MRI-derived morphological metrics unveiling GH-IGF-1 axis in modulation of adenohypophyses during peripubertal development

MRI-derived morphological metrics unveiling GH-IGF-1 axis in modulation of adenohypophyses during peripubertal development | 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 MRI-derived morphological metrics unveiling GH-IGF-1 axis in modulation of adenohypophyses during peripubertal development Jianjian Cai, Longbiao Cai, Weiyin Vivian Liu, Qin Liu, Yunyun Zhao, and 5 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7069926/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective To explore the regulatory mechanisms of adenohypophysis height and volume growth in peripubertal children via the correlation between magnetic resonance characteristics (height and volume) of the adenohypophysis and the GH-IGF-1 axis. Methods Included were 380 children (aged 3–12) suspected of growth disorders from 2020–2024. Participants underwent pituitary MRI, serological tests, and GH stimulation tests. Adenohypophysis height (aPH) and volume (aPV), along with Insulin-like Growth Factor 1(IGF-1), Insulin-like growth factor binding protein 3. (IGFBP-3), and GHmax levels, were measured. Pearson and partial correlation analyses assessed relationships among these variables. Results Pearson analysis revealed stronger correlations of aPV with IGF-1 (r = 0.609, p < 0.001) and IGFBP-3 (r = 0.560, p < 0.001) than with GHmax (r = 0.083, p = 0.105). Similarly, aPH correlated more closely with IGF-1 (r = 0.490, p < 0.001) and IGFBP-3 (r = 0.448, p < 0.001) than with GHmax (r = 0.111, p = 0.031). Partial correlation analysis, adjusting for age, height, and weight, showed improved but still weaker correlations between aPV, aPH and GHmax (r = 0.212, p < 0.01; r = 0.155, p < 0.01) compared to IGF-1 (r = 0.252–0.254, p < 0.001), suggesting confounding effects of growth-related factors. Conclusion 3D CUBE-retrieved enlarged volume and increased height of adenohypophysis during adolescence more likely attributed to the GH-IGF-1 axis rather than hormone secretion. Diagnosis Adenohypophysis Growth Hormone Insulin-like growth factor 1 Insulin-like growth factor binding protein 3 Figures Figure 1 Figure 2 Figure 3 Highlights The study uses 3D-FSE-CUBE MRI for accurate measurement of adenohypophysis volume (aPV), overcoming limitations of traditional MRI methods. aPV shows a strong correlation with IGF-1 and IGFBP-3 levels, suggesting IGF-1 mediates adenohypophysis enlargement during puberty. The findings emphasize that aPV, rather than GH levels, provides better diagnostic value for pediatric growth disorders like Growth Hormone Deficiency (GHD). 1. Introduction Adenohypophysis, as the primary endocrine organ, functions both as a secretory and regulatory hub. It is chiefly responsible for the secretion of hormones-most notably growth hormone (GH) [ 1 ] -and is subject to regulatory feedback via the GH-hepatic-derived insulin-like growth factor 1 axis (GH-IGF-1) [ 2 ] . GH influences cellular proliferation, differentiation, and apoptosis primarily through activation of the GH-IGF-1 axis, a pathway in which hepatic-derived IGF-1 mediates systemic growth effects [ 3 , 4 ] . Although the GH-IGF-1 axis plays a well-established role in pediatric development [ 5 ] , it remains unclear peripubertal enlargement of the adenohypophysis reflects GH-driven cellular hyperplasia or IGF-1-mediated trophic influences. Additionally, adenohypophysis volume positively correlates with somatic growth parameters (e.g. height and weight) [ 6 , 7 ] , underscoring its complex regulatory mechanisms during puberty. However, the mechanisms driving this volumetric expansion remain poorly understood, limiting the clinical utility of adenohypophysis size as a diagnostic parameter. Dimensions of the adenohypophysis (such as pituitary volume and height) serve as clinically valuable biomarkers for diagnosing peripubertal disorders. Patients with isolated GH deficiency (GHD) typically exhibit the most pronounced reduction in PV compared to controls, whereas individuals with idiopathic short stature (ISS) demonstrate intermediate measurements, thereby supporting PV as a diagnostic criterion for GHD [ 8 ] . Additional studies have corroborated utility of MRI-derived PV or PH in GHD assessment [ 9 , 10 ] . Interestingly, hypopituitarism due to pituitary adenoma is associated with GH hyposecretion despite glandular enlargement [ 11 , 12 ] , illustrating the complex interplay between adenohypophysis morphology and the GH-IGF-1 axis. Discrepancies in PV correlations with GH-IGF-1 dynamics have been observed; for example, severe GHD has been linked with significantly smaller PV (P = 0.082) compared to ISS and control groups [ 13 ] , though other studies have reported no intergroup differences in PV [ 14 ] . These inconsistencies suggest that PV and PH variability may not be solely GH-dependent but could also be influenced by age, anthropometry, or other unmeasured factors. From a methodological standpoint, traditional two-dimensional MRI-based assessments of adenohypophysis volume [ 15 , 16 ] approximate the gland growth using an ellipsoid morphology [ 17 ] , which may be inaccurate due to interindividual anatomical variation. To address this limitation, this study employs three-dimensional (3D) MRI sequences–specifically, the 3D fast spin-echo pulse sequence with parallel imaging and extended echo train acquisition (3D-FSE-CUBE)–which are increasingly used in clinical practice. This approach allows for more accurate quantification of true pituitary volume, and enables analysis of its correlation with serum levels of IGF-1, Insulin-like growth factor binding protein 3 (IGFBP-3), and peak GH level (GHmax), thereby providing insight into the developmental trajectory of pituitary enlargement in Peri-Pubertal children. 