Comparison of long-term height and pubertal outcomes in boys with delayed puberty due to constitutional delay in growth and puberty (CDGP) and isolated hypogonadotropic hypogonadism (iHH)

Comparison of long-term height and pubertal outcomes in boys with delayed puberty due to constitutional delay in growth and puberty (CDGP) and isolated hypogonadotropic hypogonadism (iHH) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Comparison of long-term height and pubertal outcomes in boys with delayed puberty due to constitutional delay in growth and puberty (CDGP) and isolated hypogonadotropic hypogonadism (iHH) Ozge Dogan¹, Dogus Vuralli², Huseyin Demirbilek² This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6536163/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 11 Aug, 2025 Read the published version in European Journal of Pediatrics → Version 1 posted 12 You are reading this latest preprint version Abstract Background and objective: Study aims to evaluate the pubertal development and final height(FH) outcome in patients presented with delayed puberty due to hypogonadotropic hypogonadism(HH) and constitutional delay in growth and puberty(CDGP). Design and participants: The hospital files of 1654 boys older than 14 years of age who were evaluated for delayed puberty between 01.01.2002 and 01.04.2022 in Hacettepe University İhsan Doğramacı Children's Hospital Pediatric Endocrinology Department were reviewed retrospectively. 191 patients who met the inclusion criteria were included in the study. Results: The mean age of admission was 14.6±0.9 years. Of those, 149 patients had CDGP and 42 patients had HH. The mean FH-SDS of patients with HH(-0.09±1.0) was higher than those with CDGP(-0.64±0.91)(p=0.003). In total, 118 out of 128 patients(92.2%) with CDGP and 36 out of 39 patients(92.3%) with HH had reached an FH consistent with their target height(TH). There was no statistically significant difference between the FH-SDS of patients with CDGP who received testosterone therapy for induction of puberty and those who did not receive(-0.46±0.97 SD vs. -0.74±0.87 SD; p=0.094). Conclusion: Individuals presented with delayed puberty due to both CDGP and HH have reached an FH consistent with their TH to a large extent. Patients with HH had a higher presenting and final height than those with CDGP, which was attributed to the higher TH. Induction of puberty with testosterone in boys with CDGP seems not to have a clinically meaningful impact on the FH and long-term pubertal progression. Delayed puberty isolated hypogonadotropic hypogonadism constitutional delay in growth and puberty final height prognosis testosterone induction therapy Figures Figure 1 Figure 2 Figure 3 Figure 4 Introduction Puberty represents a transitional and maturational process from childhood to adulthood. Hypothalamic-pituitary-gonadal (HPG) axis is crucial for pubertal onset, progression, maturation, and achieving fertility. Puberty initiates with the pulsatile secretion of gonadotropin-releasing hormone (GnRH) ( 1 ). Delayed puberty is defined as the absence of physical signs of puberty in boys by 14 years of age ( 2 ). Primary hypogonadism (hypergonadotropic hyogonadism) is characterized by low sex steroid levels accompanied by elevated LH and FSH levels, whereas, secondary hypogonadism (hypogonadotropic hypogonadism) is defined as low or inappropriately normal FSH and LH levels in course of low sex steroids ( 3 ). Constitutional delay in growth and puberty (CDGP), functional hypogonadotropic hypogonadism (FHH), and hypogonadotropic hypogonadism account for the underlying aetiology of secondary hypogonadism (HH) (4, 5). While serum gonadotropin and gonadal sex steroid concentrations easily differentiate between primary and secondary hypogonadism, identifying the underlying aetiology of delayed puberty associated with hypogonadotropic hypogonadism is challenged due to overlapping clinical course and hormonal profiles (6, 7). Delayed puberty can impose a psychological burden, leading to diminished self-esteem (8). This is also a key determinant from the management perspective (9, 10). In cases where a definitive diagnosis is uncertain due to overlapping findings, it is recommended to provide psychological support to the patient and family, along with regular clinical follow-up or short-term sex steroid therapy using testosterone for boys and estradiol for girls. The primary goals of short-term hormonal therapy in patients with CDGP are the appearance of age-appropriate secondary sex characteristics and the induction of a growth spurt (10). Although administration of exogenous sex steroids can potentially accelerate epiphyseal maturation (11), most studies indicate that treatment with short-term low-dose sex steroids does not negatively affect the final height (FH) (10, 12). In congenital HH, lack of neonatal activation of the HPG axis results in the absence of mini-puberty thereby cryptorchidism and micropenis in infants. These findings are preliminary diagnostic clues for identifying HH, even in infancy (13). In contrast to boys with CDGP, the majority of HH patients exhibit minimal or absent pubertal development when treated with low-dose testosterone, thus requiring continuous sex steroid replacement. This study aimed to evaluate the pubertal and height outcomes of CDGP and HH, the two most common and overlapping causes of delayed puberty in boys, which are often challenging to differentiate in the initial stages. We also assessed the height outcomes of patients diagnosed with CDGP who received testosterone therapy for pubertal induction or not. Patients and Method This study involved a retrospective evaluation of hospital records for boys with delayed puberty at Hacettepe University İhsan Doğramacı Children's Hospital, Department of Pediatric Endocrinology, from January 2002 to April 2022. The study is approved by the Institutional Ethics Committee of Hacettepe University (2022/12–80). Delayed puberty in boys was defined as the absence of testicular enlargement by the age of 14 years (3, 14). The patient's height and body weight SDS were calculated at admission, at six months, 1st year, and at final height using CDC (Centers for Disease Control and Prevention) growth charts. Patients exhibiting a height increase of less than 0.5 cm over the past year were considered reached to their final height (FH) (15). Body mass index (BMI) was calculated in kg/m², mid parental height (Target height, TH) values were derived using the established formulas and standard deviation scores (SDS) were calculated based on CDC growth charts. Predicted adult height (PAH) at admission was calculated using the Bayley and Pinneau method (6). Patients with a BMI SDS<-1 were classified as underweight, those with a BMI SDS between − 1 SD and + 1SD (-1 < SDS < + 1) were classified as normal weight, those with a BMI SDS between + 1 and + 2 (+ 1 < SDS < + 2) were classified as overweight, and those with a BMI SDS ≥ + 2 were classified as obese. The bone age at admission was assessed using the Greulich&Pyle method (16). Patients had received either induction or replacement therapy with testosterone (17, 18). The patient's final diagnosis, laboratory parameters data, pubertal prognosis during the follow-up, treatment approaches, response to hormonal treatment, duration of treatment, and age at pubertal onset were evaluated. The group that initiated puberty without intervention or following short-term testosterone induction therapy and subsequently experienced a spontaneous progression of puberty after discontinuation of hormonal therapy was considered CDGP. Patients whose testicular volumes did not reach a pubertal size with prepubertal gonadotropin and testosterone levels, thus requiring regular testosterone replacement therapy, were considered to have HH. Patient Selection The hospital records of 1654 boys presented with short stature or delayed puberty between 2002 and 2022 were retrospectively reviewed. Boys over 14 years old who had prepubertal testicle size at admission were subsequently diagnosed with HH or CDGP, and those who had at least two follow-up visits with six-month intervals were included. Patients with multiple pituitary hormone deficiency, underlying chronic diseases (such as leukaemia, cancer survivors, rheumatological disease, celiac disease, and eating disorders), concomitant endocrinological pathologies (including primary gonadal insufficiency, hypothyroidism, diabetes mellitus, growth hormone deficiency), malnutrition (defined as body mass index (BMI) standard deviation score (SDS) <-2), chromosomal abnormalities (such as Turner syndrome, Klinefelter syndrome, Prader-Willi syndrome, and Noonan syndrome), and those with lacking admission and follow-up data were excluded. 