The effect of GnRH-analogue therapy on the quality of life of girls with central precocious puberty and their families

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Although GnRH agonist (GnRHa) therapy slows pubertal progression, its impact on quality of life (QoL) and emotional perception is unclear. This study evaluated QoL and treatment-related stress in girlswith CPP and their families during and after GnRHa therapy. Methods: In this cross-sectional study, 56 females with ongoing or previous CPP (aged 4–18 years) and 30 healthy matched controls were enrolled. Patients were grouped by age (A1:4–7; A2:8–12; A3:13–18; A4:>18 years). QoL was assessed using PedsQL™ 4.0, while emotional perception and treatment-related stress were evaluated with a disease-specific Self-Perception Questionnaire (SPQ). Group comparisons and correlations with therapy duration were performed. Results: PedsQL scores did not differ significantly across CPP age groups or between patients and controls, except for lower Physical Functioning in A2 versus controls (p=0.02). No correlation was found between therapy duration and QoL. SPQ scores showed no significant differences between children and parents or across age groups, although therapy-related emotional stress tended to increase with age. In A4, longer therapy duration correlated with lower treatment-related stress (r=0.47, p=0.021), while reduced self-esteem persisted during treatment and at follow-up. Conclusion: QoL in CPP patients appears comparable to healthy peers, but emotional responses to treatment vary with age and are not captured by generic QoL tools. Disease-specific assessment highlighted age-related emotional stress and long-term self-esteem reduction, supporting psychological evaluation in CPP management. Central Precocious Puberty Quality of Life GnRH agonists Emotional stress Self-perception questionnaire Figures Figure 1 Figure 2 Introduction Precocious puberty in females is defined as the onset of secondary sexual characteristics before 8 years of age [ 1 ]. Central precocious puberty (CPP) results from premature activation of the hypothalamic-pituitary-gonadal axis, and idiopathic CPP occurs in the absence of central nervous system pathology or identifiable genetic causes [ 1 ]. Socioeconomic and ethnic factors, including poverty, family conflict, minority status, migration, and environmental exposures, have been associated with earlier pubertal onset [ 2 – 6 ]. Early puberty has been linked to emotional and behavioral difficulties, including anxiety, depression, social withdrawal, and increased psychological stress, negatively affecting quality of life (QoL) [ 7 – 9 ]. Parents of girls with CPP often report concerns regarding their child’s physical development, sexual behavior, and peer relationships, highlighting the importance of assessing psychosocial impact in both patients and families [ 8 , 10 ]. GnRH agonist (GnRHa) therapy is the standard treatment for CPP, aiming to slow sexual maturation, delay bone age advancement, and optimize adult height [ 11 ]. Although effective in managing physical outcomes, the chronic and invasive nature of the treatment may contribute to stress in patients and caregivers. Health-related quality of life (HRQoL) is a multidimensional construct encompassing physical, emotional, social, and school functioning. The Pediatric Quality of Life questionnaire (PedsQL) is a widely used generic measure, yet validated instruments specific to CPP are lacking [ 12 ]. Consequently, the relationship between disease severity, treatment duration, and QoL remains incompletely understood. Previous studies indicate that children with precocious puberty often report lower QoL scores than their peers, yet few investigations have assessed the impact of GnRHa therapy on psychosocial outcomes or family stress [ 13 – 15 ]. We performed a cross-sectional study in girls with a diagnosis of CPP to evaluate QoL and treatment-related stress in CPP patients and their families during and after GnRHa therapy, using a tailored, disease-specific questionnaire to capture patient- and family-centered outcomes associated with this chronic condition and its management. Methods Study population Girls affected by idiopathic CPP [1] who attended the Pediatric Endocrinology Outpatient Clinic of the University Hospital of Modena, Italy, between 2015 and 2016, entered this cross-sectional study. All participants and/or parents were recruited consecutively and provided written informed consent prior to participation. Exclusion criteria included the presence of organic causes of precocious puberty, chronic or endocrine disorders potentially affecting growth or psychological status, previous or current psychiatric diagnoses, and incomplete clinical or questionnaire data. Controls paired for age and level of instruction were also evaluated. Regarding the control population, both personal and family medical histories were negative for CPP as well as for other relevant medical conditions. Patients with CPP were divided into four groups according to their age at the time of questionnaire completion: (1) A1: 3 patients aged 4–7 years; (2) A2: 15 patients aged 8–12 years; (3) A3: 13 patients aged 13–18 years; and (4) A4: 25 patients aged >18 years. At the time of the study, A3 patients had already discontinued therapy but remained under follow-up, while A4 patients had completed therapy and were no longer coming to the outpatient clinic. Children Anthropometric Measurement and Puberty Stage Evaluation Anthropometric measurements were obtained at enrollment and retrospectively evaluated from the beginning of the GnRH therapy. Height was measured in the standing position, with patients barefoot, heels together, and head aligned in the Frankfurt plane, using a calibrated Harpenden stadiometer (Crymych, UK), with an approximation of 0.1 cm. Body weight was measured to the nearest 0.1 kg using a calibrated digital scale, with patients wearing minimal clothing or underwear. Anthropometric data were expressed as WHO percentiles for age and sex [16]. Pubertal development was evaluated by a trained pediatric endocrinologist according to Tanner’s criteria [17,18], assessing breast development, axillar and pubic hair distribution. Questionnaires All patients completed two questionnaires assessing quality of life and self-perception. Pediatric Quality of Life Inventory (PedsQL) The PedsQL™ 4.0 [12] is a validated instrument designed to assess health-related quality of life in children and adolescents. It includes 23 items grouped into four functional domains: physical (8 items), emotional (5 items), social (5 items), and school functioning (5 items). Each item was scored on a 5-point Likert scale reflecting the frequency of problems during the previous month: 0 = never, 1 = almost never, 2 = sometimes, 3 = often, 4 = almost always. For children aged 4–7 years, a simplified 3-point scale was used: 0 = never, 2 = sometimes, 4 = always. Items were reverse-scored and linearly transformed to a 0–100 scale (0 = 100; 1 = 75; 2 = 50; 3 = 25; 4 = 0), with higher scores indicating better quality of life. Patients in A1, A2, and A3 completed this questionnaire, and their scores were compared with those of 30 age-matched healthy controls. Self-Perception Questionnaire (SPQ) The SPQ is an experimental tool developed by the clinical psychologists of our department (Appendix A), specifically designed to evaluate self-perception and emotional response in CPP patients during or after treatment. Groups A1, A2, and A3, as well as their parents, completed the questionnaire, while A4 patients completed it twice — the first one referring to the treatment period and at the second one referring to time of the study. The scoring system of the SPQ mirrored that of the PedsQL, with higher scores corresponding to better self-perception and lower perceived stress. Statistical analysis Data analysis was performed using SPSS version 20.0 (IBM SPSS Inc., Chicago, IL). Continuous variables were expressed as mean ± standard deviation (SD) and categorical variables as frequencies and percentages. Comparisons between CPP patients and controls, as well as among age groups, were conducted using Kruskal–Wallis and Mann–Whitney U tests for continuous variables and chi-square or Fisher’s exact tests for categorical variables. Pairwise comparisons were performed when significant differences were found. A p-value <0.05 was considered statistically significant. Results Population characteristics A total of 56 female children with CPP and 30 female matched controls were enrolled in the study. Baseline characteristics, collected at the start of the treatment, of the CPP study population are presented in Table 1. Among the 56 participants affected by CPP, two (3.6%) had micropolycystic ovaries, one (1.8%) had autoimmune thyroiditis, and one (1.8%) had De Quervain’s thyroiditis. Eleven participants (19.6%) reported a first-degree family history of CPP. Fourteen participants were adopted (25%). Baseline characteristics of the population, stratified into four analysis groups and collected at the start of the treatment, are presented in Table 2 . Table 2 - Baseline characteristics, at the start of the treatment, of the CPP study population according to the four analysis group. Values are expressed as mean ± standard deviation (SD) or number (percentage), as appropriate. A1 (n=3) A2 (n= 15) A3 (n=13) A4 (n=25) Age (years) 5.12 (1.09) 7.55 (0.62) 7.23 (1.76) 8.17 (1.01) Bone age (years) 6.17 (1.53) 8.93 (1.49) 9.85 (1.97) 9.97 (1.26) D bone age-age (years) 1.05 (2.14) 1.38 (1.24) 2.61 (0.91) 1.82 (1.34) Height (cm) 111.50 (7.89) 130.14 (9.18) 131.59 (12.64) 131.54 (5.85) Height (SDS) 0.86 (1.65) 1.36 (1.31) 2.13 (0.68) 1.00 (1.10) Target height (cm) 159.88 (7.95) 162.60 (6.31) 162.77 (5.75) 159.11 (4.65) Target height (SDS) -0.69 (1.40) -0.07 (1.11) -0.37 (0.88) -0.83 (1.00) Weight (kg) 19.27 (4.55) 31.19 (7.65) 34.23 (10.15) 29.66 (4.82) BMI (kg/m 2 ) 15.32 (1.39) 18.13 (2.59) 19.52 (3.93) 17.08 (2.14) BMI (SDS) -0.01 (0.88) 1.10 (1.01) 1.55 (1.37) 0.54 (0.94) Growth velocity (cm/year) 9.92 (1.12) 8.25 (2.37) 