2. Materials and Methods This study was approved by the Institutional Review Boards (IRB) of our hospital (IRB No. TJ-RB202303157). 2.1 Clinical case collection This study included 380 children (aged 3–12 years) who presented with clinically suspected growth and developmental disorders and underwent evaluation at our hospital from May 2020 to July 2024. Eligibility criteria required complete pituitary imaging using a CUBE T1-weighted sequence on 3.0 T MRI scanner, alongside morning serological testing conducted within 48 hours before or after the MRI examination. Exclusion criteria encompassed: (1) MRI images with significant motion artifacts or other quality limitation; (2) medical conditions that could disrupt GHRH-GH-IGF axis (e.g., hypothalamic or pituitary tumors, intracranial infections, infiltration diseases, radiation injury, and head trauma; (3) a history of hormone therapy, neurofibromatosis, or congenital adrenal hyperplasia. After applying these criteria, 380 children were retained in the final study cohort. 2.2 Collection of general clinical data Patient age was calculated using the formula: Age = YEARFRAC (Date of MRI examination - Date of birth). Key serological markers including IGF-1 and IGFBP-3 were systematically collected for subsequent analysis. 2.3 Serological testing serum concentrations of IGF-1 and IGFBP-3 were quantified using an immunochemiluminescent assay. Fasting blood samples were collected at 9:00 AM to ensure standardized testing conditions and minimize circadian variation. 2.4 Growth hormone stimulation tests Following overnight fasting, each participant underwent a combined GH stimulation test imitated at 8:00 AM. This protocol included: (1) a rapid intravenous insulin infusion (0.05 U/kg for subject weighing < 20 kg; 0.075U/kg for those ≥ 20 kg; maximum dose: 4U), and (2) oral clonidine administration (0.004 mg/kg; maximum dose: 0.15mg). Serum GH level was measured at baseline and 30-minute intervals (0, 30, 60, and 90 minutes) to determine the peak response (GH max ). 2.5 MRI Examination All imaging was performed on a 3.0-T scanner (Discovery 750; GE Healthcare, USA) with a dedicated pituitary protocol. The imaging sequences included: (1) sagittal and coronal 3D T1-weighted CUBE (TR/TE = 600/14 ms, slice thickness = 1.6 mm, echo-train length = 24, matrix = 256 × 192, FOV = 200×200 mm 2 , voxel resolution = 0.3906 mm×0.3906 mm×0.8 mm, bandwidth = 41.67 Hz, NEX = 1, Cube Enhancer = Brain T1, and acquisition time = 1 minutes 47 seconds) acquired using a 32-channel head coil. 2.6 MRI Visual Assessment Two neuroradiologists respectively with 15 and 7 years of pituitary imaging experience independently and retrospectively reviewed the MRI scans of all eligible patients. Exclusion criteria included pituitary abnormalities (e.g., interrupted pituitary stalk, Rathke's cleft cyst, pituitary tumor) and any images compromised by motion artifacts or suboptimal image quality. Measurements of adenohypophysis (aPV) and midsagittal height (aPH) were performed using ITK-SNAP software (version 2003.8.0, http://www.itksnap.org/pmwiki/pmwiki.php ), adhering to the methodology previously described in our previous study [ 18 ] . All segmentation results were verified by a senior radiologist, and discrepancies were resolved through consensus. 2.7 Statistical analysis All statistical analysis was conducted using SPSS software (version 22.0, SPSS Inc., Chicago, IL, USA). Continuous variables were expressed as mean ± standard deviation (SD). Relationship between aPH, aPV, and serum levels of IGF-1, IGFBP3, and GH max concentration were assessed using Pearson correlation analysis and partial correlation analysis. 3. Results 3.1 Demographics and clinical data This study included 380 cases (168 males and 212 females), with a mean age of 7.67 ± 0.49 (range: 3.24–14.64 years). The mean GHmax concentration was 13.75 ± 7.21 ng/mL. Aamong them, 253 cases (110 males and 143 females) demonstrated a GH GHmax > 10 ng/mL, while 127 cases (58 males and 69 females) had GHmax < 10 ng/mL. The average IGF-1 value was 190.39 ± 111.29 ng/ml, and the mean IGFBP3 concentration was 4241.64 ± 1078.76 ng/mL (Fig. 1 and Table 1 ). Table 1 Demographic characteristics, MRI-derived adenohypophysis parameters, and biochemical profiles of the study cohort Characteristics (mean ± SD) n 380 age 8.34 ± 2.56 Gender, male:female 1: 1.26 Height, cm 122.38 ± 16.23 HtSDS 1.17 ± 1.07 Weight, kg 25.59 ± 9.69 BMI 17.18 ± 3.22 aPH, mm 4.05 ± 1.05 aPV, mm 3 211.03 ± 90.79 GHmax, mU/ml 13.75 ± 7.21 IGF-1, ng/ml 190.39 ± 111.29 IGFBP-3, ng/ml 4241.64 ± 1078.76 Note: The measurement data were analyzed using t-test. HtSDS: Height Standard Deviation Score, BMI: Body Mass Index, aPH: Adenohypophysis Height, aPV: Adenohypophysis Volume, IGF-1: Insulin-like Growth Factor 1, IGFBP-3: Insulin-like Growth Factor Binding Protein 3. 3.2 Correlation analysis among adenohypophysis MRI features (aPH, aPV) and biochemical indicators (GH max, IGF-1 and IGFBP3) As shown in Fig. 2 and Table 2 , aPV exhibited strong positive correlations with serum concentrations of IGF-1 and IGFBP3 (r = 0.609 and r = 0.560, respectively, all p < 0.001). Similarly, aPH showed moderate positive correlations with serum IGF-1 and IGFBP3 levels (r = 0.490 and r = 0.448, respectively, all p < 0.001). In contrast, aPH demonstrated a weak correlation with GHmax (r = 0.111, p = 0.031), while aPV did not display a significant association with GHmax (r = 0.083, p = 0.105). Additionally, GHmax did not significantly correlate with either IGF-1 (r = 0.016, p = 0.750) or IGFBP3 (r=-0.028, p = 0.581). Table 2 Correlation and partial correlation analyses of aPH、aPV with IGF-1, IGFBP-3, GHmax GHmax IGF-1 IGFBP-3 Pearson partial correlation Pearson partial correlation Pearson partial correlation aPH (mm) 0.111 * 0.155 ** 0.490 *** 0.254 *** 0.448 *** 0.178 *** aPV (mm 3 ) 0.083 0.212 ** 0.609 *** 0.252 *** 0.560 *** 0.166 ** Note: * P < 0.05, ** P < 0.01, *** P < 0.001, control variables: age; gender; body height; body weight; Abbreviatons: aPH; adenohypophyseal height; aPV: adenohypophyseal volume; GHmax: peak growth hormone; IGF-1: insulin-like growth factor 1; IGFBP-3: insulin-like growth factor binding protein 3. 