191 out of 1654 patients who met the inclusion criteria were recruited. Statistical analysis Statistical analyses were performed using IBM® SPSS version 25.0 software. Data were presented as frequency and percentage for categorical variables and mean ± standard deviation (SD) or median (min-max) for continuous variables. The continuous variables' normality distribution was assessed using visual (histogram and probability plots) and analytical methods (Kolmogorov-Smirnov/Shapiro-Wilk tests). Comparisons of independent groups for categorical variables were performed using χ2 or Fisher-Exact tests. The risk ratio of independent variables was determined using chi-square and Fisher’s exact test. For continuous variables, Student's t-test or Mann Whitney-U was used to compare two independent groups, while the One-Way Analysis of Variance (ANOVA) was used to compare 3 or more groups. Factors affecting height change over time were analyzed using repeated measures analysis of variance (Repeated Measures ANOVA). A p-value < 0.05 was considered for the statistical significance. Results Presenting characteristics A total of 191 patients were recruited. Among those, 149 patients (78%) were diagnosed with CDGP, while 42 patients (22%) were diagnosed with HH. A comparison of the presenting characteristics of CDGP and HH revealed that patients with CDGP had a younger age, lower height SDS and more prominent retarded bone age at presentation (Table 1 ). There was no statistically significant difference between the mean BMI and BMI-SDS of both groups (Table 1 ). However, the classification of age and sex-adjusted BMI SDS revealed that CDGP patients exhibited a higher underweight status prevalence compared to the HH group (33.6% vs. 16.7%; p = 0.023). Table 1 The presenting clinical and anthropometric characteristics of patients with CDGP and HH CDGP n = 149 HH n = 42 p value Chronological age (years) 14.3 ± 0.6 15.1 ± 1 < 0.001 Bone age, year 12.8 ± 1 13.7 ± 1 < 0.001 Delta bone age (year) 1.66 ± 0.73 1.03 ± 0.93 0.023 Height, cm 152.7 ± 8.7 160.2 ± 10.2 < 0.001 Height, SDS -1.66 ± 0.92 -1.1 ± 1.2 0.003 BMI, kg/m 2 20.67 ± 5.17 22.30 ± 4.70 0.051 BMI, SDS -0.05 ± 1.34 0.43 ± 1.16 0.078 TH height, cm 172.8 ± 5.1 175.9 ± 4.5 0.001 TH, SDS -0.52 ± 0.74 -0.09 ± 0.62 0.002 Predicted adult height (PAH), cm 177.2 ± 6.4 179.3 ± 8.4 < 0.001 PAH, SDS 0.06 ± 0.87 0.34 ± 1.18 < 0.001 Family history of delayed puberty 46 (30.8%) 11 (26.1%) 0.684 Cryptorchidism 4 (2.7%) 18 (42.8%) < 0.001 Micropenis 5 (3.4%) 10 (23.8%) < 0.001 Both groups had a comparable familial history of delayed puberty (p = 0.684). Micropenis was detected in 10 (10/42, 23.8%) of patients with HH and 5 (5/149, 3.4%) of patients with CDGP. Additionally, cryptorchidism was detected in 4 (4/149, 2.7%) patients with CDGP and 18 (18/42, 42.8%) patients with HH (p < 0.001) (Table 1 ). Cryptorchidism was associated with a 12.4-fold increased risk of HH (OR: 12.44, 95% CI, p < 0.001). Treatment and follow-up characteristics While 97 out of 191 patients (50.8%) were followed without hormonal therapy, 52 patients (27.2%) patients had received short-term induction testosterone therapy, and 44 patients (22%) had received regular testosterone replacement therapy. In patients with HH, the mean height and height-SDS at 6 months and 1st year were significantly higher than those of patients with CDGP (p < 0.001 and p = 0.002, respectively) (Fig. 1 A and 1 B). Conversely, growth velocity SDS in the 6th month (p = 0.035) and 1st year (p = 0.018) were lower in the HH group compared to the CDGP group (Table 2 ). During the entire follow-up period, the mean height gain was 17.1 ± 7.3 cm in CDGP (Ranges: 4.8 cm- 37.6 cm) and 13.9 ± 7.3 cm in the HH group (Ranges: 7.9 cm, 34.3 cm) (p = 0.021) (Table 2 ). Table 2 Height outcome of patients diagnosed with CDGP and HH during follow-up CDGP (Mean ± SD) (n = 149) HH (Mean ± SD) (n = 42) p value 6th month height, cm 155.7 ± 8.4 162.9 ± 10.5 < 0.001 6th month height, SDS -1.64 ± 0.85 -1 ± 1.25 0.001 6th month, growth rate, cm/year 7.14 ± 3.4 5.7 ± 3.5 0.035 6th month, growth rate, SDS 0.33 ± 1.03 -0.18 ± 0.92 0.032 First-year height, cm 159.8 ± 8.5 165.2 ± 10 0.002 First-year height, SDS -1.42 ± 0.95 -0.98 ± 1.21 0.028 First-year growth rate, cm/year 7.2 ± 2.3 6.1 ± 3.0 0.018 First-year growth rate, SDS -0.55 ± 1.01 -1.33 ± 1.02 0.027 Total height gain during follow-up, cm 17.11 ± 7.32 (n = 128) 13.92 ± 7.34 (n = 39) 0.021 Final height, cm 171.4 ± 6.74 (n = 128) 174.9 ± 8.24 (n = 39) 0.012 Final height, SDS -0.64 ± 0.91 (n = 128) -0.09 ± 1 (n = 39) 0.003 TH SDS-PAH SDS -0.6 ± 0.81 -0.44 ± 0.58 0.089 FH SDS-PAH SDS -0.86 ± 0.75 -0.51 ± 0.49 0.068 First evaluation Δheight, SDS -1.14 ± 0.79 (n = 128) -1.01 ± 0.67 (n = 39) 0.002 Final Δheight, SDS -0.26 ± 0.38 (n = 128) -0.07 ± 0.42 (n = 39) 0.003 First evaluation Δ Height: First evaluation height SDS- TH SDS, Final Δ Height SDS: Final height SDS-TH SDS The mean FH of HH patients (0.09 ± 1.0) was higher than those of CDGP patients (-0.64 ± 0.91) (p = 0.003) (Fig. 1 B). First evaluation delta height SDS (HtSDS) and final delta HtSDS were significantly higher in the CDGP group compared to the HH group (p = 0.004, p = 0.003). Delta HtSDS was improved from the baseline to the final height in both groups (p = 0.002 and p = 0.003, Fig. 2 ). Delta final height SDS-TH SDS was higher in the HH group than in the CDGP group (p = 0.003) (Table 2 ). Final height was evaluated for 128 CDGP and 39 HH patients. Of those, 118 (92.2%) patients in the CDGP group and 36 (92.3%) patients in the HH group had reached an FH consistent with their TH (p = 0.269). There was no statistically significant difference between the mean FH-SDS of CDGP patients who received pubertal induction therapy (-0.46 ± 0.97) and those who did not receive treatment (-0.74 ± 0.87) (p = 0.094) (Table 3 ). Moreover, the growth rate calculated in the 6th month, 1st year, and the entire follow-up period was similar (Fig. 3 A and 3 B). A significant positive correlation was observed between the TH-SDS and the FH-SDS in those assessed for their FH (r = 0.644, p < 0.001, Fig. 4 ). Of patients with CDGP who received testosterone induction therapy, FH was consistent with TH in 45 of 47 patients (95.75%) and short in two (4.25%). In contrast, in the group that did not receive pubertal induction, 73 of 81 patients (90.1%) had an FH consistent with TH, while 8 (9.9%) were shorter than their target height (p = 0.452). Table 3 Comparison of the final height (FH) of patients with CDGP who received testosterone induction therapy and those who did not Findings Receiving treatment Mean ± SD n = 52 Not receiving treatment Mean ± SD n = 97 p-value First evaluation age 14.55 ± 0.74 14.37 ± 0.50 0.048 First evaluation height, cm 153.26 ± 9.57 151.23 ± 6.91 0.059 First evaluation height, SDS -1.77 ± 0.86 -1.99 ± 0.78 0.061 6th month growth rate, cm/year 7.17 ± 3.73 7.13 ± 3.31 0.939 First-year growth rate, cm/year 7.35 ± 2.20 7.18 ± 2.42 0.691 6th-month growth rate, SDS 0.11 ± 0.47 0.09 ± 0.35 0.524 Follow-up annual growth rate, cm/year 5.06 ± 1.90 5.14 ± 2.1 0.819 Final height, cm 172.91 ± 7 170.62 ± 6.45 0.057 Final height, SDS -0.46 ± 0.97 -0.74 ± 0.87 0.094 MPH, cm 173.42 ± 5.15 172.34 ± 5.13 0.126 MPH, SDS -0.42 ± 0.81 -0.6 ± 0.7 0.148 FH-SDS-MPH-SDS -0.15 ± 0.75 -0.31 ± 0.78 0.216 Discussion In the present study evaluating the long-term follow-up and final height outcome of 191 patients with pubertal delay due to CDGP and HH, most patients, regardless of the aetiology and treatment options, achieved an FH consistent with their TH. A positive family history in patients with delayed puberty has been reported in a broad range of 30–79%, with a large variability due to differences in study design, inclusion criteria, definitions of delayed puberty, and population characteristics (5, 19–24). For instance, in a study by Poyrazoğlu et al., a family history of delayed puberty was identified in 25.8% of 151 patients with CDGP (19). In the present study, positive family history (30.8%) was slightly higher, which can be attributed to the patient selection criteria. Indeed, their study included both male and female patients, while the present study focused exclusively on male patients who are more likely to have CDGP. Mini-puberty refers to the transient activation of the hypothalamic-pituitary-gonadal (HPG) axis during the first few months of life (20). Hypogonadism during fetal development can lead to cryptorchidism and micropenis, as gonadotropins and testosterone are essential for testicular descent and penile growth (21, 22). Cryptorchidism is associated with an increased risk of persistent hypogonadism (OR 17.2, CI 95% CI: 3.4–85.4, P < 0.001) (23). In the present study, cryptorchidism was also found to increase the risk of HH 12.4 times, suggesting the association of delayed puberty and a history of cryptorchidism as a predictor for the high risk of permanent HH. One of the key concerns regarding delayed puberty is whether individuals will ultimately achieve an FH consistent with their TH. Patients with CDGP often experience a decelerated growth rate during the early years of life, resulting in a decline in their height percentile. This leads to growth on a lower percentile relative to their TH, followed by a delayed growth spurt, sometimes resulting in a slightly shorter but mostly appropriate FH consistent with TH(11, 24, 25). In contrast, patients with HH maintain stable linear growth during childhood but are shorter than their pubertal peers due to the absence of the pubertal growth spurt. Consistently, patients with HH presented with a higher height at the time of diagnosis than those with CDGP. On the other hand, the growth rate of patients with CDGP was higher than that of the HH group during the pubertal period, enabling CDGP patients to compensate for the height they had lost during the prepubertal years (Table 2 , Fig. 1 A and 1 B). The average height-SDS increase was higher for CDGP patients throughout the follow-up period than for HH patients. However, the final height of HH patients remained higher than CDGP patients. This discrepancy was likely due to the better TH and higher height SDS achieved by HH patients during the prepubertal period. The common perception is that individuals with CDGP will ultimately reach their genetic height potential by the end of puberty, following a delayed but rapid growth phase (18, 26–28). Similarly, our study showed a strong positive correlation between the patients' TH-SDS and FH-SDS. However, some studies have shown that these individuals may remain 0.6 to 1.5 SDS (approximately 4 to 11 cm) shorter than their TH (11, 29, 30). Zhu et al. reported that individuals with at least one