8.85 (2.65) 7.55 (2.00) Tanner stage I II III IV V - 3 (100%) - - - 3 (20%) 10 (66.7%) 2 (18.2%) - - - 12 (92.3%) 1 (7.7%) - - 4 (16%) 11 (44%) 8 (32%) 2 (8%) - Estradiol (pg/ml) <10 23.67 (11.96) 38.79 (29.24) 37.68 (38.80) The diagnosis of CPP was established based on clinical, instrumental, and biochemical findings in accordance with current guidelines [ 1 ]. As part of the diagnostic workup, all patients underwent a GnRH stimulation test. Mean age at treatment initiation was 7.87±1.33 years. The mean duration of therapy with GnRH analogue was 1.71±0.73 years. The mean age at menarche was 11.26±1.23 years. Population characteristics at the time of questionnaire The total population, as described in the methods section, was divided into four age-based groups (A1, A2, A3, A4). The characteristics of the four groups at the time of questionnaire data collection are described in Table 3 . Table 3 Characteristics of the four group (A1-A4) of the CPP study population. Values are expressed as mean ± standard deviation (SD) or number (percentage), as appropriate. A1 (n = 3) A2 (n = 15) A3 (n = 13) A4 (n = 25) Age (years) 6.17 (1.51) 9.77 (1.20) 15.67 (1.66) 22.34 (2.51) Height (cm) 121.00 (5.77) 143.48 (9.90) 162.01 (7.59) 158.65 (5.56) Height (SDS) 1.39 (1.21) 1.04 (1.28) 0.04 (1.09) -1.11 (0.99) Target height (cm) 159.86 (7.96) 161.60 (6.58) 162.77 (5.75) 159.11 (4.65) Target height (SDS) -0.69 (1.40) -0.25 (1.19) -0.37 (0.88) -0.83 (1.00) Weight (kg) 24.00 (3.74) 42.07 (10.26) 65.99 (22.90) 55.87 (8.51) BMI (kg/m 2 ) 16.31 (1.25) 20.06 (2.94) 25.46 (7.82) 22.26 (3.59) BMI (SDS) 0.49 (0.58) 1.24 (0.92) 1.06 (1.56) -0.08 (1.00) Menarche (n) 0 1 (6.7%) 13 (100%) 25 (100%) Age at menarche (years) - 10.3 10.63 (1.25) 11.61 (1.11) PedsQL questionnaire results Scores obtained by patients in each domain and the overall HRQoL scale (mean (SD)), along with statistical comparisons, are presented in Table 4 . Table 4 PedsQL scores (mean (SD)) across domains of health-related quality of life (HRQoL) in female children CPP stratified by age groups (A1–A3) and in healthy controls. Statistical comparisons were performed using the Kruskal–Wallis rank sum test for multiple group analysis and Mann–Whitney U test for pairwise comparisons. Significant p-values (< 0.05) are indicated with an *. PedQL subscales A1 (n = 3) A2 (n = 15) A3 (n = 13) Controls (n = 30) A1vsA2vsA3 CPP vs controls Physical functioning 82.64 (6.87) 77.54 (18.16)* 84.86 (12.55) 86.43 (8.85)* x2 = 0.79 p = 0.67 p = 0.066 Emotional functioning 83.30 (16.99) 76.56 (15.18) 77.88 (15.44) 77.30 (13.65) x2 = 0.72 p = 0.69 p = 0.980 Social functioning 90.00 (8.16) 86.86 (13.21) 94.23 (6.75) 89.70 (9.91) x2 = 1.84 p = 0.39 p = 0.746 School functioning 75.00 (5.00) 75.31 (19.08) 81.92 (13.52) 81.83 (12.00) x2 = 1.95 p = 0.37 p = 0.279 No significant differences were observed in any PedsQL subscale scores among CPP patients across the different age groups (A1–A3), nor in the overall comparison between the treated cohort and healthy controls. In pairwise comparisons, the only significant difference was observed in the Physical Functioning domain, with the A2 group scoring lower than controls (p = 0.02). Furthermore, no correlation was found between the duration of therapy and PedsQL scores in either the A2 or A3 groups. Self-perception questionnaire results The SPQ was completed by patients and their parents in groups A1–A3, while A4 patients completed it both retrospectively and at the time of the study. No significant differences were observed between patients and parents within any age group (A1: p = 0.70; A2: p = 0.47; A3: p = 0.63) or across age groups (all pairwise comparisons p > 0.18), indicating consistent self-perception. Although no statistically significant differences were detected among A1, A2, and A3, nor between patients and their parents, the scores showed a trend of increasing therapy-related stress in patients with advancing age (Fig. 1 ). Regarding treatment duration, no correlation was found in A2 or A3 for either patients or parents. In A4, however, a significant direct correlation was observed (r = 0.47, p = 0.021), indicating that longer therapy was associated with lower therapy-related emotional stress. Furthermore, in A4, lower self-esteem scores were observed both retrospectively, referring to the treatment period (Fig. 2 a), and at the time of questionnaire completion (Fig. 2 b). Discussion This study is a cross-sectional analysis of HRQoL and self-perception in girls with idiopathic CPP undergoing GnRH analogue therapy, including both patient- and parent-reported outcomes. Our work contributes to the contemporary literature by combining PedsQL 4.0 generic Core scale with a tailored, disease-specific Self-perception Questionnaire (SPQ), thereby providing a more nuanced evaluation of psychological well-being during and after treatment [ 8 , 9 , 13 , 19 ]. In our cohort, treatment with GnRH analogues did not appear to negatively affect HRQoL. This finding aligns with Shoelwer et al. [ 8 , 10 ], who reported no significant differences in psychological functioning of girls with CPP and their mothers over one-year period. However, the literature is not entirely consistent: some studies have observed elevated anxiety, withdrawal, and depression scores both at baseline and after treatment in girls with CPP, suggesting divergent outcomes regarding psychological functioning in treated or untreated patients [ 20 , 21 ]. Schoelwer and colleagues [ 10 ] also reported a significant decrease in perceived physical competence in girls with CPP, irrespective of treatment status, indicating that changes in self-concept may not be solely related to pubertal timing. In our cohort, the lower physical functioning score observed in the A2 group compared to controls supports the idea that self-concept evolves with age: younger children tend to overestimate their abilities, whereas older children develop more accurate self-assessment skills [ 22 ]. The PedQL, while widely used for assessing QoL in children with chronic conditions, is a generic tool and not disease-specific for CPP. Nevertheless, it has demonstrated sensitivity in discriminating between healthy children and those with chronic illness, including cancer, diabetes, and heart disease [ 14 ]. In our study, PedsQL scores suggested largely preserved QoL in treated CPP patients. However, as a generic instrument, the PedsQL may be insufficiently sensitive to detect subtle, disease-specific psychosocial difficulties, particularly following treatment discontinuation. Given their broad scope, generic measures may not adequately capture nuanced psychological changes closely related to the lived experience of CPP and its management. Consistent with this consideration, one study has reported slightly lower—but not statistically significant—QoL scores in CPP compared with controls [ 13 ], while another found reduced QoL in idiopathic CPP, especially when caregiver stress is elevated [ 14 ]. Additionally, further research has highlighted increased difficulties in peer relationship despite similar PedsQL scores, underscoring the need to evaluate more specific emotional and social vulnerabilities [ 15 ]. To address disease-specific concerns, clinical psychology team developed an ad-hoc Self-Perception Questionnaire (SPQ), assessing self-perception, emotional response, body image, peer relationships, and attitude toward therapy. No significant differences were detected among age groups A1-A3, or between patients and their parents, indicating a high degree of consistency in perceived self-functioning. Nevertheless, a developmental pattern emerged: therapy-related stress increased with age, consistent with changes in illness awareness and understanding across development [ 22 ]. Notably, SPQ data revealed that therapy-specific emotional stress increased in treated patients regardless of treatment discontinuation, indicating that psychological adjustment to the therapy may extend beyond the active treatment phase. In A4 patients, a direct correlation was observed between therapy duration and lower emotional stress scores. One may speculate that prolonged treatment facilitates psychological adaptation and reduces therapy-related stress. However, the assessment instrument used was generic and does not allow us to definitively substantiate or objectively quantify this interpretation. These findings are in line with previous reports. Menk et al. [ 11 ] similarly reported higher stress levels before the initiation of GnRH therapy, followed by a progressive reduction during treatment, reflecting an effect plausibly linked to improvements in body image and interpersonal functioning. Similarly, Wojnuisz et al. [ 19 ] found that treated CPP girls did not differ from controls in cognitive, behavioral, or social functioning, although they exhibited heightened emotional reactivity during therapy and lower resting heart rates. Taken together, these findings are consistent with longitudinal evidence indicating that treatment does not negatively impact emotional well-being and may, in fact, foster the development of adaptive coping mechanisms [ 11 , 21 ]. Study strength and limitations The study combines a widely used generic QoL tool (PedsQL) with a disease-specific questionnaire (SPQ), allowing a more nuanced assessment of treatment-related emotional stress. The inclusion of both patient- and parent-reported outcomes across different age groups and treatment stages (during and after therapy) enhances clinical relevance. The availability of data on therapy duration and follow-up timing adds insight into long-term psychological adjustment. On the other hand, the cross-sectional design precludes evaluation of changes over time, and the sample size is modest, especially in the youngest group. The SPQ is an experimental tool and would benefit from formal validation. In addition, the single-center setting and inclusion of only female patients may limit generalizability. Retrospective recall in older patients may introduce recall bias regarding treatment-related experiences. Finally, the findings may be influenced by