3.3 Partial correlation analysis among adenohypophysis MRI features(aPH, aPV) and biochemical indicators (GHmax, IGF-1、IGFBP3 ) After adjusting for age, gender, height, and weight, partial correlation analysis revealed that the correlations between aPH and both IGF-1(r = 0.254, p<0.001) and IGFBP-3 (r = 0.178, p<0.001) were significantly reduced (Fig. 3 ). Similarly, the correlatoons between aPV and IGF-1 (r = 0.252, p<0.01) and IGFBP-3 (r = 0.166, p<0.01) were reduced. Conversely, the correlations between aPH and GH max (r = 0.155, p<0.01) and between aPV and GH max (r = 0.212, p<0.01) were strengthened. Furthermore, a significant partial correlation was observed between IGF1 and GH max demonstrated (0.174, p < 0.001), whereas the association between IGFBP3 and GH max remained non-significant (r = 0.071, p < 0.001). 4. Discussion Elucidating the relationship between peripubertal adenohypophyseal morphometric changes and the GH-IGF-1 axis holds significant clinical implications. This study revealed that adenohypophysis volume (aPV) and height (aPH) were regulated by GH-IGF1 axis during peripubertal development. The robust-to-moderate correlations between adenohypophysis morphology and growth factors (IGF-1 and IGFBP-3 levels) remained significant even after controlling for anthropometric confounders such as age, height, and body weight. These findings suggested that IGF-1 may play a more prominent role in influencing adenohypophyseal growth dynamics than the association between aPV and GHmax. Adenohypophysis size serves a critical morphological biomarker in the evaluation of growth-related endocrinopathies (GHD, ISS, CPP) [ 19 – 21 ] . Although initial analyses revealed [ 13 , 22 ] no direct correlation between adenohypophysis volume and GH levels, and no significant volume differences between GHD and ISS cohorts, subsequent multivariate adjustment for anthropometric confounders (age, gender, height, and weight) revealed a significant GH-adenohypophysis association, particularly in obese pediatric population [ 23 , 24 ] .Our previous studies demonstrated the diagnostic utility of adenohypophyseal parameters, with volumetric assessment (aPV) achieving robust discrimination between incomplete and central precocious puberty (AUC = 0.829 and 0.828) [ 25 ] , while radiomic profiling enabled moderately accurate prediction of hypothalamic-pituitary-gonadal (HPG) axis activation (AUC = 0.78) [ 18 ] . Collectively, these findings highlighted the clinical significance of adenohypophyseal tissue architecture and its dynamic remodeling in response to hormonal fluctuations in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) during pubertal development. Additionally, we also had built a prediction model using adenohypophysis MRI features, age, and BMI had great potential in differentiation between GHD and ISS (AUC = 0.862) [ 26 ] . In alignment with these insights, our observed significant correlations between aPh/aPV and IGF-1/IGFBP-3 –after controlling for anthropometric confounders– further substantiate the involvement of adenohypophyseal in modulating the GH-IGF-1 axis. From a diagnostic perspective, adenohypophysis volumetry exhibits distinct clinical correlation: reduced volume in conjunction with low IGF-1 levels is indicative of growth hormone deficiency (GHD), whereas a normal or enlarged volume may indicate ISS [ 27 , 28 ] . Mechanistic studies have shown that ablation of the IGF-1 receptor paradoxically upregulates GH mRNA expression [ 29 ] , implying the presence of a negative feedback mechanism within the GH-IGF axis. This bidirectional regulatory circuits entails GH-stimulated IGF-1 synthesis, which subsequently modulates adenohypophyseal secretory function [ 30 , 31 ] . Out adjusted analyses further confirm a persistent between aPV and IGF1 correlation (r = 0.252), independent of age and weight, with IGFBP-3 exerting a secondary stabilizing effect on IGF-1 (r = 0.166). Conventional MRI methods utilizing ellipsoid approximations are constrained by geometric assumptions that limit diagnostic precision [ 32 ] . In contrast, the 3D CUBE sequence offers accurate volumetric assessment of the adenohypophysis by mitigating shape-related artifacts. This advancement is particularly advantageous in the evaluation of pediatric growth disorders, where 3D volumetry facilitates more sensitive detection of developmental anomalies in suspected GHD cases. The notably stronger correlation observed between aPV and IGF-1/IGFBP-3 levels (r = 0.609 and 0.560, respectively) compared to aPV-GHmax association (r = 0.083–0.212) implied that integrating volumetric MRI with IGF-1 profiling could optimize diagnostic accuracy while minimizing dependence on invasive GH stimulation protocols. Overall, our findings substantiate that adenohypophyseal enlargement during puberty primarily reflects IGF-1 mediated trophic effects on the gland rather than direct GH secretory activity. This revised paradigm refines the conventional understanding of GH-IGF-1 axis regulation, repositioning the adenohypophysis as both a secretory gland and a target organ responsive to IGF-1 signaling. Limitations : This study emplyed a single-center design with limited sample diversity (n = 380 cases), a broad age range (3–12 years), and lacked stratification by pubertal stage, thereby limiting its statistical power for subgroup analyses of peripubertal children. Moreover, methodological limitations constrained diagnostic efficacy, including