tall parent (height ≥ + 2 SDS) were likelier to reach or exceed their TH. In contrast, those with familial short stature and delayed puberty were likelier to remain shorter than their TH (31). In the study by Poyrazoğlu et al., where 36 patients had familial short stature, 121 of 151 (80.1%)patients whose FH could be assessed had reached their genetic potential (19). In our study, after excluding patients with familial and syndromic short stature, FH evaluation was applicable for 167 patients. Among these, 92.2% (118/128) of patients with CDGP and 92.3% (36/39) of patients with HH reached an FH consistent with their TH. This suggests that when confounding factors like familial short stature are excluded, CDGP and HH patients reach their genetic height potential to a large extent. Another key issue in the management of delayed puberty is whether patients with CDGP require testosterone therapy for pubertal induction. The prevailing belief in the literature is that genetic potential is preserved in CDGP, regardless of whether testosterone therapy is administered. Therefore, if height is not a significant concern, it is often sufficient to provide reassurance and an estimate of TH, particularly if signs of puberty have already started to appear. However, when there are significant concerns about delayed growth or puberty, especially in individuals with low self-esteem, testosterone therapy may be worth initiating (10, 17, 24). Testosterone induction can trigger a growth spurt, potentially improving the patient’s psychosocial well-being. Although some studies suggest that patients with CDGP who receive testosterone induction therapy may have a shorter FH due to accelerated bone age (11, 17), the majority of studies report that these patients ultimately reach an FH consistent with their TH (18, 19, 28, 32, 33). Similarly, in our study, the mean FH-SDS for CDGP patients who received induction therapy was similar to those who did not (Table 3 , Fig. 3 A and 3 B). Besides, the difference between FH-SDS and TH-SDS of CDGP patients receiving induction therapy was similar to those who did not receive treatment (Table 3 ). This finding is particularly valuable, as it has not been previously addressed in the literature (18, 19, 32). Furthermore, the growth rate during the 6-month, first-year, and entire follow-up periods was similar in both treated and untreated patients (Fig. 3 A and 3 B). This suggests that a significant pubertal growth spurt occurs in CDGP patients, regardless of whether pubertal induction therapy is applied. Finally, FH assessments conducted in 47 of 52 patients with CDGP who received testosterone therapy revealed that 95.75% (45/47) achieved an FH consistent with their TH, suggesting short-term, low-dose testosterone therapy does not have a clinically meaningful adverse impact on the FH in CDGP. The strength of the present study was to evaluate the height prognosis of patients diagnosed with CDGP and HH, which is very few in the literature. Data were collected from 20 years of follow-up of patients at a single tertiary centre. Unlike many other studies on this topic, our study focused exclusively on male patients over the age of 14 with a diagnosis of CDGP and HH. We also excluded data from the patient group with confounding factors such as familial short stature (FHH), malnutrition, and underlying chronic diseases. This study's limitations were its retrospective design, the inability to access data for some patients, and the lack of standardized anthropometric measurements for patients and their parents, as different devices were used over the long while. In conclusion, patients with HH and CDGP, which are often difficult to differentiate, showed similar outcomes regarding height prognosis. Both groups largely reached an FH consistent with their TH. While patients with the HH group were taller than CDGP patients at the time of initial diagnosis and had higher TH and PAH, the CDGP group had a higher growth rate and height gain during follow-up, which provided achieving an FH consistent with their genetic potential. Testosterone induction for puberty did not impact height outcomes in the CDGP group, suggesting that individuals with CDGP eventually reached their genetic potential after a delayed but accelerated growth spurt. Abbreviations BMI: Body Mass Index CDC: Centers for Disease Control and Prevention CDGP: Constituional Delay in Growth and Puberty FH: Final Height FHH: Functional Hypogonadotropic Hypogonadism GnRH: Gonadotropin-Releasing Hormone HH: Hypogonadotropic Hypogonadism HPG: Hypothalamic- Pituitary- Gonadal HtSDS: Height Standard Deviation Scores PAH: Predicted Adult Height SDS: Standard Deviation Scores TH: Target Height Declarations Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Competing Interests The authors have no relevant financial or non-financial interests to disclose. Author Contributions All authors contributed to the study conception and design. 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Final height in girls with untreated constitutional delay in growth and puberty. Eur J Endocrinol. 1991;150 (10):708–12. Zhu J CY. Adult consequences of self-limited delayed puberty. Pediatrics. 2017;139(6). Lawaetz JG HC, Mieritz MG, Jensen MB, Petersen JH, Juul A. Evaluation of 451 Danish boys with delayed puberty: diagnostic use of a new puberty nomogram and effects of oral testosterone therapy. J Clin Endocrinol Metab. 2015;100(4):1376–85. Kelly BP PW, Donaldson MDC. Final height outcome and value of height prediction in boys with constitutional delay in growth and adolescence treated with intramuscular testosterone 125 mg per month for 3 months. Clin Endocrinol (Oxf). 2003;58(3):267–72. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 11 Aug, 2025 Read the published version in European Journal of Pediatrics → Version 1 posted Editorial decision: Revision requested 27 Jun, 2025 Reviews received at journal 27 Jun, 2025 Reviewers agreed at journal 24 Jun, 2025 Reviewers agreed at journal 24 Jun, 2025 Reviews received at journal 31 May, 2025 Reviewers agreed at journal 27 May, 2025 Reviewers agreed at journal 24 May, 2025 Reviewers agreed at journal 02 May, 2025 Reviewers invited by journal 30 Apr, 2025 Editor assigned by journal 30 Apr, 2025 Submission checks completed at journal 30 Apr, 2025 First submitted to journal 26 Apr, 2025 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. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6536163","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":451108061,"identity":"2ac138a8-8f71-4b00-9a94-ec57acb145dd","order_by":0,"name":"Ozge Dogan¹","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA10lEQVRIiWNgGAWjYNACNgYGfhCdUECKFskGkBYDUrQYHAAxiNHCz3/84qMbZbV5xudXJ354YMAgzy92AL8WyYYzxcY5544Xm914u1kC6DDDmbMT8GsxONiTJp3bdixx242zG0BaEgxuE9JymCf9N0jL5hlnN/8gTssx9mPMuW01iRv4e7cRZ4tkDw+zdM65A4kzbvBus0gwkCDsF2CIPfycU1aX2N9/dvPNHxU28vzSBLQwMPCA4uIwA4MEWKUEIeUgwP4ASNQB7TtAjOpRMApGwSgYiQAAAOFI/Q05eS8AAAAASUVORK5CYII=","orcid":"","institution":"¹Hacettepe University","correspondingAuthor":true,"prefix":"","firstName":"Ozge","middleName":"","lastName":"Dogan¹","suffix":""},{"id":451108062,"identity":"c1ba9813-9aa5-4a8d-9dd8-5ff8629a048c","order_by":1,"name":"Dogus Vuralli²","email":"","orcid":"","institution":"¹Hacettepe University","correspondingAuthor":false,"prefix":"","firstName":"Dogus","middleName":"","lastName":"Vuralli²","suffix":""},{"id":451108063,"identity":"eeb2ac02-a2ec-4faf-bbd9-10c26fff78a9","order_by":2,"name":"Huseyin Demirbilek²","email":"","orcid":"","institution":"¹Hacettepe University","correspondingAuthor":false,"prefix":"","firstName":"Huseyin","middleName":"","lastName":"Demirbilek²","suffix":""}],"badges":[],"createdAt":"2025-04-26 16:38:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6536163/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6536163/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00431-025-06374-4","type":"published","date":"2025-08-11T15:57:39+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":82298853,"identity":"67944da1-c2ed-4bc3-ab4b-af095ec2337b","added_by":"auto","created_at":"2025-05-08 20:29:09","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":46858,"visible":true,"origin":"","legend":"\u003cp\u003eHeight change (in cm) (A), and (in SDS) (B) during the follow-up period in patients with CDGP and HH\u003c/p\u003e","description":"","filename":"1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6536163/v1/17b02c0d8618e6b1b9799ce1.jpg"},{"id":82298856,"identity":"182f6a5a-ab00-4b68-ae22-aaeb65f3a491","added_by":"auto","created_at":"2025-05-08 20:29:09","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":41290,"visible":true,"origin":"","legend":"\u003cp\u003eΔ height change of patients diagnosed with CDGP and HH\u003c/p\u003e","description":"","filename":"2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6536163/v1/3ae3638582469c29440230cc.jpg"},{"id":82298855,"identity":"9850f90d-4734-4987-85e3-e348d44d6720","added_by":"auto","created_at":"2025-05-08 20:29:09","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":32170,"visible":true,"origin":"","legend":"\u003cp\u003eThe effect of induction therapy on height cm (A), SDS (B) change in patients with CDGP\u003c/p\u003e","description":"","filename":"3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6536163/v1/dedcf67001cdb77c0054da08.jpg"},{"id":82298857,"identity":"fe8a10b3-d3d2-4af4-a680-194990b8c2c5","added_by":"auto","created_at":"2025-05-08 20:29:09","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":57371,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelation analysis revealed a positive, strong correlation between TH-SDS and FH-SDS in CDGP patients (SDS)\u003c/p\u003e","description":"","filename":"4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6536163/v1/6fe182d610db8cc41269acaf.jpg"},{"id":89310665,"identity":"94063f6e-b234-4c27-aa93-7f5a031bc5aa","added_by":"auto","created_at":"2025-08-18 16:09:24","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":821953,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6536163/v1/402df381-e0e4-406a-9c21-cf2dad3777b7.