the characteristics of the assessment instruments employed. Future research should incorporate more structured and multidimensional evaluation protocols to comprehensively assess psychological and emotional functioning across developmental stages. Conclusions In conclusion, our findings indicate that GnRH therapy appears to be psychologically well tolerated and, when delivered within a multidisciplinary care setting, does not adversely affect quality of life. Both the child’s age and treatment duration were associated with variations in perceived stress and self-esteem. Younger girls reported lower levels of therapy-related stress, possibly reflecting differences in illness awareness and cognitive understanding across developmental stages, whereas longer treatment duration in older patients was associated with lower emotional distress, potentially suggesting progressive psychological adaptation over time. These results are consistent with previous evidence emphasizing the importance of early intervention and supportive care in moderating the psychological impact of CPP. Moreover, they underscore the value of incorporating disease-specific assessment tools to identify subtle psychosocial challenges that may not be captured by generic measures. Declarations Funding No funding was received for this study. Competing interests The authors have no competing interests to declare that are relevant to the content of this article. Ethicas approval The study was conducted in accordance with the Declaration of Helsinki and approved by AOU of Modena Ethics Committee. Consent to participate Informed consent to participation and publication of the data was obtained from caregivers of all individual participants included in the study. Authors’ contribution statements Study conception and design: LL, MP. Data acquisition: VT, PB, SFM, FC, MV. Data analysis and interpretation: VT, LL. Questionnaire development and psychological assessment: MP, CM, FC. Drafting of the manuscript: VT. Critical revision of the manuscript: LL, MP, LI, BP. Supervision and overall responsibility: LI, BP. Acknowledgements The authors sincerely thank the patients and their families for their willingness to participate in the study and for their time and collaboration throughout the data collection process. Their contribution was essential for the completion of this research. Furthermore, we would like to acknowledge all the residents and trainees of the Pediatric clinic of the University of Modena and Reggio Emilia who contributed to data collection and family interviews, dedicating significant effort and time to ensure the accuracy and completeness of the information gathered. References Carel JC, Leger J (2008) Clinical practice. Precocious puberty. N Engl J Med 358:2366–2377. https://doi.org/10.1056/NEJMcp0800459 Hiatt RA, Stewart SL, Deardorff J, Danial E, Abdiwahab E, Pinney SM, Teitelbaum SL, Windham GC, Wolff MS, Kushi LH, Biro FM (2021) Childhood socioeconomic status and menarche: a prospective study. J Adolesc Health 69:33–40. https://doi.org/10.1016/j.jadohealth.2021.02.003 Acker J, Mujahid M, Aghaee S, Gomez S, Shariff-Marco S, Chu B, Deardorff J, Kubo A (2023) Neighborhood racial and economic privilege and timing of pubertal onset in girls. J Adolesc Health 72:419–427. https://doi.org/10.1016/j.jadohealth.2022.10.013 April-Sanders AK, Tehranifar P, Terry MB, Crookes DM, Isasi CR, Gallo LC, Fernandez-Rhodes L, Perreira KM, Daviglus ML, Suglia SF (2025) Family functioning and pubertal maturation in Hispanic/Latino children from the HCHS/SOL youth. Int J Environ Res Public Health 22:576. https://doi.org/10.3390/ijerph22040576 Lucaccioni L, Trevisani V, Marrozzini L, Bertoncelli N, Predieri B, Lugli L, Berardi A, Iughetti L (2020) Endocrine-disrupting chemicals and their effects during female puberty: a review of current evidence. Int J Mol Sci 21:2078. https://doi.org/10.3390/ijms21062078 Kelly Y et al (2017) Early puberty in 11-year-old girls: Millennium Cohort Study findings. Arch Dis Child 102:232–237 Mrug S et al (2014) Early puberty, negative peer influence, and problem behaviors in adolescent girls. Pediatrics 133:7–14 Schoelwer MJ (2017) One-year follow-up of girls with precocious puberty and their mothers: do psychological assessments change over time or with treatment? Horm Res Paediatr 88:347–353 Williams V, Soliman A, Barrett A, Klein K (2018) Review and evaluation of patient-centred psychosocial assessments for children with central precocious puberty or early puberty. J Pediatr Endocrinol Metab Schoelwer MJ (2015) Psychological assessment of mothers and their daughters at the time of diagnosis of precocious puberty. Int J Pediatr Endocrinol 2015:5 Menk T (2017) Assessment of stress levels in girls with central precocious puberty before and during long-acting gonadotropin-releasing hormone agonist treatment: a pilot study. J Pediatr Endocrinol Metab 30:657–662 Varni JW, Seid M, Rode CA (1999) The PedsQL: measurement model for the pediatric quality of life inventory. Med Care 37:126–139. https://doi.org/10.1097/00005650-199902000-00003 Yilmazer IN, Abseyi SN, Senyazar G, Berberoglu M, Siklar Z, Aycan Z (2024) Evaluation of quality of life in children with precocious puberty. Clin Endocrinol (Oxf) 100:338–342. https://doi.org/10.1111/cen.15033 Yang H, Luo S, Liang X et al (2021) The association between family impact and health-related quality of life of children with idiopathic central precocious puberty in Chongqing, China. Health Qual Life Outcomes 19:171. https://doi.org/10.1186/s12955-021-01805-w Coban OG, Bedel A, Onder A, Adanir AS, Tuhan H, Parlak M (2021) Psychiatric disorders, peer-victimization, and quality of life in girls with central precocious puberty. J Psychosom Res 143:110401. https://doi.org/10.1016/j.jpsychores.2021.110401 WHO Multicentre Growth Reference Study Group (2006) WHO child growth standards based on length/height, weight and age. Acta Paediatr Suppl 450:76–85. https://doi.org/10.1111/j.1651-2227.2006.tb02378.x Marshall WA, Tanner JM (1969) Variations in the pattern of pubertal changes in girls. Arch Dis Child 44:291–303 Marshall WA, Tanner JM (1970) Variations in the pattern of pubertal changes in boys. Arch Dis Child 45:13–23 Wojniusz S, Callens N, Sutterlin S et al (2016) Cognitive, emotional and psychosocial functioning of girls treated with pharmacological puberty blockage for idiopathic central precocious puberty. Front Psychol 7:1053 Turan AP, Akca SO (2021) The quality of life of children with precocious puberty and healthy children in Turkey. Am J Health Behav 45:62–70. https://doi.org/10.5993/AJHB.45.1.5 Sen P, Dabas A, Kumar R, Yadav S (2025) Clinical outcomes and quality of life in children with central precocious puberty: a pragmatic analysis. J Obstet Gynaecol India 75:129–134. https://doi.org/10.1007/s13224-024-02031-2 Mantzicopoulos P (2006) Younger children’s changing self-concepts: boys and girls from pre-school through second grade. J Genet Psychol 167:289–308 Supplementary Files Supplementary.docx Cite Share Download PDF Status: Under Revision Version 1 posted Editorial decision: Major revisions 20 Apr, 2026 Reviewers agreed at journal 25 Feb, 2026 Reviewers invited by journal 25 Feb, 2026 Editor assigned by journal 19 Feb, 2026 First submitted to journal 18 Feb, 2026 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-8909378","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":596870554,"identity":"ef5d0340-dbc9-4a83-96dd-9aea0300ed64","order_by":0,"name":"Viola Trevisani","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCUlEQVRIie3QMUvDQBTA8VcC1+Vs1ivV5Cs86aIg+lUSCmYSVydJObxJ9/RbZHRwuOOGLvkAKXURoZNCsym06NGUdMnF1eH+w/EI+fGOA3C5/mMe9GQ99VJzsGA/ABA7AUOwIeMDsZqG1MVpM1oIzj0pv2Bz67MJX38/nyX5kj/k1csFDMK0nWgSqUfA81kWi+FTwW7yVyUW2eraerEhpygpIGKhBBwJQ8pYLKnUnURtDLkqFK+2giVYkx8r8T2KerelP01HZku0J7KDkEgf4xjZfCpGJ4KdzgxZZHJCCYlaCfG1evu4C9Dn/ffqU9yHgzJZlWt5GYRctq+p363lG+343+VyuVx/9AuC41rVmiSIxgAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0001-5224-8073","institution":"University of Modena and Reggio Emilia: Universita degli Studi di Modena e Reggio Emilia","correspondingAuthor":true,"prefix":"","firstName":"Viola","middleName":"","lastName":"Trevisani","suffix":""},{"id":596870555,"identity":"055946b5-e945-4cf9-92ab-36e25765098f","order_by":1,"name":"Laura Lucaccioni","email":"","orcid":"https://orcid.org/0000-0003-0288-8990","institution":"University of Modena and Reggio Emilia - Reggio Emilia Campus: Universita degli Studi di Modena e Reggio Emilia - Sede di Reggio Emilia","correspondingAuthor":false,"prefix":"","firstName":"Laura","middleName":"","lastName":"Lucaccioni","suffix":""},{"id":596870556,"identity":"477dc7ad-ce76-4d03-9058-36bb7616b585","order_by":2,"name":"Patrizia Bruzzi","email":"","orcid":"","institution":"Azienda Ospedaliero-Universitaria di Modena Policlinico di Modena: Azienda Ospedaliero-Universitaria di Modena","correspondingAuthor":false,"prefix":"","firstName":"Patrizia","middleName":"","lastName":"Bruzzi","suffix":""},{"id":596870557,"identity":"edc3612c-8d15-481f-a703-1afa5d01a6aa","order_by":3,"name":"Camilla Migliozzi","email":"","orcid":"","institution":"Azienda Ospedaliero-Universitaria di Modena Policlinico di Modena: Azienda Ospedaliero-Universitaria di Modena","correspondingAuthor":false,"prefix":"","firstName":"Camilla","middleName":"","lastName":"Migliozzi","suffix":""},{"id":596870558,"identity":"64c567a9-a02a-4a00-9957-783ee1c4568d","order_by":4,"name":"Francesca Culzoni","email":"","orcid":"","institution":"Azienda Ospedaliero-Universitaria di Modena Policlinico di Modena: Azienda Ospedaliero-Universitaria di Modena","correspondingAuthor":false,"prefix":"","firstName":"Francesca","middleName":"","lastName":"Culzoni","suffix":""},{"id":596870559,"identity":"ee6ec837-830f-4c7a-afe2-e72be24dadf0","order_by":5,"name":"Francesco Candia","email":"","orcid":"","institution":"Azienda Ospedaliero-Universitaria di Modena Policlinico di Modena: Azienda Ospedaliero-Universitaria di Modena","correspondingAuthor":false,"prefix":"","firstName":"Francesco","middleName":"","lastName":"Candia","suffix":""},{"id":596870560,"identity":"87feef03-222d-4237-9c40-beca1198a45e","order_by":6,"name":"Anna