the absence of multimodal diagnostic algorithms that integrate additional serum biomarkers and longitudinal growth velocity data, and the lack of validation in genetic syndromes affecting GH-IGF1 axis. Finally, mechanistic gaps remain; further investigation using animal models is necessary to elucidate the cellular mechanisms by which IGF-1 mediates adenohypophyseal growth, as well as the temporal dynamics between hormonal changes (GH, IGF-1, and IGFBP-3) and volumetric alterations 5. Conclussion Peripubertal adenohypophysis enlargement predominately represents an IGF-1 mediated target organ response rather than secretory hyperplasia. MRI-derived 3D CUBE volumetry demonstrated considerable promise as a non-invasive biomarker for assessing GH-IGF1 axis function, warranting further validation in multicenter cohorts. Abbreviations aPH: Adenohypophyseal height; aPV: Adenohypophyseal volume; GH: Growth hormone; GH max : Peak growth hormone concentration; GHD: Growth hormone deficiency; IGF-1: Insulin-like growth factor 1; IGFBP-3: Insulin-like growth factor binding protein 3; HtSDS: Height standard deviation score; BMI: Body mass index; ISS: Idiopathic short stature; MRI: Magnetic resonance imaging; IRB: Institutional Review Board. Declarations Ethics approval and consent to participate This study was approved by the Institutional Review Boards (IRB) of Tongji Hospital (IRB No. TJ-RB202303157) in accordance with the ethical principles of the Declaration of Helsinki. Written informed consent was obtained from the legal guardians of all participants under 16 years of age. Consent for publication Not applicable. (No identifiable personal/clinical images compromising anonymity are included. Figure 1 displays anonymized MRI scans without patient identifiers.) Availability of data and materials Data is provided within the manuscript or supplementary information files. The datasets generated and/or analyzed during this study are available from the corresponding author upon reasonable request. Competing Interests The authors declare that they have no competing interests. Funding This study has received funding from the Hubei Provincial Natural Science Foundation of China (grant number: 2023AFB862). Competing interests The authors declare that they have no competing interests. Authors' contributions Writing – Original Draft: Jianjian Cai, Longbiao Cai, Chengdong Peng, Dong Liu ; Conceptualization & Methodology: Weiyin Vivian Liu ; Investigation, Data Curation & Formal Analysis: Qin Liu, Yunyun Zhao, Tian Tian; Visualization: Xianrong Kong, Guojun Ding (Figures 1-3); Writing – Review & Editing: All authors Jianjian Cai and Longbiao Cai authors contributed equally to this work. Acknowledgements Not applicable. References Tian W, Qi H, Wang Z, Qiao S, Wang P, Dong J, Wang H. Hormone supply to the pituitary gland: A comprehensive investigation of female‑related tumors (Review). Int J Mol Med. 2022 Oct;50(4):122. Gusmao DO, de Sousa ME, Tavares MR, Donato J. Increased GH Secretion and Body Growth in Mice Carrying Ablation of IGF-1 Receptor in GH-releasing Hormone Cells. Endocrinology. 2022 Oct11;163(11):bqac151. Pagani S, Bozzola E, Acquafredda G, Terlizzi V, Raia V, Majo F, Villani A, Bozzola M. GH-IGF-1 Axis in Children with Cystic Fibrosis. 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Romero CJ, Pine-Twaddell E, Sima DI, Miller RS, He L, Wondisford F, Radovick S. Insulin-like growth factor 1 mediates negative feedback to somatotroph GH expression via POU1F1/CREB binding protein interactions. Mol Cell Biol. 2012 Nov;32(21):4258-69. Chen J, Wang X, He C, Wei S. MRI Findings of Pituitary Gland in Growth Hormone-Deficient Children and Their Correlation with Growth Hormone Peak during Growth Hormone Stimulation Tests. Contrast Media Mol Imaging. 2022 Aug 10;2022:3111585. Additional Declarations No competing interests reported. Supplementary Files Abstractgraph.tif Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7069926","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":505045150,"identity":"1e6da9df-a81d-4f19-a4bd-03334a7439a7","order_by":0,"name":"Jianjian Cai","email":"","orcid":"","institution":"Huazhong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Jianjian","middleName":"","lastName":"Cai","suffix":""},{"id":505045151,"identity":"1550d04c-58f6-4e51-9c4e-c0d25418b2fa","order_by":1,"name":"Longbiao Cai","email":"","orcid":"","institution":"Huazhong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Longbiao","middleName":"","lastName":"Cai","suffix":""},{"id":505045152,"identity":"a1162440-bf0a-40d6-b389-067824944c15","order_by":2,"name":"Weiyin Vivian Liu","email":"","orcid":"","institution":"MR Research, GE Healthcare","correspondingAuthor":false,"prefix":"","firstName":"Weiyin","middleName":"Vivian","lastName":"Liu","suffix":""},{"id":505045153,"identity":"8a4182e7-c754-42bc-92f1-03671db9cf0e","order_by":3,"name":"Qin Liu","email":"","orcid":"","institution":"Huazhong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Qin","middleName":"","lastName":"Liu","suffix":""},{"id":505045154,"identity":"eb5af2a3-eb64-45c2-81cb-880145e21736","order_by":4,"name":"Yunyun Zhao","email":"","orcid":"","institution":"Huazhong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Yunyun","middleName":"","lastName":"Zhao","suffix":""},{"id":505045155,"identity":"479f19c1-65c0-4975-97a1-4d6602062267","order_by":5,"name":"Xianrong Kong","email":"","orcid":"","institution":"Huazhong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Xianrong","middleName":"","lastName":"Kong","suffix":""},{"id":505045156,"identity":"e13d0cfe-0cb0-4b8f-bcd4-9732c8dd7d18","order_by":6,"name":"Guojun Ding","email":"","orcid":"","institution":"Huazhong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Guojun","middleName":"","lastName":"Ding","suffix":""},{"id":505045157,"identity":"e6c1d713-ff0b-418c-b391-32bc1e18f721","order_by":7,"name":"Tian