome, 5 (1%) with Testotoxicosis, 12 (2.4%) with congenital adrenal hyperplasia, 14 (2.8%) with 21 hydroxylase deficiency, and 44 (8.9%) with Arrested or regressed precocious puberty. Therefore,\u0026nbsp;232 (43.6%) had central precocious puberty and were considered. However, among these, 2 had arrested puberty, and 34 had received treatment for less than two years and, therefore, were excluded. Ultimately, 196 cases (7 boys and 189 girls) were included.\u003c/p\u003e\n\u003cp\u003eIn addition, 7 girls (3%) had disorders in the brain (3 cases had astrocytoma and 4 cases, each one suffering from hamartoma, pinealoma, pineal cyst, and prolactinoma), and 3 (30%) boys had brain lesions (each 1 case suffering from hamartoma, temporal cyst, or brain atrophy). (Table 1)\u003c/p\u003e\n\u003cp\u003e[Table 1]\u003c/p\u003e\n\u003cp\u003eThe patients were evaluated for 1.1 \u0026plusmn; 0.94 years before therapy started. Moreover, the therapy lasted for 3.2 \u0026plusmn; 1.3 years and 2.7 \u0026plusmn; 1.3 years in girls and boys, respectively, discontinuing at mean ages of 10.1 \u0026plusmn; 1 and 11.1\u0026plusmn; 1.1 years in girls and boys. Bone age at the time of therapy discontinuation in girls and boys was 11.7 \u0026plusmn; 1 and 13.7 \u0026plusmn; 0.8 years, respectively. Furthermore, the analyses revealed that treatment significantly decreased BA-CA differences (p \u0026lt; 0.001).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFinal Height\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDue to the low number of boys in our study, only 3 reached their final respective height, and, therefore, they were not included in our analyses. Girls\u0026apos; mean final height was significantly higher than the target height (p \u0026lt; 0.001) but significantly lower than the predicted height at the end of treatment (p = 0.011). Moreover, the mean predicted height at the end of treatment was significantly higher than that of pre-treatment (p = 0.016). Furthermore, the final height SDS was significantly better than the target height SDS (p \u0026lt; 0.001) and worse than the pre-treatment height SDS (p \u0026lt; 0.001). In addition, the mean Height SDS at the end of treatment was significantly lower than the pre-treatment height SDS (p \u0026lt; 0.001). (Table 2)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eBody mass index (BMI)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn boys, the BMI SDS did not change significantly after therapy (1.9 \u0026plusmn; 0.9 vs. 1.8 \u0026plusmn; 0.7, p \u0026gt; 0.05). However, after treatment, in the girls, BMI SDS significantly increased (1.2 \u0026plusmn; 1.0 vs. 1.3 \u0026plusmn;0.9, p = 0.033). (Table 2)\u003c/p\u003e\n\u003cp\u003e[Table 2]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGrowth velocity index (GVI)\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIt has been found that even though GVI in the first year since the initiation of therapy was not significantly different compared to pre-treatment (115.1 \u0026plusmn; 25.9 vs. 119 \u0026plusmn; 37.7, P = NS), it significantly declined in the second and third years of treatment (103.6 \u0026plusmn; 31.4 and 87.6 \u0026plusmn; 29.6, with a mean difference of 5.7 \u0026plusmn; 1.7 and 5.1 \u0026plusmn; 1.5, respectively, p \u0026lt; 0.05).\u003c/p\u003e\n\u003cp\u003eIn addition, 1-year post-treatment GVI was significantly higher than GVI during the last year of therapy (96.8 \u0026plusmn; 33.6 vs. 84 \u0026plusmn; 40.1, p = 0.003), although it was significantly lower than pre-treatment GVI (p = 0.02). Furthermore, the index progressively declined in the second (74.2 \u0026plusmn; 41.4) and third (58.2 \u0026plusmn; 45.6) post-treatment years. (Tables 3 and 4 and Figures 1 and 2)\u003c/p\u003e\n\u003cp\u003e[Table 3]\u003c/p\u003e\n\u003cp\u003e[Table 4]\u003c/p\u003e\n\u003cp\u003e[Figure 1]\u003c/p\u003e\n\u003cp\u003e[Figure 2]\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMenarche\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIt took 1.1 \u0026plusmn; 0.7 (range 0.1-6) years following the last dose of triptorelin for the girls to experience menarche (occurring in 43.6%), 50% of whom had irregular cycles.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eAlthough depot GnRH analogs have been used to treat precocious puberty for many years, few studies have assessed their effects on anthropometric parameters other than height or bone age, such as weight, BMI, and overall growth. Moreover, some have stated that FH as an outcome can be compounded by several factors (e.g., age and bone age on initiation of therapy and therapy duration), impacting its accuracy and relevance (Mul \u0026amp; Hughes, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e2008\u003c/span\u003e). Furthermore, many studies have solely relied on height predictions rather than the final achieved height, limiting its reliability (Bertelloni \u0026amp; Mul, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2008\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eTherefore, our study aimed to assess other anthropometric parameters mentioned above, revealing that FH in girls who received GnRHa exceeded target height but was similar to the pre-treatment predicted adult height and significantly lower than post-treatment predicted height. GVI declined progressively throughout the years of therapy. In addition, even though BMI did not change during therapy in boys, it considerably increased in girls.