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Comparison of long-term height and pubertal outcomes in boys with delayed puberty due to constitutional delay in growth and puberty (CDGP) and isolated hypogonadotropic hypogonadism (iHH)","fulltext":[{"header":"Introduction","content":"\u003cp\u003ePuberty represents a transitional and maturational process from childhood to adulthood. Hypothalamic-pituitary-gonadal (HPG) axis is crucial for pubertal onset, progression, maturation, and achieving fertility. Puberty initiates with the pulsatile secretion of gonadotropin-releasing hormone (GnRH) (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). Delayed puberty is defined as the absence of physical signs of puberty in boys by 14 years of age (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Primary hypogonadism (hypergonadotropic hyogonadism) is characterized by low sex steroid levels accompanied by elevated LH and FSH levels, whereas, secondary hypogonadism (hypogonadotropic hypogonadism) is defined as low or inappropriately normal FSH and LH levels in course of low sex steroids (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Constitutional delay in growth and puberty (CDGP), functional hypogonadotropic hypogonadism (FHH), and hypogonadotropic hypogonadism account for the underlying aetiology of secondary hypogonadism (HH) (4, 5). While serum gonadotropin and gonadal sex steroid concentrations easily differentiate between primary and secondary hypogonadism, identifying the underlying aetiology of delayed puberty associated with hypogonadotropic hypogonadism is challenged due to overlapping clinical course and hormonal profiles (6, 7).\u003c/p\u003e \u003cp\u003eDelayed puberty can impose a psychological burden, leading to diminished self-esteem (8). This is also a key determinant from the management perspective (9, 10). In cases where a definitive diagnosis is uncertain due to overlapping findings, it is recommended to provide psychological support to the patient and family, along with regular clinical follow-up or short-term sex steroid therapy using testosterone for boys and estradiol for girls. The primary goals of short-term hormonal therapy in patients with CDGP are the appearance of age-appropriate secondary sex characteristics and the induction of a growth spurt (10). Although administration of exogenous sex steroids can potentially accelerate epiphyseal maturation (11), most studies indicate that treatment with short-term low-dose sex steroids does not negatively affect the final height (FH) (10, 12).\u003c/p\u003e \u003cp\u003eIn congenital HH, lack of neonatal activation of the HPG axis results in the absence of mini-puberty thereby cryptorchidism and micropenis in infants. These findings are preliminary diagnostic clues for identifying HH, even in infancy (13). In contrast to boys with CDGP, the majority of HH patients exhibit minimal or absent pubertal development when treated with low-dose testosterone, thus requiring continuous sex steroid replacement.\u003c/p\u003e \u003cp\u003eThis study aimed to evaluate the pubertal and height outcomes of CDGP and HH, the two most common and overlapping causes of delayed puberty in boys, which are often challenging to differentiate in the initial stages. We also assessed the height outcomes of patients diagnosed with CDGP who received testosterone therapy for pubertal induction or not.\u003c/p\u003e"},{"header":"Patients and Method","content":"\u003cp\u003eThis study involved a retrospective evaluation of hospital records for boys with delayed puberty at Hacettepe University İhsan Doğramacı Children's Hospital, Department of Pediatric Endocrinology, from January 2002 to April 2022. The study is approved by the Institutional Ethics Committee of Hacettepe University (2022/12\u0026ndash;80).\u003c/p\u003e \u003cp\u003eDelayed puberty in boys was defined as the absence of testicular enlargement by the age of 14 years (3, 14). The patient's height and body weight SDS were calculated at admission, at six months, 1st year, and at final height using CDC (Centers for Disease Control and Prevention) growth charts. Patients exhibiting a height increase of less than 0.5 cm over the past year were considered reached to their final height (FH) (15). Body mass index (BMI) was calculated in kg/m\u0026sup2;, mid parental height (Target height, TH) values were derived using the established formulas and standard deviation scores (SDS) were calculated based on CDC growth charts. Predicted adult height (PAH) at admission was calculated using the Bayley and Pinneau method (6). Patients with a BMI SDS\u0026lt;-1 were classified as underweight, those with a BMI SDS between \u0026minus;\u0026thinsp;1 SD and +\u0026thinsp;1SD (-1\u0026thinsp;\u0026lt;\u0026thinsp;SDS\u0026thinsp;\u0026lt;\u0026thinsp;+\u0026thinsp;1) were classified as normal weight, those with a BMI SDS between +\u0026thinsp;1 and +\u0026thinsp;2 (+\u0026thinsp;1\u0026thinsp;\u0026lt;\u0026thinsp;SDS\u0026thinsp;\u0026lt;\u0026thinsp;+\u0026thinsp;2) were classified as overweight, and those with a BMI SDS\u0026thinsp;\u003cb\u003e\u0026ge;\u0026thinsp;+\u003c/b\u003e\u0026thinsp;2 were classified as obese. The bone age at admission was assessed using the Greulich\u0026amp;Pyle method (16). Patients had received either induction or replacement therapy with testosterone (17, 18). The patient's final diagnosis, laboratory parameters data, pubertal prognosis during the follow-up, treatment approaches, response to hormonal treatment, duration of treatment, and age at pubertal onset were evaluated. The group that initiated puberty without intervention or following short-term testosterone induction therapy and subsequently experienced a spontaneous progression of puberty after discontinuation of hormonal therapy was considered CDGP. Patients whose testicular volumes did not reach a pubertal size with prepubertal gonadotropin and testosterone levels, thus requiring regular testosterone replacement therapy, were considered to have HH.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient Selection\u003c/h2\u003e \u003cp\u003eThe hospital records of 1654 boys presented with short stature or delayed puberty between 2002 and 2022 were retrospectively reviewed. Boys over 14 years old who had prepubertal testicle size at admission were subsequently diagnosed with HH or CDGP, and those who had at least two follow-up visits with six-month intervals were included. Patients with multiple pituitary hormone deficiency, underlying chronic diseases (such as leukaemia, cancer survivors, rheumatological disease, celiac disease, and eating disorders), concomitant endocrinological pathologies (including primary gonadal insufficiency, hypothyroidism, diabetes mellitus, growth hormone deficiency), malnutrition (defined as body mass index (BMI) standard deviation score (SDS) \u0026lt;-2), chromosomal abnormalities (such as Turner syndrome, Klinefelter syndrome, Prader-Willi syndrome, and Noonan syndrome), and those with lacking admission and follow-up data were excluded. 191 out of 1654 patients who met the inclusion criteria were recruited.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eStatistical analyses were performed using IBM\u0026reg; SPSS version 25.0 software. Data were presented as frequency and percentage for categorical variables and mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) or median (min-max) for continuous variables. The continuous variables' normality distribution was assessed using visual (histogram and probability plots) and analytical methods (Kolmogorov-Smirnov/Shapiro-Wilk tests). Comparisons of independent groups for categorical variables were performed using χ2 or Fisher-Exact tests. The risk ratio of independent variables was determined using chi-square and Fisher\u0026rsquo;s exact test. For continuous variables, Student's t-test or Mann Whitney-U was used to compare two independent groups, while the One-Way Analysis of Variance (ANOVA) was used to compare 3 or more groups. Factors affecting height change over time were analyzed using repeated measures analysis of variance (Repeated Measures ANOVA). A p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered for the statistical significance.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003ePresenting characteristics\u003c/h2\u003e \u003cp\u003eA total of 191 patients were recruited. Among those, 149 patients (78%) were diagnosed with CDGP, while 42 patients (22%) were diagnosed with HH. A comparison of the presenting characteristics of CDGP and HH revealed that patients with CDGP had a younger age, lower height SDS and more prominent retarded bone age at presentation (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). There was no statistically significant difference between the mean BMI and BMI-SDS of both groups (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). However, the classification of age and sex-adjusted BMI SDS revealed that CDGP patients exhibited a higher underweight status prevalence compared to the HH group (33.6% vs. 16.7%; p\u0026thinsp;=\u0026thinsp;0.023).