Tian","email":"","orcid":"","institution":"Huazhong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Tian","middleName":"","lastName":"Tian","suffix":""},{"id":505045158,"identity":"8da67e49-a6b2-4726-aa00-f412a28fce7f","order_by":8,"name":"Chengdong Peng","email":"","orcid":"","institution":"Huazhong University of Science and Technology","correspondingAuthor":false,"prefix":"","firstName":"Chengdong","middleName":"","lastName":"Peng","suffix":""},{"id":505045159,"identity":"e1d42b3d-18c1-457a-ac93-d6f31e2b718c","order_by":9,"name":"Dong Liu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2klEQVRIiWNgGAWjYBACPmYGBgkQw4CBuYHhg4GNHUEtbAgtjA2MMwrSkglrYUDSwszz4RBjA0Et7DyGNz7uqLU3Z29sfGxjcICZgf3w0Q34HcZjbDnzzPHEnT0Hm41zDO7wMfCkpd0goMVMmrftWILBjcQ26RyDZ8wMEjxmRGmxB2pp/21hcJixgUgtNYwbgLYwMxCnha3YcmbbgcQNZw42S/YYpCWzEfILP//hjTc+ttXZGxxvPvjhxx8bO372w8fwaoGCw0j2EqEcBOqIVDcKRsEoGAUjEgAAWiNGffzcYUAAAAAASUVORK5CYII=","orcid":"","institution":"Huazhong University of Science and Technology","correspondingAuthor":true,"prefix":"","firstName":"Dong","middleName":"","lastName":"Liu","suffix":""}],"badges":[],"createdAt":"2025-07-08 03:08:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7069926/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7069926/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":90316023,"identity":"c67554e8-ac73-4f6d-95c5-9c08b13529e3","added_by":"auto","created_at":"2025-09-01 10:17:36","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1392255,"visible":true,"origin":"","legend":"\u003cp\u003eManually delineated adenohypophyseal regions of interest on CUBE T1WI images are shown in in (A, E) sagittal, (B, F) axial and (C, G) coronal views as well as (D, H) 3D volume rendering image. Case 1 (male, A-D) with age = 6.74 years, height = 107.80 cm, weight = 18.50 kg, BMI = 15.92, HtSDS = -2.43, GH\u003csub\u003emax\u003c/sub\u003e = 4.11 ng/mL, IGF-1 = 87.60 ng/ml, IGFBP-3 = 3740.00 ng/mL, aPH =3.60 mm, aPV = 243.80 mm\u003csup\u003e3\u003c/sup\u003e; case 2 (female, E-H) with age =7.59 years, height =121.00 cm, weight = 20.50 kg, BMI = 14.00, HtSDS = -0.89, GH\u003csub\u003emax\u003c/sub\u003e = 15.00ng/mL, IGF-1 = 182.00 ng/mL, IGFBP-3 = 4480.00ng/mL, aPH = 4.00 mm and aPV = 135.20mm\u003csup\u003e3\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eGH\u003csub\u003emax\u003c/sub\u003e: peak growth hormone concentration, aPH: adenohypophyseal height, aPV: adenohypophyseal volume; IGF-1, insulin-like growth factor 1; IGFBP-3, insulin-like growth factor binding protein 3; HtSDS: height standard deviation score, BMI: body mass index.\u003c/p\u003e","description":"","filename":"figure1.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7069926/v1/499ef17721d6d3fe96206f84.jpg"},{"id":90317124,"identity":"867097f5-cbe7-4b01-83be-769b62d19754","added_by":"auto","created_at":"2025-09-01 10:25:36","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1062675,"visible":true,"origin":"","legend":"\u003cp\u003eCorrelation matrix illustrating relationshiips among clinical characteristics, adenohypophysis MRI features and biochemical indicators.\u003c/p\u003e\n\u003cp\u003eaPH; adenohypophyseal height; aPV: adenohypophyseal volume; GHmax: peak growth hormone; IGF-1: insulin-like growth factor 1; IGFBP-3: insulin-like growth factor binding protein 3.\u003c/p\u003e","description":"","filename":"figure2.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7069926/v1/2bacffd4a4273063af7579fd.jpg"},{"id":90318429,"identity":"a848ecf0-1264-4613-ae3d-afaf25f4976e","added_by":"auto","created_at":"2025-09-01 10:33:37","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":611930,"visible":true,"origin":"","legend":"\u003cp\u003ePartial correlation matrix of aPH, aPV, IGF-1, IGFBP-3, and GHmax\u003c/p\u003e\n\u003cp\u003eaPH; adenohypophyseal height; aPV: adenohypophyseal volume; GHmax: peak growth hormone; IGF-1: insulin-like growth factor 1; IGFBP-3: insulin-like growth factor binding protein 3.\u003c/p\u003e","description":"","filename":"figure3.tif.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7069926/v1/195d79ae24a3865201022e56.jpg"},{"id":92912130,"identity":"494466fb-8d39-42bb-a85d-a9a1ba9a0e13","added_by":"auto","created_at":"2025-10-07 04:08:57","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":3938034,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7069926/v1/d22c8e2c-c01a-4d3a-b284-4acfb84c0b72.pdf"},{"id":90317123,"identity":"039f2eed-534a-4f38-81e3-fa13dd0a8cc4","added_by":"auto","created_at":"2025-09-01 10:25:36","extension":"tif","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":2183764,"visible":true,"origin":"","legend":"","description":"","filename":"Abstractgraph.tif","url":"https://assets-eu.researchsquare.com/files/rs-7069926/v1/1cd0d06cbfe0b67753560c59.tif"}],"financialInterests":"No competing interests reported.","formattedTitle":"MRI-derived morphological metrics unveiling GH-IGF-1 axis in modulation of adenohypophyses during peripubertal development","fulltext":[{"header":"Highlights","content":"\u003cp\u003eThe study uses 3D-FSE-CUBE MRI for accurate measurement of adenohypophysis volume (aPV), overcoming limitations of traditional MRI methods.\u003c/p\u003e\u003cp\u003eaPV shows a strong correlation with IGF-1 and IGFBP-3 levels, suggesting IGF-1 mediates adenohypophysis enlargement during puberty.\u003c/p\u003e\u003cp\u003eThe findings emphasize that aPV, rather than GH levels, provides better diagnostic value for pediatric growth disorders like Growth Hormone Deficiency (GHD).