Insalaco","email":"","orcid":"","institution":"University of Modena and Reggio Emilia: Universita degli Studi di Modena e Reggio Emilia","correspondingAuthor":false,"prefix":"","firstName":"Anna","middleName":"","lastName":"Insalaco","suffix":""},{"id":596870561,"identity":"b4f649be-1b9c-403e-97e9-89006a6f3864","order_by":7,"name":"Marialucia Villanova","email":"","orcid":"","institution":"University of Modena and Reggio Emilia: Universita degli Studi di Modena e Reggio Emilia","correspondingAuthor":false,"prefix":"","firstName":"Marialucia","middleName":"","lastName":"Villanova","suffix":""},{"id":596870562,"identity":"593d6291-8747-442d-b4b2-05cc9b7c0111","order_by":8,"name":"Simona Filomena Madeo","email":"","orcid":"","institution":"Azienda Ospedaliero-Universitaria di Modena Policlinico di Modena: Azienda Ospedaliero-Universitaria di Modena","correspondingAuthor":false,"prefix":"","firstName":"Simona","middleName":"Filomena","lastName":"Madeo","suffix":""},{"id":596870563,"identity":"b0567cf6-4e5e-4830-987b-61a1e0888c7c","order_by":9,"name":"Lorenzo Iughetti","email":"","orcid":"","institution":"University of Modena and Reggio Emilia: Universita degli Studi di Modena e Reggio Emilia","correspondingAuthor":false,"prefix":"","firstName":"Lorenzo","middleName":"","lastName":"Iughetti","suffix":""},{"id":596870564,"identity":"0d9b6ecc-704e-4c15-b119-93a0303ac10f","order_by":10,"name":"Marisa Pugliese","email":"","orcid":"","institution":"Azienda Ospedaliero-Universitaria di Modena Policlinico di Modena: Azienda Ospedaliero-Universitaria di Modena","correspondingAuthor":false,"prefix":"","firstName":"Marisa","middleName":"","lastName":"Pugliese","suffix":""},{"id":596870565,"identity":"4a8d5612-cefe-44da-b587-f5781faeecdd","order_by":11,"name":"Barbara Predieri","email":"","orcid":"","institution":"University of Modena and Reggio Emilia: Universita degli Studi di Modena e Reggio Emilia","correspondingAuthor":false,"prefix":"","firstName":"Barbara","middleName":"","lastName":"Predieri","suffix":""}],"badges":[],"createdAt":"2026-02-18 12:35:31","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8909378/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8909378/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":103733561,"identity":"9dd6c692-f978-4b05-93ff-0e02732be6f1","added_by":"auto","created_at":"2026-03-02 09:28:47","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":107528,"visible":true,"origin":"","legend":"\u003cp\u003eTherapy-related emotional stress scores from the Self-Perception Questionnaire (SPQ) across age groups (A1–A4). Box plots represent the distribution of scores, with the median, interquartile range, and minimum/maximum values. Subgroups are labeled as follows: A1c–A3c for patients, A1p–A3p for parents, and A4 for patients only.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-8909378/v1/c17f5cfe14ad235db672e6a1.png"},{"id":103733716,"identity":"d8f88c7a-1b27-4d6d-b7b9-bca9645413d0","added_by":"auto","created_at":"2026-03-02 09:29:19","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":398723,"visible":true,"origin":"","legend":"\u003cp\u003eSelf-esteem scores from the SPQ in A4 patients. Panel (2a) shows scores retrospectively referring to the treatment period, while panel (2b) shows scores at the time of questionnaire completion. Box plots represent the median, interquartile range, and minimum/maximum values, illustrating lower self-esteem scores during both periods.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-8909378/v1/26d67bef92c6f78165e82dd7.png"},{"id":103733853,"identity":"3b620aa2-f9c1-4d18-ab8b-73d9082d6cfc","added_by":"auto","created_at":"2026-03-02 09:29:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1246675,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8909378/v1/2df5f501-da5b-4501-a010-5e7b65ce6c20.pdf"},{"id":103733689,"identity":"85e6489b-09b1-46e0-97a2-42125177d8b1","added_by":"auto","created_at":"2026-03-02 09:29:12","extension":"docx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":30852,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementary.docx","url":"https://assets-eu.researchsquare.com/files/rs-8909378/v1/885a0ea8af6f12e2d6548e38.docx"}],"financialInterests":"","formattedTitle":"\u003cp\u003eThe effect of GnRH-analogue therapy on the quality of life of girls with central precocious puberty and their families\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePrecocious puberty in females is defined as the onset of secondary sexual characteristics before 8 years of age [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Central precocious puberty (CPP) results from premature activation of the hypothalamic-pituitary-gonadal axis, and idiopathic CPP occurs in the absence of central nervous system pathology or identifiable genetic causes [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSocioeconomic and ethnic factors, including poverty, family conflict, minority status, migration, and environmental exposures, have been associated with earlier pubertal onset [\u003cspan additionalcitationids=\"CR3 CR4 CR5\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eEarly puberty has been linked to emotional and behavioral difficulties, including anxiety, depression, social withdrawal, and increased psychological stress, negatively affecting quality of life (QoL) [\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Parents of girls with CPP often report concerns regarding their child\u0026rsquo;s physical development, sexual behavior, and peer relationships, highlighting the importance of assessing psychosocial impact in both patients and families [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eGnRH agonist (GnRHa) therapy is the standard treatment for CPP, aiming to slow sexual maturation, delay bone age advancement, and optimize adult height [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Although effective in managing physical outcomes, the chronic and invasive nature of the treatment may contribute to stress in patients and caregivers.\u003c/p\u003e \u003cp\u003eHealth-related quality of life (HRQoL) is a multidimensional construct encompassing physical, emotional, social, and school functioning. The Pediatric Quality of Life questionnaire (PedsQL) is a widely used generic measure, yet validated instruments specific to CPP are lacking [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Consequently, the relationship between disease severity, treatment duration, and QoL remains incompletely understood. Previous studies indicate that children with precocious puberty often report lower QoL scores than their peers, yet few investigations have assessed the impact of GnRHa therapy on psychosocial outcomes or family stress [\u003cspan additionalcitationids=\"CR14\" citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWe performed a cross-sectional study in girls with a diagnosis of CPP to evaluate QoL and treatment-related stress in CPP patients and their families during and after GnRHa therapy, using a tailored, disease-specific questionnaire to capture patient- and family-centered outcomes associated with this chronic condition and its management.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cem\u003eStudy population\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eGirls affected by idiopathic CPP [1] who attended the Pediatric Endocrinology Outpatient Clinic of the University Hospital of Modena, Italy, between 2015 and 2016, entered this cross-sectional study. \u003c/p\u003e\n\u003cp\u003eAll participants and/or parents were recruited consecutively and provided written informed consent prior to participation. Exclusion criteria included the presence of organic causes of precocious puberty, chronic or endocrine disorders potentially affecting growth or psychological status, previous or current psychiatric diagnoses, and incomplete clinical or questionnaire data.\u003c/p\u003e\n\u003cp\u003eControls paired for age and level of instruction were also evaluated. Regarding the control population, both personal and family medical histories were negative for CPP as well as for other relevant medical conditions.\u003c/p\u003e\n\u003cp\u003ePatients with CPP were divided into four groups according to their age at the time of questionnaire completion: (1) A1: 3 patients aged 4\u0026ndash;7 years; (2) A2: 15 patients aged 8\u0026ndash;12 years; (3) A3: 13 patients aged 13\u0026ndash;18 years; and (4) A4: 25 patients aged \u0026gt;18 years.\u003c/p\u003e\n\u003cp\u003eAt the time of the study, A3 patients had already discontinued therapy but remained under follow-up, while A4 patients had completed therapy and were no longer coming to the outpatient clinic.\u003c/p\u003e\n\n\u003cp\u003e\u003cem\u003eChildren Anthropometric Measurement and Puberty Stage Evaluation\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAnthropometric measurements were obtained at enrollment and retrospectively evaluated from the beginning of the GnRH therapy.\u003c/p\u003e\n\u003cp\u003eHeight was measured in the standing position, with patients barefoot, heels together, and head aligned in the Frankfurt plane, using a calibrated Harpenden stadiometer (Crymych, UK), with an approximation of 0.1 cm.\u003c/p\u003e\n\u003cp\u003eBody weight was measured to the nearest 0.1 kg using a calibrated digital scale, with patients wearing minimal clothing or underwear.\u003c/p\u003e\n\u003cp\u003eAnthropometric data were expressed as WHO percentiles for age and sex [16].\u003c/p\u003e\n\u003cp\u003ePubertal development was evaluated by a trained pediatric endocrinologist according to Tanner\u0026rsquo;s criteria [17,18], assessing breast development, axillar and pubic hair distribution.\u003c/p\u003e\n\n\u003cp\u003e\u003cem\u003eQuestionnaires\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAll patients completed two questionnaires assessing quality of life and self-perception.