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eThe presenting clinical and anthropometric characteristics of patients with CDGP and HH\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCDGP\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;149\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHH\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;42\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronological age (years)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14.3\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBone age, year\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e13.7\u0026thinsp;\u0026plusmn;\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDelta bone age (year)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.66\u0026thinsp;\u0026plusmn;\u0026thinsp;0.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.03\u0026thinsp;\u0026plusmn;\u0026thinsp;0.93\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.023\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeight, cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e152.7\u0026thinsp;\u0026plusmn;\u0026thinsp;8.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e160.2\u0026thinsp;\u0026plusmn;\u0026thinsp;10.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHeight, SDS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-1.66\u0026thinsp;\u0026plusmn;\u0026thinsp;0.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-1.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.003\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI, kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e20.67\u0026thinsp;\u0026plusmn;\u0026thinsp;5.17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22.30\u0026thinsp;\u0026plusmn;\u0026thinsp;4.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.051\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI, SDS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.05\u0026thinsp;\u0026plusmn;\u0026thinsp;1.34\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.43\u0026thinsp;\u0026plusmn;\u0026thinsp;1.16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.078\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTH height, cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e172.8\u0026thinsp;\u0026plusmn;\u0026thinsp;5.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e175.9\u0026thinsp;\u0026plusmn;\u0026thinsp;4.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTH, SDS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e-0.52\u0026thinsp;\u0026plusmn;\u0026thinsp;0.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-0.09\u0026thinsp;\u0026plusmn;\u0026thinsp;0.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.002\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePredicted adult height (PAH), cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e177.2\u0026thinsp;\u0026plusmn;\u0026thinsp;6.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e179.3\u0026thinsp;\u0026plusmn;\u0026thinsp;8.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePAH, SDS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.06\u0026thinsp;\u0026plusmn;\u0026thinsp;0.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.34\u0026thinsp;\u0026plusmn;\u0026thinsp;1.18\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFamily history of delayed puberty\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46 (30.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e11 (26.1%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.684\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCryptorchidism\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (2.7%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e18 (42.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMicropenis\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e5 (3.4%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e10 (23.8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eBoth groups had a comparable familial history of delayed puberty (p\u0026thinsp;=\u0026thinsp;0.684). Micropenis was detected in 10 (10/42, 23.8%) of patients with HH and 5 (5/149, 3.4%) of patients with CDGP. Additionally, cryptorchidism was detected in 4 (4/149, 2.7%) patients with CDGP and 18 (18/42, 42.8%) patients with HH (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Cryptorchidism was associated with a 12.4-fold increased risk of HH (OR: 12.44, 95% CI, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eTreatment and follow-up characteristics\u003c/h3\u003e\n\u003cp\u003eWhile 97 out of 191 patients (50.8%) were followed without hormonal therapy, 52 patients (27.2%) patients had received short-term induction testosterone therapy, and 44 patients (22%) had received regular testosterone replacement therapy.\u003c/p\u003e \u003cp\u003eIn patients with HH, the mean height and height-SDS at 6 months and 1st year were significantly higher than those of patients with CDGP (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 and p\u0026thinsp;=\u0026thinsp;0.002, respectively) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA and \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). Conversely, growth velocity SDS in the 6th month (p\u0026thinsp;=\u0026thinsp;0.035) and 1st year (p\u0026thinsp;=\u0026thinsp;0.018) were lower in the HH group compared to the CDGP group (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). During the entire follow-up period, the mean height gain was 17.1\u0026thinsp;\u0026plusmn;\u0026thinsp;7.3 cm in CDGP (Ranges: 4.8 cm- 37.6 cm) and 13.9\u0026thinsp;\u0026plusmn;\u0026thinsp;7.3 cm in the HH group (Ranges: 7.9 cm, 34.3 cm) (p\u0026thinsp;=\u0026thinsp;0.021) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eHeight outcome of patients diagnosed with CDGP and HH during follow-up\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCDGP\u003c/p\u003e \u003cp\u003e(Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;149)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eHH\u003c/p\u003e \u003cp\u003e(Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;42)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6th month height, cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e155.7\u0026thinsp;\u0026plusmn;\u0026thinsp;8.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e162.9\u0026thinsp;\u0026plusmn;\u0026thinsp;10.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6th month height, SDS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e-1.64\u0026thinsp;\u0026plusmn;\u0026thinsp;0.85\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e-1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6th month, growth rate, cm/year\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e7.14\u0026thinsp;\u0026plusmn;\u0026thinsp;3.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e5.7\u0026thinsp;\u0026plusmn;\u0026thinsp;3.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.035\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6th month, growth rate, SDS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e0.33\u0026thinsp;\u0026plusmn;\u0026thinsp;1.03\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e-0.18\u0026thinsp;\u0026plusmn;\u0026thinsp;0.92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.032\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFirst-year height, cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e159.8\u0026thinsp;\u0026plusmn;\u0026thinsp;8.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e165.2\u0026thinsp;\u0026plusmn;\u0026thinsp;10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFirst-year height, SDS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e-1.42\u0026thinsp;\u0026plusmn;\u0026thinsp;0.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e-0.98\u0026thinsp;\u0026plusmn;\u0026thinsp;1.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.028\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFirst-year growth rate, cm/year\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e7.2\u0026thinsp;\u0026plusmn;\u0026thinsp;2.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e6.1\u0026thinsp;\u0026plusmn;\u0026thinsp;3.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.018\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFirst-year growth rate, SDS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e-0.55\u0026thinsp;\u0026plusmn;\u0026thinsp;1.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e-1.33\u0026thinsp;\u0026plusmn;\u0026thinsp;1.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.027\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal height gain during follow-up, cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e17.11\u0026thinsp;\u0026plusmn;\u0026thinsp;7.32\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;128)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e13.92\u0026thinsp;\u0026plusmn;\u0026thinsp;7.34\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.021\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFinal height, cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e171.4\u0026thinsp;\u0026plusmn;\u0026thinsp;6.74\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;128)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e174.9\u0026thinsp;\u0026plusmn;\u0026thinsp;8.24\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.012\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFinal height, SDS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e-0.64\u0026thinsp;\u0026plusmn;\u0026thinsp;0.91\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;128)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e-0.09\u0026thinsp;\u0026plusmn;\u0026thinsp;1\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTH SDS-PAH SDS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e-0.