\u003c/p\u003e\u003cp\u003eRegarding the final height (FH), girls achieved outcomes comparable to those predicted by their pre-treatment adult heights and even exceeded their target height. This finding was similar to the reports already demonstrated (Carel et al., \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e1999\u003c/span\u003e; Heger et al., \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e1999\u003c/span\u003e; Oostdijk et al., \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e1996\u003c/span\u003e). Although FH exceeded the pre-treatment predicted height in some studies, it failed to surpass the target height (although it fell within the genetically acceptable range) (Mul et al., \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e2000\u003c/span\u003e; Tanaka et al., \u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e2005\u003c/span\u003e; Traggiai et al., \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e2005\u003c/span\u003e). However, an increase in the predicted height during treatment was noted, which led to a higher post-treatment predicted height, similar to previous studies (Klein et al., \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e2001\u003c/span\u003e; Oostdijk et al., \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e1991\u003c/span\u003e; Oostdijk et al., \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e1996\u003c/span\u003e). Consequently, FH was significantly lower than the post-treatment predicted height.\u003c/p\u003e\u003cp\u003eThe Growth velocity (GV) during the first year of therapy was similar to before, yet it progressively declined throughout the study, reaching its nadir at about 11 years. In addition, the Height velocity (HV) increased briefly after the discontinuation of therapy but decreased afterward. This finding means that patients will not experience a post-treatment growth spurt.\u003c/p\u003e\u003cp\u003eSome studies have shown that GV decreases by about 60% during the first year of therapy, with more significant decreases found in those with the most advanced bone age and relatively taller. However, GV is usually appropriate for the respective bone age from the second year onward (Carel et al., \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e1999\u003c/span\u003e; Mouat et al., \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e2009\u003c/span\u003e; Sklar et al., \u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e1991\u003c/span\u003e; Weise et al., \u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e2004\u003c/span\u003e). Moreover, one study has also reported that even though HV stabilized after three years of therapy, it increased over the first six months after the discontinuation of therapy and continued to remain higher than its pre-treatment values in the second 6 months. However, the 2nd year following therapy discontinuation coincided with a decrease in HV (Oostdijk et al., \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e1991\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThis study used BMI as an indirect body fat index, and BMI data were expressed with age and sex-appropriate normative values. In boys, the mean BMI SDS changes during GnRHa therapy were insignificant. However, BMI SDS in girls was significantly higher at the end of therapy. Unfortunately, the few available literature regarding the effects of GnRHa therapy on body composition are controversial, with some having emphasized that obesity is a frequent finding among children with CPP and not related to GnRHa therapy, indicating that it seldom fosters the development of obesity (Heger et al., \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e1999\u003c/span\u003e; Traggiai et al., \u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e2005\u003c/span\u003e). However, some have also reported that GnRHa therapy induces a reduction in BMI, especially in girls (Arrigo et al., \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2004\u003c/span\u003e). Nevertheless, several studies have also indicated that BMI does increase during therapy, and its trend persists even after its discontinuation, while some report that the higher baseline values of BMI predict the onward trend after therapy cessation (Oostdijk et al., \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e1996\u003c/span\u003e; Palmert, Mansfield, et al., \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e1999\u003c/span\u003e; Unal et al., \u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e2003\u003c/span\u003e). Therefore, future studies should compare such changes with anthropometrically similar control groups.\u003c/p\u003e\u003cp\u003eRegarding the onset of menarche following CPP treatment, there is some evidence that when treatment is discontinued even after long-term therapy, it reverses the gonadal suppression within a few weeks to months, leading to a rise in the concentrations of plasma gonadal steroids, the progression of sexual maturation, and the appearance menstrual cycles (Feuillan et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e1999\u003c/span\u003e; Heger et al., \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e1999\u003c/span\u003e; Manasco et al., \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e1988\u003c/span\u003e). In those who experienced menarche in our study (less than 50%), the phenomenon occurred within 1-1.5 years following the discontinuation of therapy, which aligns with previous studies (Heger et al., \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e1999\u003c/span\u003e; Jay et al., \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e1992\u003c/span\u003e; Oostdijk et al., \u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e1996\u003c/span\u003e; SHLOMO MELMED, 2011). However, it has also been demonstrated that more than 90% of girls experience menarche within two years, which can also be true in our study sample, but the data regarding it is lacking (Antoniazzi et al., \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2000\u003c/span\u003e; SHLOMO MELMED, 2011). Therefore, future studies should extend their follow-up period to at least two years after therapy cessation to make conclusions more accurate and reliable.