\u003c/p\u003e\n\u003col\u003e\n\u003cli\u003e\u003cem\u003ePediatric Quality of Life Inventory (PedsQL)\u003c/em\u003e\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eThe PedsQL\u0026trade; 4.0 [12] is a validated instrument designed to assess health-related quality of life in children and adolescents. It includes 23 items grouped into four functional domains: physical (8 items), emotional (5 items), social (5 items), and school functioning (5 items).\u003c/p\u003e\n\u003cp\u003eEach item was scored on a 5-point Likert scale reflecting the frequency of problems during the previous month: 0 = never, 1 = almost never, 2 = sometimes, 3 = often, 4 = almost always.\u003c/p\u003e\n\u003cp\u003eFor children aged 4\u0026ndash;7 years, a simplified 3-point scale was used: 0 = never, 2 = sometimes, 4 = always.\u003c/p\u003e\n\u003cp\u003eItems were reverse-scored and linearly transformed to a 0\u0026ndash;100 scale (0 = 100; 1 = 75; 2 = 50; 3 = 25; 4 = 0), with higher scores indicating better quality of life.\u003c/p\u003e\n\u003cp\u003ePatients in A1, A2, and A3 completed this questionnaire, and their scores were compared with those of 30 age-matched healthy controls.\u003c/p\u003e\n\u003col start=\"2\"\u003e\n\u003cli\u003e\u003cem\u003eSelf-Perception Questionnaire (SPQ)\u003c/em\u003e\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003eThe SPQ is an experimental tool developed by the clinical psychologists of our department (Appendix A), specifically designed to evaluate self-perception and emotional response in CPP patients during or after treatment.\u003c/p\u003e\n\u003cp\u003eGroups A1, A2, and A3, as well as their parents, completed the questionnaire, while A4 patients completed it twice \u0026mdash; the first one referring to the treatment period and at the second one referring to time of the study.\u003c/p\u003e\n\u003cp\u003eThe scoring system of the SPQ mirrored that of the PedsQL, with higher scores corresponding to better self-perception and lower perceived stress.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e \u003c/em\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eStatistical analysis\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eData analysis was performed using SPSS version 20.0 (IBM SPSS Inc., Chicago, IL). Continuous variables were expressed as mean \u0026plusmn; standard deviation (SD) and categorical variables as frequencies and percentages. Comparisons between CPP patients and controls, as well as among age groups, were conducted using Kruskal\u0026ndash;Wallis and Mann\u0026ndash;Whitney U tests for continuous variables and chi-square or Fisher\u0026rsquo;s exact tests for categorical variables. Pairwise comparisons were performed when significant differences were found. A p-value \u0026lt;0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\"\u003e\n \u003ch2\u003ePopulation characteristics\u003c/h2\u003e\n \u003cp\u003eA total of 56 female children with CPP and 30 female matched controls were enrolled in the study. Baseline characteristics, collected at the start of the treatment, of the CPP study population are presented in Table 1.\u003cimg 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\"\u003e\u003c/p\u003e\n \u003cp\u003eAmong the 56 participants affected by CPP, two (3.6%) had micropolycystic ovaries, one (1.8%) had autoimmune thyroiditis, and one (1.8%) had De Quervain\u0026rsquo;s thyroiditis. Eleven participants (19.6%) reported a first-degree family history of CPP. Fourteen participants were adopted (25%).\u003c/p\u003e\n \u003cp\u003eBaseline characteristics of the population, stratified into four analysis groups and collected at the start of the treatment, are presented in Table \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003cp\u003eTable 2 -\u0026nbsp;Baseline characteristics, at the start of the treatment, of the CPP study population according to the four analysis group. Values are expressed as mean \u0026plusmn; standard deviation (SD) or number (percentage), as appropriate.\u003c/p\u003e\n \u003cdiv align=\"center\"\u003e\n \u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.5306%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eA1\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e(n=3)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eA2\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e(n=\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003cem\u003e15)\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eA3\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e(n=13)\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e\u003cstrong\u003eA4\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003e(n=25)\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.5306%;\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e5.12 (1.09)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e7.55 (0.62)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e7.23 (1.76)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e8.17 (1.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.5306%;\"\u003e\n \u003cp\u003eBone age (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e6.17 (1.53)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e8.93 (1.49)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e9.85 (1.97)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e9.97 (1.26)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.5306%;\"\u003e\n \u003cp\u003eD\u0026nbsp;bone age-age (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e1.05 (2.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e1.38 (1.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e2.61 (0.91)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e1.82 (1.34)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.5306%;\"\u003e\n \u003cp\u003eHeight (cm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e111.50 (7.89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e130.14 (9.18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e131.59 (12.64)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e131.54 (5.85)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.5306%;\"\u003e\n \u003cp\u003eHeight (SDS)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e0.86 (1.65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e1.36 (1.31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e2.13 (0.68)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e1.00 (1.10)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.5306%;\"\u003e\n \u003cp\u003eTarget height (cm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e159.88 (7.95)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e162.60 (6.31)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e162.77 (5.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e159.11 (4.65)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.5306%;\"\u003e\n \u003cp\u003eTarget height (SDS)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e-0.69 (1.40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e-0.07 (1.11)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e-0.37 (0.88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e-0.83 (1.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.5306%;\"\u003e\n \u003cp\u003eWeight (kg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e19.27 (4.55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e31.19 (7.65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e34.23 (10.15)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e29.66 (4.82)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.5306%;\"\u003e\n \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e15.32 (1.39)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e18.13 (2.59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e19.52 (3.93)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e17.08 (2.14)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.5306%;\"\u003e\n \u003cp\u003eBMI (SDS)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e-0.01 (0.88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e1.10 (1.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e1.55 (1.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e0.54 (0.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.5306%;\"\u003e\n \u003cp\u003eGrowth velocity (cm/year)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e9.92 (1.12)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e8.25 (2.37)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e8.85 (2.65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e7.55 (2.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.5306%;\"\u003e\n \u003cp\u003eTanner stage\u0026nbsp;\u003c/p\u003e\n \u003cp\u003eI\u003c/p\u003e\n \u003cp\u003eII\u003c/p\u003e\n \u003cp\u003eIII\u003c/p\u003e\n \u003cp\u003eIV\u003c/p\u003e\n \u003cp\u003eV\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e3 (100%)\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e3 (20%)\u003c/p\u003e\n \u003cp\u003e10 (66.7%)\u003c/p\u003e\n \u003cp\u003e2 (18.2%)\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e12 (92.3%)\u003c/p\u003e\n \u003cp\u003e1 (7.7%)\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e4 (16%)\u003c/p\u003e\n \u003cp\u003e11 (44%)\u003c/p\u003e\n \u003cp\u003e8 (32%)\u003c/p\u003e\n \u003cp\u003e2 (8%)\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 26.5306%;\"\u003e\n \u003cp\u003eEstradiol (pg/ml)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e\u0026lt;10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e23.67 (11.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e38.79 (29.24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 18.3673%;\"\u003e\n \u003cp\u003e37.68 (38.80)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003c/div\u003e\n \u003cdiv align=\"left\" class=\"colspec\"\u003e\u003cbr\u003e\u003c/div\u003e\n \u003cdiv align=\"char\" class=\"colspec\"\u003eThe diagnosis of CPP was established based on clinical, instrumental, and biochemical findings in accordance with current guidelines [\u003cspan class=\"CitationRef\"\u003e1\u003c/span\u003e]. As part of the diagnostic workup, all patients underwent a GnRH stimulation test. Mean age at treatment initiation was 7.87\u0026plusmn;1.33 years. The mean duration of therapy with GnRH analogue was 1.71\u0026plusmn;0.73 years. The mean age at menarche was 11.26\u0026plusmn;1.23 years.