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e-0.44\u0026thinsp;\u0026plusmn;\u0026thinsp;0.58\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.089\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFH SDS-PAH SDS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e-0.86\u0026thinsp;\u0026plusmn;\u0026thinsp;0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e-0.51\u0026thinsp;\u0026plusmn;\u0026thinsp;0.49\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.068\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFirst evaluation Δheight, SDS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e-1.14\u0026thinsp;\u0026plusmn;\u0026thinsp;0.79\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;128)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e-1.01\u0026thinsp;\u0026plusmn;\u0026thinsp;0.67\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFinal Δheight, SDS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e-0.26\u0026thinsp;\u0026plusmn;\u0026thinsp;0.38\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;128)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e-0.07\u0026thinsp;\u0026plusmn;\u0026thinsp;0.42\u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;39)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.003\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eFirst evaluation Δ Height: First evaluation height SDS- TH SDS, Final Δ Height SDS: Final height SDS-TH SDS\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe mean FH of HH patients (0.09\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0) was higher than those of CDGP patients (-0.64\u0026thinsp;\u0026plusmn;\u0026thinsp;0.91) (p\u0026thinsp;=\u0026thinsp;0.003) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). First evaluation delta height SDS (HtSDS) and final delta HtSDS were significantly higher in the CDGP group compared to the HH group (p\u0026thinsp;=\u0026thinsp;0.004, p\u0026thinsp;=\u0026thinsp;0.003). Delta HtSDS was improved from the baseline to the final height in both groups (p\u0026thinsp;=\u0026thinsp;0.002 and p\u0026thinsp;=\u0026thinsp;0.003, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Delta final height SDS-TH SDS was higher in the HH group than in the CDGP group (p\u0026thinsp;=\u0026thinsp;0.003) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eFinal height was evaluated for 128 CDGP and 39 HH patients. Of those, 118 (92.2%) patients in the CDGP group and 36 (92.3%) patients in the HH group had reached an FH consistent with their TH (p\u0026thinsp;=\u0026thinsp;0.269).\u003c/p\u003e \u003cp\u003eThere was no statistically significant difference between the mean FH-SDS of CDGP patients who received pubertal induction therapy (-0.46\u0026thinsp;\u0026plusmn;\u0026thinsp;0.97) and those who did not receive treatment (-0.74\u0026thinsp;\u0026plusmn;\u0026thinsp;0.87) (p\u0026thinsp;=\u0026thinsp;0.094) (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Moreover, the growth rate calculated in the 6th month, 1st year, and the entire follow-up period was similar (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). A significant positive correlation was observed between the TH-SDS and the FH-SDS in those assessed for their FH (r\u0026thinsp;=\u0026thinsp;0.644, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Of patients with CDGP who received testosterone induction therapy, FH was consistent with TH in 45 of 47 patients (95.75%) and short in two (4.25%). In contrast, in the group that did not receive pubertal induction, 73 of 81 patients (90.1%) had an FH consistent with TH, while 8 (9.9%) were shorter than their target height (p\u0026thinsp;=\u0026thinsp;0.452).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eComparison of the final height (FH) of patients with CDGP who received testosterone induction therapy and those who did not\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\"\u0026plusmn;\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFindings\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eReceiving treatment\u003c/p\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;52\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eNot receiving treatment\u003c/p\u003e \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e \u003cp\u003en\u0026thinsp;=\u0026thinsp;97\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep-value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFirst evaluation age\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e14.55\u0026thinsp;\u0026plusmn;\u0026thinsp;0.74\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e14.37\u0026thinsp;\u0026plusmn;\u0026thinsp;0.50\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.048\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFirst evaluation height, cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e153.26\u0026thinsp;\u0026plusmn;\u0026thinsp;9.57\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e151.23\u0026thinsp;\u0026plusmn;\u0026thinsp;6.91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.059\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFirst evaluation height, SDS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e-1.77\u0026thinsp;\u0026plusmn;\u0026thinsp;0.86\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e-1.99\u0026thinsp;\u0026plusmn;\u0026thinsp;0.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.061\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6th month growth rate, cm/year\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e7.17\u0026thinsp;\u0026plusmn;\u0026thinsp;3.73\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e7.13\u0026thinsp;\u0026plusmn;\u0026thinsp;3.31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.939\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFirst-year growth rate, cm/year\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e7.35\u0026thinsp;\u0026plusmn;\u0026thinsp;2.20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e7.18\u0026thinsp;\u0026plusmn;\u0026thinsp;2.42\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.691\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e6th-month growth rate, SDS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e0.11\u0026thinsp;\u0026plusmn;\u0026thinsp;0.47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e0.09\u0026thinsp;\u0026plusmn;\u0026thinsp;0.35\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.524\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFollow-up annual growth rate, cm/year\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e5.06\u0026thinsp;\u0026plusmn;\u0026thinsp;1.90\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e5.14\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.819\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFinal height, cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e172.91\u0026thinsp;\u0026plusmn;\u0026thinsp;7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e170.62\u0026thinsp;\u0026plusmn;\u0026thinsp;6.45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.057\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFinal height, SDS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e-0.46\u0026thinsp;\u0026plusmn;\u0026thinsp;0.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e-0.74\u0026thinsp;\u0026plusmn;\u0026thinsp;0.87\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.094\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMPH, cm\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e173.42\u0026thinsp;\u0026plusmn;\u0026thinsp;5.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e172.34\u0026thinsp;\u0026plusmn;\u0026thinsp;5.13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.126\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMPH, SDS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e-0.42\u0026thinsp;\u0026plusmn;\u0026thinsp;0.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e-0.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.148\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFH-SDS-MPH-SDS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c2\"\u003e \u003cp\u003e-0.15\u0026thinsp;\u0026plusmn;\u0026thinsp;0.75\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\"\u0026plusmn;\" colname=\"c3\"\u003e \u003cp\u003e-0.31\u0026thinsp;\u0026plusmn;\u0026thinsp;0.78\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.216\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn the present study evaluating the long-term follow-up and final height outcome of 191 patients with pubertal delay due to CDGP and HH, most patients, regardless of the aetiology and treatment options, achieved an FH consistent with their TH.\u003c/p\u003e \u003cp\u003eA positive family history in patients with delayed puberty has been reported in a broad range of 30\u0026ndash;79%, with a large variability due to differences in study design, inclusion criteria, definitions of delayed puberty, and population characteristics (5, 19\u0026ndash;24). For instance, in a study by Poyrazoğlu et al., a family history of delayed puberty was identified in 25.8% of 151 patients with CDGP (19). In the present study, positive family history (30.8%) was slightly higher, which can be attributed to the patient selection criteria. Indeed, their study included both male and female patients, while the present study focused exclusively on male patients who are more likely to have CDGP.\u003c/p\u003e \u003cp\u003eMini-puberty refers to the transient activation of the hypothalamic-pituitary-gonadal (HPG) axis during the first few months of life (20). Hypogonadism during fetal development can lead to cryptorchidism and micropenis, as gonadotropins and testosterone are essential for testicular descent and penile growth (21, 22). Cryptorchidism is associated with an increased risk of persistent hypogonadism (OR 17.2, CI 95% CI: 3.4\u0026ndash;85.4, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (23). In the present study, cryptorchidism was also found to increase the risk of HH 12.4 times, suggesting the association of delayed puberty and a history of cryptorchidism as a predictor for the high risk of permanent HH.