\u003c/p\u003e\u003cp\u003eIn girls with precocious puberty who received GnRHa, the final height was higher than the target height. In girls, BMI-SDS after treatment increased, so prevention of obesity by an appropriate diet and follow-up is recommended. Growth velocity should be followed during therapy; if it is lower than 4 cm/year, growth hormone should be added. Treatment significantly decreased bone age advancement to chronological age.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e The authors would like to acknowledge the assistance of the Pediatric Endocrinology staff at Aliasghar Children\u0026rsquo;s Hospital for their guidance and support throughout this project.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthorship:\u003c/strong\u003e All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work, and approve this version to be published.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contribution:\u0026nbsp;\u003c/strong\u003eM.R. led the clinical section and writing of the paper. A.T. and E.M. conceived the project, did the clinical assessments, and oversaw the project\u0026apos;s progress. E.M. performed statistical analyses. A.T., S.S., and E.M. were equally responsible for the preparation of data as well as the collection of statistics. E.M. wrote the main manuscript text, and S.S. prepared figures.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;All authors reviewed the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests:\u0026nbsp;\u003c/strong\u003eNone.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval:\u0026nbsp;\u003c/strong\u003eThe study received approval from the Ethics Committee of Iran University of Medical Sciences (TUMS), and the participants and their legal guardians provided written informed consent\u003cspan dir=\"RTL\"\u003e.\u003c/span\u003e Moreover, it followed the guidelines provided in the Declaration of Helsinki. (The grant number has not been allocated according to the university policy.)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of supporting data:\u003c/strong\u003e The dataset supporting the conclusions of this article is available upon request to the corresponding author.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e None.\u003c/p\u003e\n\u003cp\u003eNo grant was taken from the Iran University of Medical Sciences or any other organization. \u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAntoniazzi, F., Arrigo, T., Cisternino, M., Galluzzi, F., Bertelloni, S., Pasquino, A. M., Borrelli, P., Osio, D., Mengarda, F., De Luca, F., \u0026amp; Tato, L. (2000). 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Outcome after depot gonadotrophin-releasing hormone agonist treatment for central precocious puberty: effects on body mass index and final height. \u003cem\u003eEur J Endocrinol\u003c/em\u003e,\u003cem\u003e 153\u003c/em\u003e(3), 463-464. https://doi.org/10.1530/eje.1.01975 \u003c/li\u003e\n\u003cli\u003eUnal, O., Berberoglu, M., Evliyaoglu, O., Adiyaman, P., Aycan, Z., \u0026amp; Ocal, G. (2003). Effects on bone mineral density of gonadotropin releasing hormone analogs used in the treatment of central precocious puberty. \u003cem\u003eJ Pediatr Endocrinol Metab\u003c/em\u003e,\u003cem\u003e 16\u003c/em\u003e(3), 407-411.\u003c/li\u003e\n\u003cli\u003eWeise, M., Flor, A., Barnes, K. M., Cutler, G. B., Jr., \u0026amp; Baron, J. (2004). Determinants of growth during gonadotropin-releasing hormone analog therapy for precocious puberty. \u003cem\u003eJ Clin Endocrinol Metab\u003c/em\u003e,\u003cem\u003e 89\u003c/em\u003e(1), 103-107.\u003c/li\u003e\n\u003cli\u003eWierman, M. E., Beardsworth, D. E., Crawford, J. D., Crigler, J. F., Jr., Mansfield, M. J., Bode, H. H., Boepple, P. A., Kushner, D. C., \u0026amp; Crowley, W. F., Jr. (1986). Adrenarche and skeletal maturation during luteinizing hormone releasing hormone analogue suppression of gonadarche. \u003cem\u003eJ Clin Invest\u003c/em\u003e,\u003cem\u003e 77\u003c/em\u003e(1), 121-126. https://doi.org/10.1172/jci112265 \u003c/li\u003e\n\u003cli\u003eZachmann, M., Prader, A., Kind, H. P., Hafliger, H., \u0026amp; Budliger, H. (1974). Testicular volume during adolescence. Cross-sectional and longitudinal studies. \u003cem\u003eHelv Paediatr Acta\u003c/em\u003e,\u003cem\u003e 29\u003c/em\u003e(1), 61-72.\u003c/li\u003e\n\u003cli\u003eZachmann, M., Sobradillo, B., Frank, M., Frisch, H., \u0026amp; Prader, A. (1978). Bayley-Pinneau, Roche-Wainer-Thissen, and Tanner height predictions in normal children and in patients with various pathologic conditions. \u003cem\u003eJ Pediatr\u003c/em\u003e,\u003cem\u003e 93\u003c/em\u003e(5), 749-755.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e Baseline Characteristics of Participants\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 45px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGirls (n = 189)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eMean\u0026nbsp;\u003c/strong\u003e\u0026plusmn;\u003cstrong\u003e\u0026nbsp;SD (Min-Max)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBoys (n = 7)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eMean\u0026nbsp;\u003c/strong\u003e\u0026plusmn;\u003cstrong\u003e\u0026nbsp;SD (Min-Max)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 45px;\"\u003e\n \u003cp\u003eAge-onset of clinical signs (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27px;\"\u003e\n \u003cp\u003e6.7 \u0026plusmn; 1.4 (0.33 - 8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27px;\"\u003e\n \u003cp\u003e7.9 \u0026plusmn; 0.9 (6.75 - 8.