\u003c/p\u003e"},{"header":"1. Introduction","content":"\u003cp\u003eAdenohypophysis, as the primary endocrine organ, functions both as a secretory and regulatory hub. It is chiefly responsible for the secretion of hormones-most notably growth hormone (GH) \u003csup\u003e[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]\u003c/sup\u003e-and is subject to regulatory feedback via the GH-hepatic-derived insulin-like growth factor 1 axis (GH-IGF-1) \u003csup\u003e[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]\u003c/sup\u003e. GH influences cellular proliferation, differentiation, and apoptosis primarily through activation of the GH-IGF-1 axis, a pathway in which hepatic-derived IGF-1 mediates systemic growth effects \u003csup\u003e[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]\u003c/sup\u003e. Although the GH-IGF-1 axis plays a well-established role in pediatric development \u003csup\u003e[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]\u003c/sup\u003e, it remains unclear peripubertal enlargement of the adenohypophysis reflects GH-driven cellular hyperplasia or IGF-1-mediated trophic influences. Additionally, adenohypophysis volume positively correlates with somatic growth parameters (e.g. height and weight) \u003csup\u003e[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]\u003c/sup\u003e, underscoring its complex regulatory mechanisms during puberty. However, the mechanisms driving this volumetric expansion remain poorly understood, limiting the clinical utility of adenohypophysis size as a diagnostic parameter.\u003c/p\u003e\u003cp\u003eDimensions of the adenohypophysis (such as pituitary volume and height) serve as clinically valuable biomarkers for diagnosing peripubertal disorders. Patients with isolated GH deficiency (GHD) typically exhibit the most pronounced reduction in PV compared to controls, whereas individuals with idiopathic short stature (ISS) demonstrate intermediate measurements, thereby supporting PV as a diagnostic criterion for GHD \u003csup\u003e[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/sup\u003e. Additional studies have corroborated utility of MRI-derived PV or PH in GHD assessment \u003csup\u003e[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]\u003c/sup\u003e. Interestingly, hypopituitarism due to pituitary adenoma is associated with GH hyposecretion despite glandular enlargement \u003csup\u003e[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]\u003c/sup\u003e, illustrating the complex interplay between adenohypophysis morphology and the GH-IGF-1 axis. Discrepancies in PV correlations with GH-IGF-1 dynamics have been observed; for example, severe GHD has been linked with significantly smaller PV (P\u0026thinsp;=\u0026thinsp;0.082) compared to ISS and control groups \u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]\u003c/sup\u003e, though other studies have reported no intergroup differences in PV \u003csup\u003e[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]\u003c/sup\u003e. These inconsistencies suggest that PV and PH variability may not be solely GH-dependent but could also be influenced by age, anthropometry, or other unmeasured factors.\u003c/p\u003e\u003cp\u003eFrom a methodological standpoint, traditional two-dimensional MRI-based assessments of adenohypophysis volume \u003csup\u003e[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]\u003c/sup\u003e approximate the gland growth using an ellipsoid morphology \u003csup\u003e[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]\u003c/sup\u003e, which may be inaccurate due to interindividual anatomical variation. To address this limitation, this study employs three-dimensional (3D) MRI sequences\u0026ndash;specifically, the 3D fast spin-echo pulse sequence with parallel imaging and extended echo train acquisition (3D-FSE-CUBE)\u0026ndash;which are increasingly used in clinical practice.\u003c/p\u003e\u003cp\u003eThis approach allows for more accurate quantification of true pituitary volume, and enables analysis of its correlation with serum levels of IGF-1, Insulin-like growth factor binding protein 3 (IGFBP-3), and peak GH level (GHmax), thereby providing insight into the developmental trajectory of pituitary enlargement in Peri-Pubertal children.\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cp\u003eThis study was approved by the Institutional Review Boards (IRB) of our hospital (IRB No. TJ-RB202303157).\u003c/p\u003e\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003e2.1 Clinical case collection\u003c/h2\u003e\u003cp\u003eThis study included 380 children (aged 3\u0026ndash;12 years) who presented with clinically suspected growth and developmental disorders and underwent evaluation at our hospital from May 2020 to July 2024. Eligibility criteria required complete pituitary imaging using a CUBE T1-weighted sequence on 3.0 T MRI scanner, alongside morning serological testing conducted within 48 hours before or after the MRI examination. Exclusion criteria encompassed: (1) MRI images with significant motion artifacts or other quality limitation; (2) medical conditions that could disrupt GHRH-GH-IGF axis (e.g., hypothalamic or pituitary tumors, intracranial infections, infiltration diseases, radiation injury, and head trauma; (3) a history of hormone therapy, neurofibromatosis, or congenital adrenal hyperplasia. After applying these criteria, 380 children were retained in the final study cohort.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003e2.2 Collection of general clinical data\u003c/h2\u003e\u003cp\u003ePatient age was calculated using the formula: Age\u0026thinsp;=\u0026thinsp;YEARFRAC (Date of MRI examination - Date of birth). Key serological markers including IGF-1 and IGFBP-3 were systematically collected for subsequent analysis.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\u003ch2\u003e2.3 Serological testing\u003c/h2\u003e\u003cp\u003eserum concentrations of IGF-1 and IGFBP-3 were quantified using an immunochemiluminescent assay. Fasting blood samples were collected at 9:00 AM to ensure standardized testing conditions and minimize circadian variation.