\u003c/div\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003ch3\u003ePopulation characteristics at the time of questionnaire\u003c/h3\u003e\n\u003cp\u003eThe total population, as described in the methods section, was divided into four age-based groups (A1, A2, A3, A4). The characteristics of the four groups at the time of questionnaire data collection are described in Table \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e.\u0026nbsp;\u003c/p\u003e\u0026nbsp;\u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eCharacteristics of the four group (A1-A4) of the CPP study population. Values are expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) or number (percentage), as appropriate.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eA1\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eA2\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e(n\u0026thinsp;=\u0026thinsp;15)\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eA3\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e(n\u0026thinsp;=\u0026thinsp;13)\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eA4\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e(n\u0026thinsp;=\u0026thinsp;25)\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6.17 (1.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e9.77 (1.20)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15.67 (1.66)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22.34 (2.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHeight (cm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e121.00 (5.77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e143.48 (9.90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e162.01 (7.59)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e158.65 (5.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHeight (SDS)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.39 (1.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.04 (1.28)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.04 (1.09)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-1.11 (0.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTarget height (cm)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e159.86 (7.96)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e161.60 (6.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e162.77 (5.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e159.11 (4.65)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTarget height (SDS)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.69 (1.40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e-0.25 (1.19)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.37 (0.88)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.83 (1.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eWeight (kg)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24.00 (3.74)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e42.07 (10.26)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e65.99 (22.90)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e55.87 (8.51)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16.31 (1.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e20.06 (2.94)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25.46 (7.82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e22.26 (3.59)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eBMI (SDS)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.49 (0.58)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.24 (0.92)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.06 (1.56)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-0.08 (1.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMenarche (n)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1 (6.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25 (100%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge at menarche (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e10.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10.63 (1.25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11.61 (1.11)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003ch3\u003ePedsQL questionnaire results\u003c/h3\u003e\n\u003cp\u003eScores obtained by patients in each domain and the overall HRQoL scale (mean (SD)), along with statistical comparisons, are presented in Table \u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e.\u003c/p\u003e\u0026nbsp;\u003ctable id=\"Tab4\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003ePedsQL scores (mean (SD)) across domains of health-related quality of life (HRQoL) in female children CPP stratified by age groups (A1\u0026ndash;A3) and in healthy controls. Statistical comparisons were performed using the Kruskal\u0026ndash;Wallis rank sum test for multiple group analysis and Mann\u0026ndash;Whitney U test for pairwise comparisons. Significant p-values (\u0026lt;\u0026thinsp;0.05) are indicated with an *.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ePedQL subscales\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eA1\u003c/p\u003e\n \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;3)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eA2\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e(n\u0026thinsp;=\u0026thinsp;15)\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eA3\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e(n\u0026thinsp;=\u0026thinsp;13)\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eControls\u003c/p\u003e\n \u003cp\u003e\u003cem\u003e(n\u0026thinsp;=\u0026thinsp;30)\u003c/em\u003e\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eA1vsA2vsA3\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCPP vs controls\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003ePhysical functioning\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e82.64 (6.87)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e77.54 (18.16)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e84.86 (12.55)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e86.43 (8.85)*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ex2\u0026thinsp;=\u0026thinsp;0.79\u003c/p\u003e\n \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.066\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eEmotional functioning\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e83.30 (16.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e76.56 (15.18)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e77.88 (15.44)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e77.30 (13.65)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ex2\u0026thinsp;=\u0026thinsp;0.72\u003c/p\u003e\n \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.980\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eSocial functioning\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e90.00 (8.16)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e86.86 (13.21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e94.23 (6.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e89.70 (9.91)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ex2\u0026thinsp;=\u0026thinsp;1.84\u003c/p\u003e\n \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.746\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eSchool functioning\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e75.00 (5.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e75.31 (19.08)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e81.92 (13.52)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e81.83 (12.00)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ex2\u0026thinsp;=\u0026thinsp;1.95\u003c/p\u003e\n \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep\u0026thinsp;=\u0026thinsp;0.279\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003c/p\u003e\n\u003cp\u003eNo significant differences were observed in any PedsQL subscale scores among CPP patients across the different age groups (A1\u0026ndash;A3), nor in the overall comparison between the treated cohort and healthy controls. In pairwise comparisons, the only significant difference was observed in the Physical Functioning domain, with the A2 group scoring lower than controls (p\u0026thinsp;=\u0026thinsp;0.02). Furthermore, no correlation was found between the duration of therapy and PedsQL scores in either the A2 or A3 groups.\u003c/p\u003e\n\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\n \u003ch2\u003eSelf-perception questionnaire results\u003c/h2\u003e\n \u003cp\u003eThe SPQ was completed by patients and their parents in groups A1\u0026ndash;A3, while A4 patients completed it both retrospectively and at the time of the study. No significant differences were observed between patients and parents within any age group (A1: p\u0026thinsp;=\u0026thinsp;0.70; A2: p\u0026thinsp;=\u0026thinsp;0.47; A3: p\u0026thinsp;=\u0026thinsp;0.63) or across age groups (all pairwise comparisons p\u0026thinsp;\u0026gt;\u0026thinsp;0.18), indicating consistent self-perception. Although no statistically significant differences were detected among A1, A2, and A3, nor between patients and their parents, the scores showed a trend of increasing therapy-related stress in patients with advancing age (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003eRegarding treatment duration, no correlation was found in A2 or A3 for either patients or parents. In A4, however, a significant direct correlation was observed (r\u0026thinsp;=\u0026thinsp;0.47, p\u0026thinsp;=\u0026thinsp;0.021), indicating that longer therapy was associated with lower therapy-related emotional stress. Furthermore, in A4, lower self-esteem scores were observed both retrospectively, referring to the treatment period (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003ea), and at the time of questionnaire completion (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003eb).