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 45px;\"\u003e\n \u003cp\u003eDuration of evaluation before therapy (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27px;\"\u003e\n \u003cp\u003e0.98 \u0026plusmn; 0.95 (0.33 - 5.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27px;\"\u003e\n \u003cp\u003e0.80 \u0026plusmn; 0.67 (0.34 - 1.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 45px;\"\u003e\n \u003cp\u003eAge at\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003einitiation of therapy (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27px;\"\u003e\n \u003cp\u003e7.7 \u0026plusmn; 1.2 (2.33 - 10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27px;\"\u003e\n \u003cp\u003e9.0 \u0026plusmn; 1.0 (7.0 - 9.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 45px;\"\u003e\n \u003cp\u003eAge at\u003cspan dir=\"RTL\"\u003e\u0026nbsp;\u003c/span\u003ediscontinuation of therapy (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27px;\"\u003e\n \u003cp\u003e11.1 \u0026plusmn; 0.9 (8.7 - 14.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27px;\"\u003e\n \u003cp\u003e12.3 \u0026plusmn; 0.5 (11.7 - 13.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 45px;\"\u003e\n \u003cp\u003eTherapy duration (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27px;\"\u003e\n \u003cp\u003e3.4 \u0026plusmn; 1.2 (2 - 8.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 27px;\"\u003e\n \u003cp\u003e3.2 \u0026plusmn; 1 (2.4 - 4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: SD, standard deviation\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u003c/strong\u003e Height, Body mass index, and bone-chronological age differences during the study\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristic\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean \u0026plusmn; SD (Min-Max)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e(BA - CA), pre- treatment\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1.5 \u0026plusmn; 1.3 (-1.95 - 5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e(BA - CA), post-treatment\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.7 \u0026plusmn; 1.1 (-2.16 - 3.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHeight\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003eFinal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e161.4 \u0026plusmn; 4.2 (149.5 -173)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003eTarget\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e157.9 \u0026plusmn; 4.8 (147.5 -174)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003ePredicted, pre-treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e160.4 \u0026plusmn; 7.4 (138.6 -178.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003ePredicted, post-treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e162 \u0026plusmn; 6 (140.7 - 175)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003eSDS final\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e-0.28\u0026plusmn; 0.66 (-2.13 - 1.49)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003eSDS target\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e-0.8 \u0026plusmn; 0.7 (-2.44 -1.64)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003eSDS, pre-treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.9 \u0026plusmn; 1 (-2.8 - 3.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003eSDS, post-treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e0.7 \u0026plusmn; 1.1 (-3 - 3.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eBMI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003eSDS, pre-treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1.2 \u0026plusmn; 1 (-0.49 - 5.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 33px;\"\u003e\n \u003cp\u003eSDS, post-treatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 66px;\"\u003e\n \u003cp\u003e1.3 \u0026plusmn; 0.9 (-0.29 - 4.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: SD, standard deviation; SDS, Standard deviation score; BMI, Body mass index\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.\u003c/strong\u003e Growth velocity index measurements in follow-up sessions during GnRHa therapy and after its discontinuation\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGVI\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eMean \u0026plusmn; SD (Min-Max)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDuring therapy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e1\u003csup\u003est\u003c/sup\u003e year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e116.6 \u0026plusmn; 24.7 (11.5 - 211.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e2\u003csup\u003end\u003c/sup\u003e year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e104.7 \u0026plusmn; 22.2 (27.75 - 173.63)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e3\u003csup\u003erd\u003c/sup\u003e year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e86.2 \u0026plusmn; 26.5 (0 - 149.85)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e4th year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e77.4 \u0026plusmn; 25.4 (21.06 - 119.42)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 100px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePost-treatment\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e1\u003csup\u003est\u003c/sup\u003e year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e117.6 \u0026plusmn; 39.6 (9.05 - 232.48)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e2\u003csup\u003end\u003c/sup\u003e year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e102 \u0026plusmn; 30.3 (29.98 - 173.