\u003c/p\u003e \u003cp\u003eOne of the key concerns regarding delayed puberty is whether individuals will ultimately achieve an FH consistent with their TH. Patients with CDGP often experience a decelerated growth rate during the early years of life, resulting in a decline in their height percentile. This leads to growth on a lower percentile relative to their TH, followed by a delayed growth spurt, sometimes resulting in a slightly shorter but mostly appropriate FH consistent with TH(11, 24, 25). In contrast, patients with HH maintain stable linear growth during childhood but are shorter than their pubertal peers due to the absence of the pubertal growth spurt. Consistently, patients with HH presented with a higher height at the time of diagnosis than those with CDGP.\u003c/p\u003e \u003cp\u003eOn the other hand, the growth rate of patients with CDGP was higher than that of the HH group during the pubertal period, enabling CDGP patients to compensate for the height they had lost during the prepubertal years (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA and \u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). The average height-SDS increase was higher for CDGP patients throughout the follow-up period than for HH patients. However, the final height of HH patients remained higher than CDGP patients. This discrepancy was likely due to the better TH and higher height SDS achieved by HH patients during the prepubertal period.\u003c/p\u003e \u003cp\u003eThe common perception is that individuals with CDGP will ultimately reach their genetic height potential by the end of puberty, following a delayed but rapid growth phase (18, 26\u0026ndash;28). Similarly, our study showed a strong positive correlation between the patients' TH-SDS and FH-SDS. However, some studies have shown that these individuals may remain 0.6 to 1.5 SDS (approximately 4 to 11 cm) shorter than their TH (11, 29, 30). Zhu et al. reported that individuals with at least one tall parent (height\u0026thinsp;\u003cb\u003e\u0026ge;\u0026thinsp;+\u003c/b\u003e\u0026thinsp;2 SDS) were likelier to reach or exceed their TH. In contrast, those with familial short stature and delayed puberty were likelier to remain shorter than their TH (31). In the study by Poyrazoğlu et al., where 36 patients had familial short stature, 121 of 151 (80.1%)patients whose FH could be assessed had reached their genetic potential (19). In our study, after excluding patients with familial and syndromic short stature, FH evaluation was applicable for 167 patients. Among these, 92.2% (118/128) of patients with CDGP and 92.3% (36/39) of patients with HH reached an FH consistent with their TH. This suggests that when confounding factors like familial short stature are excluded, CDGP and HH patients reach their genetic height potential to a large extent.\u003c/p\u003e \u003cp\u003eAnother key issue in the management of delayed puberty is whether patients with CDGP require testosterone therapy for pubertal induction. The prevailing belief in the literature is that genetic potential is preserved in CDGP, regardless of whether testosterone therapy is administered. Therefore, if height is not a significant concern, it is often sufficient to provide reassurance and an estimate of TH, particularly if signs of puberty have already started to appear. However, when there are significant concerns about delayed growth or puberty, especially in individuals with low self-esteem, testosterone therapy may be worth initiating (10, 17, 24). Testosterone induction can trigger a growth spurt, potentially improving the patient\u0026rsquo;s psychosocial well-being. Although some studies suggest that patients with CDGP who receive testosterone induction therapy may have a shorter FH due to accelerated bone age (11, 17), the majority of studies report that these patients ultimately reach an FH consistent with their TH (18, 19, 28, 32, 33). Similarly, in our study, the mean FH-SDS for CDGP patients who received induction therapy was similar to those who did not (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). Besides, the difference between FH-SDS and TH-SDS of CDGP patients receiving induction therapy was similar to those who did not receive treatment (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). This finding is particularly valuable, as it has not been previously addressed in the literature (18, 19, 32). Furthermore, the growth rate during the 6-month, first-year, and entire follow-up periods was similar in both treated and untreated patients (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eA and \u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003eB). This suggests that a significant pubertal growth spurt occurs in CDGP patients, regardless of whether pubertal induction therapy is applied. Finally, FH assessments conducted in 47 of 52 patients with CDGP who received testosterone therapy revealed that 95.75% (45/47) achieved an FH consistent with their TH, suggesting short-term, low-dose testosterone therapy does not have a clinically meaningful adverse impact on the FH in CDGP.\u003c/p\u003e \u003cp\u003eThe strength of the present study was to evaluate the height prognosis of patients diagnosed with CDGP and HH, which is very few in the literature. Data were collected from 20 years of follow-up of patients at a single tertiary centre. Unlike many other studies on this topic, our study focused exclusively on male patients over the age of 14 with a diagnosis of CDGP and HH. We also excluded data from the patient group with confounding factors such as familial short stature (FHH), malnutrition, and underlying chronic diseases. This study's limitations were its retrospective design, the inability to access data for some patients, and the lack of standardized anthropometric measurements for patients and their parents, as different devices were used over the long while.\u003c/p\u003e \u003cp\u003eIn conclusion, patients with HH and CDGP, which are often difficult to differentiate, showed similar outcomes regarding height prognosis. Both groups largely reached an FH consistent with their TH. While patients with the HH group were taller than CDGP patients at the time of initial diagnosis and had higher TH and PAH, the CDGP group had a higher growth rate and height gain during follow-up, which provided achieving an FH consistent with their genetic potential. Testosterone induction for puberty did not impact height outcomes in the CDGP group, suggesting that individuals with CDGP eventually reached their genetic potential after a delayed but accelerated growth spurt.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eBMI: Body Mass Index\u003c/p\u003e\n\u003cp\u003eCDC: Centers for Disease Control and Prevention\u003c/p\u003e\n\u003cp\u003eCDGP: Constituional Delay in Growth and Puberty\u003c/p\u003e\n\u003cp\u003eFH: Final Height\u003c/p\u003e\n\u003cp\u003eFHH: Functional Hypogonadotropic Hypogonadism\u003c/p\u003e\n\u003cp\u003eGnRH: Gonadotropin-Releasing Hormone\u003c/p\u003e\n\u003cp\u003eHH: Hypogonadotropic Hypogonadism\u003c/p\u003e\n\u003cp\u003eHPG: Hypothalamic- Pituitary- Gonadal\u003c/p\u003e\n\u003cp\u003eHtSDS: Height Standard Deviation Scores\u003c/p\u003e\n\u003cp\u003ePAH: Predicted Adult Height\u003c/p\u003e\n\u003cp\u003eSDS: Standard Deviation Scores\u003c/p\u003e\n\u003cp\u003eTH: Target Height\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCompeting Interests\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAuthor Contributions\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Ozge Dogan and Huseyin Demirbilek. The first draft of the manuscript was written by Ozge Dogan and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eDye AM NG, Diaz-Thomas A. Delayed puberty. Pediatr Ann 2018;47(1):e16\u0026ndash;22.\u003c/li\u003e\n\u003cli\u003eAbitbol L ZS, Palmert MR. Evaluation of delayed puberty: What diagnostic tests should be performed in the seemingly otherwise well adolescent? . Arch Dis Child. 2016;101(8):767\u0026ndash;71.\u003c/li\u003e\n\u003cli\u003ePA L CH. Puberty and its disorder. In: Lifshitz F, ed Pediatric Endocrinology 5th ed London, United Kingdom: Informa Healthcare USA. 2009;273\u0026ndash;303 p.\u003c/li\u003e\n\u003cli\u003eAK T. Update on the Genetics of Idiopathic Hypogonadotropic Hypogonadism. J Clin Res Pediatr Endocrinol. 2017;9(Suppl 2):113\u0026ndash;22\u003c/li\u003e\n\u003cli\u003eSedlmeyer IL PM, Hospital CNS. Delayed puberty: Analysis of a large case series from an academic center. J Clin Endocrinol Metab. 2002;87(4):1613\u0026ndash;20.\u003c/li\u003e\n\u003cli\u003eRL R. Diagnosis and management of delayed puberty. J Clin Endocrinol Metab. 1990;70(3):559\u0026ndash;62.\u003c/li\u003e\n\u003cli\u003ePB K. Delayed puberty. Pediatr Rev. 2010;31(5):189\u0026ndash;95.\u003c/li\u003e\n\u003cli\u003eGiwercman A GY. Hypogonadism in young men treated for cancer. Hormones. 2015;14(4):590\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003eCG B. Management of delayed puberty. Br Med J (Clin Res Ed). 1985;290:657\u0026ndash;8.\u003c/li\u003e\n\u003cli\u003eSoliman AT KM. Testosterone treatment in adolescent boys with constitutional delay of growth and development. Minerva Pediatr. 2002;54(6):709.\u003c/li\u003e\n\u003cli\u003eAlbanese A SR. Predictive factors in the determination of final height in boys with constitutional delay of growth and puberty. J Pediatr. 1995;126(4):545\u0026ndash;50.