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study is a cross-sectional analysis of HRQoL and self-perception in girls with idiopathic CPP undergoing GnRH analogue therapy, including both patient- and parent-reported outcomes. Our work contributes to the contemporary literature by combining PedsQL 4.0 generic Core scale with a tailored, disease-specific Self-perception Questionnaire (SPQ), thereby providing a more nuanced evaluation of psychological well-being during and after treatment [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eIn our cohort, treatment with GnRH analogues did not appear to negatively affect HRQoL. This finding aligns with Shoelwer et al. [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e], who reported no significant differences in psychological functioning of girls with CPP and their mothers over one-year period. However, the literature is not entirely consistent: some studies have observed elevated anxiety, withdrawal, and depression scores both at baseline and after treatment in girls with CPP, suggesting divergent outcomes regarding psychological functioning in treated or untreated patients [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSchoelwer and colleagues [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e] also reported a significant decrease in perceived physical competence in girls with CPP, irrespective of treatment status, indicating that changes in self-concept may not be solely related to pubertal timing. In our cohort, the lower physical functioning score observed in the A2 group compared to controls supports the idea that self-concept evolves with age: younger children tend to overestimate their abilities, whereas older children develop more accurate self-assessment skills [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe PedQL, while widely used for assessing QoL in children with chronic conditions, is a generic tool and not disease-specific for CPP. Nevertheless, it has demonstrated sensitivity in discriminating between healthy children and those with chronic illness, including cancer, diabetes, and heart disease [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In our study, PedsQL scores suggested largely preserved QoL in treated CPP patients. However, as a generic instrument, the PedsQL may be insufficiently sensitive to detect subtle, disease-specific psychosocial difficulties, particularly following treatment discontinuation. Given their broad scope, generic measures may not adequately capture nuanced psychological changes closely related to the lived experience of CPP and its management.\u003c/p\u003e \u003cp\u003eConsistent with this consideration, one study has reported slightly lower\u0026mdash;but not statistically significant\u0026mdash;QoL scores in CPP compared with controls [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], while another found reduced QoL in idiopathic CPP, especially when caregiver stress is elevated [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Additionally, further research has highlighted increased difficulties in peer relationship despite similar PedsQL scores, underscoring the need to evaluate more specific emotional and social vulnerabilities [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eTo address disease-specific concerns, clinical psychology team developed an ad-hoc Self-Perception Questionnaire (SPQ), assessing self-perception, emotional response, body image, peer relationships, and attitude toward therapy. No significant differences were detected among age groups A1-A3, or between patients and their parents, indicating a high degree of consistency in perceived self-functioning. Nevertheless, a developmental pattern emerged: therapy-related stress increased with age, consistent with changes in illness awareness and understanding across development [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Notably, SPQ data revealed that therapy-specific emotional stress increased in treated patients regardless of treatment discontinuation, indicating that psychological adjustment to the therapy may extend beyond the active treatment phase.\u003c/p\u003e \u003cp\u003eIn A4 patients, a direct correlation was observed between therapy duration and lower emotional stress scores. One may speculate that prolonged treatment facilitates psychological adaptation and reduces therapy-related stress. However, the assessment instrument used was generic and does not allow us to definitively substantiate or objectively quantify this interpretation.\u003c/p\u003e \u003cp\u003eThese findings are in line with previous reports. Menk et al. [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e] similarly reported higher stress levels before the initiation of GnRH therapy, followed by a progressive reduction during treatment, reflecting an effect plausibly linked to improvements in body image and interpersonal functioning. Similarly, Wojnuisz et al. [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e] found that treated CPP girls did not differ from controls in cognitive, behavioral, or social functioning, although they exhibited heightened emotional reactivity during therapy and lower resting heart rates. Taken together, these findings are consistent with longitudinal evidence indicating that treatment does not negatively impact emotional well-being and may, in fact, foster the development of adaptive coping mechanisms [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eStudy strength and limitations\u003c/h2\u003e \u003cp\u003eThe study combines a widely used generic QoL tool (PedsQL) with a disease-specific questionnaire (SPQ), allowing a more nuanced assessment of treatment-related emotional stress. The inclusion of both patient- and parent-reported outcomes across different age groups and treatment stages (during and after therapy) enhances clinical relevance. The availability of data on therapy duration and follow-up timing adds insight into long-term psychological adjustment.\u003c/p\u003e \u003cp\u003eOn the other hand, the cross-sectional design precludes evaluation of changes over time, and the sample size is modest, especially in the youngest group. The SPQ is an experimental tool and would benefit from formal validation. In addition, the single-center setting and inclusion of only female patients may limit generalizability. Retrospective recall in older patients may introduce recall bias regarding treatment-related experiences.\u003c/p\u003e \u003cp\u003eFinally, the findings may be influenced by the characteristics of the assessment instruments employed. Future research should incorporate more structured and multidimensional evaluation protocols to comprehensively assess psychological and emotional functioning across developmental stages.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, our findings indicate that GnRH therapy appears to be psychologically well tolerated and, when delivered within a multidisciplinary care setting, does not adversely affect quality of life. Both the child\u0026rsquo;s age and treatment duration were associated with variations in perceived stress and self-esteem. Younger girls reported lower levels of therapy-related stress, possibly reflecting differences in illness awareness and cognitive understanding across developmental stages, whereas longer treatment duration in older patients was associated with lower emotional distress, potentially suggesting progressive psychological adaptation over time. These results are consistent with previous evidence emphasizing the importance of early intervention and supportive care in moderating the psychological impact of CPP. Moreover, they underscore the value of incorporating disease-specific assessment tools to identify subtle psychosocial challenges that may not be captured by generic measures.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eFunding\u003c/p\u003e\n\u003cp\u003eNo funding was received for this study.\u003c/p\u003e\n\u003cp\u003eCompeting interests\u003c/p\u003e\n\u003cp\u003eThe authors have no competing interests to declare that are relevant to the content of this article.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eEthicas approval\u003c/p\u003e\n\u003cp\u003eThe study was conducted in accordance with the Declaration of Helsinki and approved by AOU of Modena Ethics Committee.\u003c/p\u003e\n\u003cp\u003eConsent to participate\u003c/p\u003e\n\u003cp\u003eInformed consent to participation and publication of the data was obtained from caregivers of all individual participants included in the study.\u003c/p\u003e\n\u003cp\u003eAuthors\u0026rsquo; contribution statements\u003c/p\u003e\n\u003cp\u003eStudy conception and design: LL, MP. Data acquisition: VT, PB, SFM, FC, MV. Data analysis and interpretation: VT, LL. Questionnaire development and psychological assessment: MP, CM, FC. Drafting of the manuscript: VT. Critical revision of the manuscript: LL, MP, LI, BP. Supervision and overall responsibility: LI, BP.\u003c/p\u003e\n\u003cp\u003eAcknowledgements\u003c/p\u003e\n\u003cp\u003eThe authors sincerely thank the patients and their families for their willingness to participate in the study and for their time and collaboration throughout the data collection process. Their contribution was essential for the completion of this research.\u003c/p\u003e\n\u003cp\u003eFurthermore, we would like to acknowledge all the residents and trainees of the Pediatric clinic of the University of Modena and Reggio Emilia who contributed to data collection and family interviews, dedicating significant effort and time to ensure the accuracy and completeness of the information gathered.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCarel JC, Leger J (2008) Clinical practice. Precocious puberty. N Engl J Med 358:2366\u0026ndash;2377. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1056/NEJMcp0800459\u003c/span\u003e\u003cspan address=\"10.1056/NEJMcp0800459\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHiatt RA, Stewart SL, Deardorff J, Danial E, Abdiwahab E, Pinney SM, Teitelbaum SL, Windham GC, Wolff MS, Kushi LH, Biro FM (2021) Childhood socioeconomic status and menarche: a prospective study. J Adolesc Health 69:33\u0026ndash;40. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.jadohealth.2021.02.003\u003c/span\u003e\u003cspan address=\"10.1016/j.jadohealth.2021.02.003\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAcker J, Mujahid M, Aghaee S, Gomez S, Shariff-Marco S, Chu B, Deardorff J, Kubo A (2023) Neighborhood racial and economic privilege and timing of pubertal onset in girls. J Adolesc Health 72:419\u0026ndash;427. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.jadohealth.2022.10.013\u003c/span\u003e\u003cspan address=\"10.1016/j.jadohealth.2022.10.013\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eApril-Sanders AK, Tehranifar P, Terry MB, Crookes DM, Isasi CR, Gallo LC, Fernandez-Rhodes L, Perreira KM, Daviglus ML, Suglia SF (2025) Family functioning and pubertal maturation in Hispanic/Latino children from the HCHS/SOL youth. Int J Environ Res Public Health 22:576. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/ijerph22040576\u003c/span\u003e\u003cspan address=\"10.3390/ijerph22040576\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLucaccioni L, Trevisani V, Marrozzini L, Bertoncelli N, Predieri B, Lugli L, Berardi A, Iughetti L (2020) Endocrine-disrupting chemicals and their effects during female puberty: a review of current evidence. Int J Mol Sci 21:2078. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3390/ijms21062078\u003c/span\u003e\u003cspan address=\"10.3390/ijms21062078\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKelly Y et al (2017) Early puberty in 11-year-old girls: Millennium Cohort Study findings. Arch Dis Child 102:232\u0026ndash;237\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMrug S et al (2014) Early puberty, negative peer influence, and problem behaviors in adolescent girls. Pediatrics 133:7\u0026ndash;14\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchoelwer MJ (2017) One-year follow-up of girls with precocious puberty and their mothers: do psychological assessments change over time or with treatment? Horm Res Paediatr 88:347\u0026ndash;353\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWilliams V, Soliman A, Barrett A, Klein K (2018) Review and evaluation of patient-centred psychosocial assessments for children with central precocious puberty or early puberty. J Pediatr Endocrinol Metab\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSchoelwer MJ (2015) Psychological assessment of mothers and their daughters at the time of diagnosis of precocious puberty. Int J Pediatr Endocrinol 2015:5\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMenk T (2017) Assessment of stress levels in girls with central precocious puberty before and during long-acting gonadotropin-releasing hormone agonist treatment: a pilot study. J Pediatr Endocrinol Metab 30:657\u0026ndash;662\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVarni JW, Seid M, Rode CA (1999) The PedsQL: measurement model for the pediatric quality of life inventory. Med Care 37:126\u0026ndash;139. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1097/00005650-199902000-00003\u003c/span\u003e\u003cspan address=\"10.1097/00005650-199902000-00003\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYilmazer IN, Abseyi SN, Senyazar G, Berberoglu M, Siklar Z, Aycan Z (2024) Evaluation of quality of life in children with precocious puberty. Clin Endocrinol (Oxf) 100:338\u0026ndash;342. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/cen.15033\u003c/span\u003e\u003cspan address=\"10.1111/cen.15033\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYang H, Luo S, Liang X et al (2021) The association between family impact and health-related quality of life of children with idiopathic central precocious puberty in Chongqing, China. Health Qual Life Outcomes 19:171. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/s12955-021-01805-w\u003c/span\u003e\u003cspan address=\"10.1186/s12955-021-01805-w\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCoban OG, Bedel A, Onder A, Adanir AS, Tuhan H, Parlak M (2021) Psychiatric disorders, peer-victimization, and quality of life in girls with central precocious puberty. J Psychosom Res 143:110401. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.jpsychores.2021.110401\u003c/span\u003e\u003cspan address=\"10.1016/j.jpsychores.2021.110401\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWHO Multicentre Growth Reference Study Group (2006) WHO child growth standards based on length/height, weight and age. Acta Paediatr Suppl 450:76\u0026ndash;85. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/j.1651-2227.2006.tb02378.x\u003c/span\u003e\u003cspan address=\"10.1111/j.1651-2227.2006.tb02378.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarshall WA, Tanner JM (1969) Variations in the pattern of pubertal changes in girls. Arch Dis Child 44:291\u0026ndash;303\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarshall WA, Tanner JM (1970) Variations in the pattern of pubertal changes in boys. Arch Dis Child 45:13\u0026ndash;23\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWojniusz S, Callens N, Sutterlin S et al (2016) Cognitive, emotional and psychosocial functioning of girls treated with pharmacological puberty blockage for idiopathic central precocious puberty. Front Psychol 7:1053\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTuran AP, Akca SO (2021) The quality of life of children with precocious puberty and healthy children in Turkey. Am J Health Behav 45:62\u0026ndash;70. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.5993/AJHB.45.1.5\u003c/span\u003e\u003cspan address=\"10.5993/AJHB.45.1.5\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSen P, Dabas A, Kumar R, Yadav S (2025) Clinical outcomes and quality of life in children with central precocious puberty: a pragmatic analysis. J Obstet Gynaecol India 75:129\u0026ndash;134. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1007/s13224-024-02031-2\u003c/span\u003e\u003cspan address=\"10.1007/s13224-024-02031-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMantzicopoulos P (2006) Younger children\u0026rsquo;s changing self-concepts: boys and girls from pre-school through second grade. J Genet Psychol 167:289\u0026ndash;308\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"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":"hormones","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"HORM","sideBox":"Learn more about [Hormones](https://www.springer.com/journal/42000)","snPcode":"42000","submissionUrl":"https://www.editorialmanager.com/horm/default2.aspx","title":"Hormones","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Central Precocious Puberty, Quality of Life, GnRH agonists, Emotional stress, Self-perception questionnaire","lastPublishedDoi":"10.21203/rs.3.rs-8909378/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8909378/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground: Central precocious puberty (CPP) results from premature activation of the hypothalamic–pituitary–gonadal axis and may affect psychological well-being in patients and families. Although GnRH agonist (GnRHa) therapy slows pubertal progression, its impact on quality of life (QoL) and emotional perception is unclear. This study evaluated QoL and treatment-related stress in girlswith CPP and their families during and after GnRHa therapy.\u003c/p\u003e\n\u003cp\u003eMethods: In this cross-sectional study, 56 females with ongoing or previous CPP (aged 4–18 years) and 30 healthy matched controls were enrolled. Patients were grouped by age (A1:4–7; A2:8–12; A3:13–18; A4:\u0026gt;18 years). QoL was assessed using PedsQL™ 4.0, while emotional perception and treatment-related stress were evaluated with a disease-specific Self-Perception Questionnaire (SPQ). Group comparisons and correlations with therapy duration were performed.\u003c/p\u003e\n\u003cp\u003eResults: PedsQL scores did not differ significantly across CPP age groups or between patients and controls, except for lower Physical Functioning in A2 versus controls (p=0.02). No correlation was found between therapy duration and QoL. SPQ scores showed no significant differences between children and parents or across age groups, although therapy-related emotional stress tended to increase with age. In A4, longer therapy duration correlated with lower treatment-related stress (r=0.47, p=0.021), while reduced self-esteem persisted during treatment and at follow-up.\u003c/p\u003e\n\u003cp\u003eConclusion: QoL in CPP patients appears comparable to healthy peers, but emotional responses to treatment vary with age and are not captured by generic QoL tools. Disease-specific assessment highlighted age-related emotional stress and long-term self-esteem reduction, supporting psychological evaluation in CPP management.\u003c/p\u003e","manuscriptTitle":"The effect of GnRH-analogue therapy on the quality of life of girls with central precocious puberty and their families","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-02 09:25:48","doi":"10.21203/rs.3.rs-8909378/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revisions","date":"2026-04-20T05:52:34+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2026-02-25T12:05:20+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-25T10:56:21+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-19T09:39:08+00:00","index":"","fulltext":""},{"type":"submitted","content":"Hormones","date":"2026-02-18T07:35:18+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"hormones","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"HORM","sideBox":"Learn more about [Hormones](https://www.springer.com/journal/42000)","snPcode":"42000","submissionUrl":"https://www.editorialmanager.com/horm/default2.aspx","title":"Hormones","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"d65d3b17-e463-4015-b9ff-783d61acc64b","owner":[],"postedDate":"March 2nd, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"in-revision","subjectAreas":[],"tags":[],"updatedAt":"2026-04-20T11:18:10+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-02 09:25:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8909378","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8909378","identity":"rs-8909378","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}