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e3\u003csup\u003erd\u003c/sup\u003e year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 50px;\"\u003e\n \u003cp\u003e72.7 \u0026plusmn; 36.4 (0 - 174.76)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4.\u003c/strong\u003e Statistical analysis of changes in Growth velocity index during GnRHa therapy and after its discontinuation (described in P-values)\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\" class=\"fr-table-selection-hover\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" rowspan=\"2\" style=\"width: 25px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFollow-up session\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" valign=\"top\" style=\"width: 41px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDuring therapy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 33px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePost-treatment\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e2\u003csup\u003end\u003c/sup\u003e year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e3\u003csup\u003erd\u003c/sup\u003e year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e4\u003csup\u003eth\u0026nbsp;\u003c/sup\u003eyear\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003eLast year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e1\u003csup\u003est\u003c/sup\u003e year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e2\u003csup\u003end\u003c/sup\u003e year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e3\u003csup\u003erd\u003c/sup\u003e year\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"5\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDuring therapy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e1\u003csup\u003est\u003c/sup\u003e year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026gt; 0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e2\u003csup\u003end\u003c/sup\u003e year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e0.032\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026gt; 0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e3\u003csup\u003erd\u003c/sup\u003e year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026gt; 0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003e4\u003csup\u003eth\u003c/sup\u003e year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 10px;\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e0.015\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026gt; 0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 12px;\"\u003e\n \u003cp\u003eLast year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026gt; 0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 13px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePost-treatment\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e1\u003csup\u003est\u003c/sup\u003e year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e0.026\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 12px;\"\u003e\n \u003cp\u003e2\u003csup\u003end\u003c/sup\u003e year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 10px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 11px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 11px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Precocious puberty, Gonadotropin-releasing hormone agonists, Body Height, Body Mass Index, Growth and Development","lastPublishedDoi":"10.21203/rs.3.rs-8037280/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8037280/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eGonadotropin-releasing hormone agonist (GnRHa) therapy is widely endorsed for Central Precocious Puberty (CPP). This longitudinal observational study aimed to assess the influence of GnRHa on anthropometric measures over a decade. Pre- and post-treatment clinical records of 196 patients (7 boys, 189 girls) who received GnRHa therapy were reviewed. The study showed that in girls, post-treatment final height exceeded pre-treatment predicted adult height (p \u0026lt; 0.001). BMI-SDS notably increased in treated girls (p \u0026lt; 0.001) contrasting with boys. GVI declined during therapy (p \u0026lt; 0.001) but rebounded post-therapy (p \u0026lt; 0.05), without reaching pre-treatment levels. Additionally, 43.7% of girls reported menarche 1.1 ± 0.7 years after therapy, but 50% experienced irregular cycles. Conclusion: GnRHa has positive effect on final height.\u003c/p\u003e","manuscriptTitle":"Outcomes Following Depot Gonadotropin-Releasing Hormone Agonist Treatment in Children with Central Precocious Puberty: A Retrospective Analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-11-23 11:38:15","doi":"10.21203/rs.3.rs-8037280/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"17e23b60-ddf7-4ed5-97b8-19df83525fb2","owner":[],"postedDate":"November 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-11-26T19:23:32+00:00","versionOfRecord":[],"versionCreatedAt":"2025-11-23 11:38:15","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8037280","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8037280","identity":"rs-8037280","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}