\u003c/li\u003e\n\u003cli\u003eB\u0026uuml;y\u0026uuml;kgebiz A. Treatment of constitutional delayed puberty with a combination of testosterone esters. Horm Res. \u003cstrong\u003e1995\u003c/strong\u003e;44:3:32-4.\u003c/li\u003e\n\u003cli\u003eEVAIN-BRION D, GENDREL, D., BOZZOLA, M., CHAUSSAIN, J. L., \u0026amp; JOB JC. DIAGNOSIS OF KALLMANN\u0026rsquo;S SYNDROME IN EARLY INFANCY. Acta Pediatr. 1982;71(6):937\u0026ndash;40.\u003c/li\u003e\n\u003cli\u003eHarrington J PM. Distinguishing constitutional delay of growth and puberty from isolated hypogonadotropic hypogonadism: Critical appraisal of available diagnostic tests. J Clin Endocrinol Metab. 2012;97(9):3056\u0026ndash;67.\u003c/li\u003e\n\u003cli\u003eKlein KO BK, Jones J V., Feuillan PP, Cutler GB. Increased final height in precocious puberty after long-term treatment with LHRH agonists: The national institutes of health experience. J Clin Endocrinol Metab. 2001;86(10):4711\u0026ndash;6.\u003c/li\u003e\n\u003cli\u003eGaskin Cree M. KSL, Bertozzi J. Christopher BPM. Skeletal Development of the Hand and Wrist2011.\u003c/li\u003e\n\u003cli\u003eRA R LK. Testosterone treatment in adolescent boys with consititutioonal delay in growth and development. N Eng J Me. 1988;319:1563.\u003c/li\u003e\n\u003cli\u003eArrigo T CM, De Luca F, Saggese G, Messina MF, Pasquino AM, et al. Final height outcome in both untreated and testosterone-treated boys with constitutional delay of growth and puberty. J Pediatr Endocrinol Metab. 1996;9(5):511\u0026ndash;7.\u003c/li\u003e\n\u003cli\u003ePoyrazoǧlu Ş GH, Darendeliler F, Saka N, Bundak R, Baş F. Constitutional delay of growth and puberty: From presentation to final height. J Pediatr Endocrinol Metab. 2005;18(2):171\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eWood CL LL, Cheetham T. Puberty: Normal physiology (brief overview). Best Pract Res Clin Endocrinol Metab. 2019;33(3):101265.\u003c/li\u003e\n\u003cli\u003eSidhoum VF CY, Lippincott MF, Balasubramanian R, Quinton R, Plummer L, et al. Reversal and relapse of hypogonadotropic hypogonadism: Resilience and fragility of the reproductive neuroendocrine system. J Clin Endocrinol Metab. 2014;99(3):861\u0026ndash;70.\u003c/li\u003e\n\u003cli\u003eRaivio T MP. Constitutional delay of puberty versus congenital hypogonadotropic hypogonadism: Genetics, management and updates. Best Pract Res Clin Endocrinol Metab. 2019;33(3).\u003c/li\u003e\n\u003cli\u003eVarimo T MP, K\u0026auml;ns\u0026auml;koski J, Raivio T, Hero M. Congenital hypogonadotropic hypogonadism, functional hypogonadotropism or constitutional delay of growth and puberty? An analysis of a large patient series from a single tertiary center. Hum Reprod. 2017;32(1):147\u0026ndash;53.\u003c/li\u003e\n\u003cli\u003eDunkel L QR. Transition in endocrinology: Induction of puberty. Eur J Endocrinol. 2014;170(6):229\u0026ndash;39.\u003c/li\u003e\n\u003cli\u003eTanner JM WR. Clinical longitudinal standards for height, weight, height velocity, weight velocity, and stages of puberty. Arch Dis Child. 1976;51(3):170\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eG von Kalckreuth 1 FH, M Kessler RHR. Constitutional delay of growth and puberty: do they really reach their target height? . Horm Res. 1991;35(6):222\u0026ndash;5.\u003c/li\u003e\n\u003cli\u003eFinkelstein JS KA, Neer RM, Vermes I. Comment on normal volumetric bone mineral density and bone turnover in young men with histories of constitutional delay of puberty. J Clin Endocrinol Metab. 1999;84(9):3400\u0026ndash;1.\u003c/li\u003e\n\u003cli\u003eRensonnet C KF, Coremans C, Ernould C, Albert A, Bourguignon JP. Pubertal growth as a determinant of adult height in boys with constitutional delay of growth and puberty. Horm Res. 1999;51(5):223\u0026ndash;9.\u003c/li\u003e\n\u003cli\u003eJ.L TJERMC. Etiologies of Late Puberty. Horm Res. 1991;36:136\u0026ndash;40.\u003c/li\u003e\n\u003cli\u003eE C Crowne 1 SMS, W H Wallace, D M Eminson DAP. Final height in girls with untreated constitutional delay in growth and puberty. Eur J Endocrinol. 1991;150 (10):708\u0026ndash;12.\u003c/li\u003e\n\u003cli\u003eZhu J CY. Adult consequences of self-limited delayed puberty. Pediatrics. 2017;139(6).\u003c/li\u003e\n\u003cli\u003eLawaetz JG HC, Mieritz MG, Jensen MB, Petersen JH, Juul A. Evaluation of 451 Danish boys with delayed puberty: diagnostic use of a new puberty nomogram and effects of oral testosterone therapy. J Clin Endocrinol Metab. 2015;100(4):1376\u0026ndash;85.\u003c/li\u003e\n\u003cli\u003eKelly BP PW, Donaldson MDC. Final height outcome and value of height prediction in boys with constitutional delay in growth and adolescence treated with intramuscular testosterone 125 mg per month for 3 months. Clin Endocrinol (Oxf). 2003;58(3):267\u0026ndash;72.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejpe","sideBox":"Learn more about [European Journal of Pediatrics](https://www.springer.com/journal/431)","snPcode":"431","submissionUrl":"https://submission.nature.com/new-submission/431/3","title":"European Journal of Pediatrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Delayed puberty, isolated hypogonadotropic hypogonadism, constitutional delay in growth and puberty, final height prognosis, testosterone induction therapy","lastPublishedDoi":"10.21203/rs.3.rs-6536163/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6536163/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground and objective:\u003c/strong\u003e Study aims to evaluate the pubertal development and final height(FH) outcome in patients presented with delayed puberty due to hypogonadotropic hypogonadism(HH) and constitutional delay in growth and puberty(CDGP).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDesign and participants:\u003c/strong\u003e The hospital files of 1654 boys older than 14 years of age who were evaluated for delayed puberty between 01.01.2002 and 01.04.2022 in Hacettepe University İhsan Doğramacı Children's Hospital Pediatric Endocrinology Department were reviewed retrospectively. 191 patients who met the inclusion criteria were included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e The mean age of admission was 14.6±0.9 years. Of those, 149 patients had CDGP and 42 patients had HH. The mean FH-SDS of patients with HH(-0.09±1.0) was higher than those with CDGP(-0.64±0.91)(p=0.003). In total, 118 out of 128 patients(92.2%) with CDGP and 36 out of 39 patients(92.3%) with HH had reached an FH consistent with their target height(TH). There was no statistically significant difference between the FH-SDS of patients with CDGP who received testosterone therapy for induction of puberty and those who did not receive(-0.46±0.97 SD vs. -0.74±0.87 SD; p=0.094).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e Individuals presented with delayed puberty due to both CDGP and HH have reached an FH consistent with their TH to a large extent. Patients with HH had a higher presenting and final height than those with CDGP, which was attributed to the higher TH. Induction of puberty with testosterone in boys with CDGP seems not to have a clinically meaningful impact on the FH and long-term pubertal progression.\u003c/p\u003e","manuscriptTitle":"Comparison of long-term height and pubertal outcomes in boys with delayed puberty due to constitutional delay in growth and puberty (CDGP) and isolated hypogonadotropic hypogonadism (iHH)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-08 20:29:05","doi":"10.21203/rs.3.rs-6536163/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-06-27T07:13:43+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-27T05:29:10+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"131305277810680191803071344493585049760","date":"2025-06-24T12:13:17+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"7753069093562348189245934171454865836","date":"2025-06-24T08:50:37+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-31T22:06:14+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"223834539173566527042747610411298116832","date":"2025-05-27T10:28:52+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"252167561157394292130955003837044877274","date":"2025-05-24T14:11:28+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"991443421598596007232220568796927573","date":"2025-05-02T12:52:24+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-04-30T09:59:51+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-04-30T08:59:10+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-04-30T08:50:57+00:00","index":"","fulltext":""},{"type":"submitted","content":"European Journal of Pediatrics","date":"2025-04-26T16:26:10+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"european-journal-of-pediatrics","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ejpe","sideBox":"Learn more about [European Journal of Pediatrics](https://www.springer.com/journal/431)","snPcode":"431","submissionUrl":"https://submission.nature.com/new-submission/431/3","title":"European Journal of Pediatrics","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"dfe56d65-cf06-499a-ae78-9fe628789298","owner":[],"postedDate":"May 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-08-18T16:05:37+00:00","versionOfRecord":{"articleIdentity":"rs-6536163","link":"https://doi.org/10.1007/s00431-025-06374-4","journal":{"identity":"european-journal-of-pediatrics","isVorOnly":false,"title":"European Journal of Pediatrics"},"publishedOn":"2025-08-11 15:57:39","publishedOnDateReadable":"August 11th, 2025"},"versionCreatedAt":"2025-05-08 20:29:05","video":"","vorDoi":"10.1007/s00431-025-06374-4","vorDoiUrl":"https://doi.org/10.1007/s00431-025-06374-4","workflowStages":[]},"version":"v1","identity":"rs-6536163","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6536163","identity":"rs-6536163","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}