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\u003ch2\u003e2.4 Growth hormone stimulation tests\u003c/h2\u003e\u003cp\u003eFollowing overnight fasting, each participant underwent a combined GH stimulation test imitated at 8:00 AM. This protocol included: (1) a rapid intravenous insulin infusion (0.05 U/kg for subject weighing\u0026thinsp;\u0026lt;\u0026thinsp;20 kg; 0.075U/kg for those\u0026thinsp;\u0026ge;\u0026thinsp;20 kg; maximum dose: 4U), and (2) oral clonidine administration (0.004 mg/kg; maximum dose: 0.15mg). Serum GH level was measured at baseline and 30-minute intervals (0, 30, 60, and 90 minutes) to determine the peak response (GH\u003csub\u003emax\u003c/sub\u003e).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\u003ch2\u003e2.5 MRI Examination\u003c/h2\u003e\u003cp\u003eAll imaging was performed on a 3.0-T scanner (Discovery 750; GE Healthcare, USA) with a dedicated pituitary protocol. The imaging sequences included: (1) sagittal and coronal 3D T1-weighted CUBE (TR/TE\u0026thinsp;=\u0026thinsp;600/14 ms, slice thickness\u0026thinsp;=\u0026thinsp;1.6 mm, echo-train length\u0026thinsp;=\u0026thinsp;24, matrix\u0026thinsp;=\u0026thinsp;256 \u0026times; 192, FOV\u0026thinsp;=\u0026thinsp;200\u0026times;200 mm\u003csup\u003e2\u003c/sup\u003e, voxel resolution\u0026thinsp;=\u0026thinsp;0.3906 mm\u0026times;0.3906 mm\u0026times;0.8 mm, bandwidth\u0026thinsp;=\u0026thinsp;41.67 Hz, NEX\u0026thinsp;=\u0026thinsp;1, Cube Enhancer\u0026thinsp;=\u0026thinsp;Brain T1, and acquisition time\u0026thinsp;=\u0026thinsp;1 minutes 47 seconds) acquired using a 32-channel head coil.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003e2.6 MRI Visual Assessment\u003c/h2\u003e\u003cp\u003eTwo neuroradiologists respectively with 15 and 7 years of pituitary imaging experience independently and retrospectively reviewed the MRI scans of all eligible patients. Exclusion criteria included pituitary abnormalities (e.g., interrupted pituitary stalk, Rathke's cleft cyst, pituitary tumor) and any images compromised by motion artifacts or suboptimal image quality. Measurements of adenohypophysis (aPV) and midsagittal height (aPH) were performed using ITK-SNAP software (version 2003.8.0, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.itksnap.org/pmwiki/pmwiki.php\u003c/span\u003e\u003cspan address=\"http://www.itksnap.org/pmwiki/pmwiki.php\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e), adhering to the methodology previously described in our previous study \u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. All segmentation results were verified by a senior radiologist, and discrepancies were resolved through consensus.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e\u003ch2\u003e2.7 Statistical analysis\u003c/h2\u003e\u003cp\u003eAll statistical analysis was conducted using SPSS software (version 22.0, SPSS Inc., Chicago, IL, USA). Continuous variables were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD). Relationship between aPH, aPV, and serum levels of IGF-1, IGFBP3, and GH\u003csub\u003emax\u003c/sub\u003e concentration were assessed using Pearson correlation analysis and partial correlation analysis.\u003c/p\u003e\u003c/div\u003e"},{"header":"3. Results","content":"\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003e3.1 Demographics and clinical data\u003c/h2\u003e\u003cp\u003eThis study included 380 cases (168 males and 212 females), with a mean age of 7.67\u0026thinsp;\u0026plusmn;\u0026thinsp;0.49 (range: 3.24\u0026ndash;14.64 years). The mean GHmax concentration was 13.75\u0026thinsp;\u0026plusmn;\u0026thinsp;7.21 ng/mL. Aamong them, 253 cases (110 males and 143 females) demonstrated a GH GHmax\u0026thinsp;\u0026gt;\u0026thinsp;10 ng/mL, while 127 cases (58 males and 69 females) had GHmax\u0026thinsp;\u0026lt;\u0026thinsp;10 ng/mL. The average IGF-1 value was 190.39\u0026thinsp;\u0026plusmn;\u0026thinsp;111.29 ng/ml, and the mean IGFBP3 concentration was 4241.64\u0026thinsp;\u0026plusmn;\u0026thinsp;1078.76 ng/mL (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e and Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\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\u003eDemographic characteristics, MRI-derived adenohypophysis parameters, and biochemical profiles of the study cohort\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\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\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eCharacteristics\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003e(mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003en\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e380\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eage\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8.34\u0026thinsp;\u0026plusmn;\u0026thinsp;2.56\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGender, male:female\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1: 1.26\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\u003e122.38\u0026thinsp;\u0026plusmn;\u0026thinsp;16.23\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHtSDS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.17\u0026thinsp;\u0026plusmn;\u0026thinsp;1.07\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eWeight, kg\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e25.59\u0026thinsp;\u0026plusmn;\u0026thinsp;9.69\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eBMI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e17.18\u0026thinsp;\u0026plusmn;\u0026thinsp;3.22\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eaPH, mm\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4.05\u0026thinsp;\u0026plusmn;\u0026thinsp;1.05\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eaPV, mm\u003csup\u003e3\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e211.03\u0026thinsp;\u0026plusmn;\u0026thinsp;90.79\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGHmax, mU/ml\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e13.75\u0026thinsp;\u0026plusmn;\u0026thinsp;7.21\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIGF-1, ng/ml\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e190.39\u0026thinsp;\u0026plusmn;\u0026thinsp;111.29\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIGFBP-3, ng/ml\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4241.64\u0026thinsp;\u0026plusmn;\u0026thinsp;1078.76\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"2\"\u003eNote: The measurement data were analyzed using t-test. HtSDS: Height Standard Deviation Score, BMI: Body Mass Index, aPH: Adenohypophysis Height, aPV: Adenohypophysis Volume, IGF-1: Insulin-like Growth Factor 1, IGFBP-3: Insulin-like Growth Factor Binding Protein 3.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003e3.2 Correlation analysis among adenohypophysis MRI features (aPH, aPV) and biochemical indicators (GH max, IGF-1 and IGFBP3)\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e and Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, aPV exhibited strong positive correlations with serum concentrations of IGF-1 and IGFBP3 (r\u0026thinsp;=\u0026thinsp;0.609 and r\u0026thinsp;=\u0026thinsp;0.560, respectively, all p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Similarly, aPH showed moderate positive correlations with serum IGF-1 and IGFBP3 levels (r\u0026thinsp;=\u0026thinsp;0.490 and r\u0026thinsp;=\u0026thinsp;0.448, respectively, all p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). In contrast, aPH demonstrated a weak correlation with GHmax (r\u0026thinsp;=\u0026thinsp;0.111, p\u0026thinsp;=\u0026thinsp;0.031), while aPV did not display a significant association with GHmax (r\u0026thinsp;=\u0026thinsp;0.083, p\u0026thinsp;=\u0026thinsp;0.105). Additionally, GHmax did not significantly correlate with either IGF-1 (r\u0026thinsp;=\u0026thinsp;0.016, p\u0026thinsp;=\u0026thinsp;0.750) or IGFBP3 (r=-0.028, p\u0026thinsp;=\u0026thinsp;0.581).\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\u003eCorrelation and partial correlation analyses of aPH、aPV with IGF-1, IGFBP-3, GHmax\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"7\"\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=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e\u003cp\u003eGHmax\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e\u003cp\u003eIGF-1\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e\u003cp\u003eIGFBP-3\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003ePearson\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003epartial correlation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003ePearson\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003epartial correlation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003ePearson\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003epartial correlation\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eaPH\u003c/p\u003e\u003cp\u003e(mm)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.111\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.155\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.490\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.254\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.448\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.178\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eaPV\u003c/p\u003e\u003cp\u003e(mm\u003csup\u003e3\u003c/sup\u003e)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.083\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.212\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.609\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.252\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.560\u003csup\u003e***\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.166\u003csup\u003e**\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"7\"\u003eNote: \u003csup\u003e*\u003c/sup\u003e \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.05, \u003csup\u003e**\u003c/sup\u003e \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01, \u003csup\u003e***\u003c/sup\u003e \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001, control variables: age; gender; body height; body weight;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd colspan=\"7\"\u003eAbbreviatons: aPH; adenohypophyseal height; aPV: adenohypophyseal volume; GHmax: peak growth hormone; IGF-1: insulin-like growth factor 1; IGFBP-3: insulin-like growth factor binding protein 3.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003e3.3 Partial correlation analysis among adenohypophysis MRI features(aPH, aPV) and biochemical indicators (GHmax, IGF-1、IGFBP3 )\u003c/h2\u003e\u003cp\u003eAfter adjusting for age, gender, height, and weight, partial correlation analysis revealed that the correlations between aPH and both IGF-1(r\u0026thinsp;=\u0026thinsp;0.254, p\u0026lt;0.001) and IGFBP-3 (r\u0026thinsp;=\u0026thinsp;0.178, p\u0026lt;0.001) were significantly reduced (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Similarly, the correlatoons between aPV and IGF-1 (r\u0026thinsp;=\u0026thinsp;0.252, p\u0026lt;0.01) and IGFBP-3 (r\u0026thinsp;=\u0026thinsp;0.166, p\u0026lt;0.01) were reduced. Conversely, the correlations between aPH and GH\u003csub\u003emax\u003c/sub\u003e (r\u0026thinsp;=\u0026thinsp;0.155, p\u0026lt;0.01) and between aPV and GH\u003csub\u003emax\u003c/sub\u003e (r\u0026thinsp;=\u0026thinsp;0.212, p\u0026lt;0.01) were strengthened. Furthermore, a significant partial correlation was observed between IGF1 and GH\u003csub\u003emax\u003c/sub\u003e demonstrated (0.174, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), whereas the association between IGFBP3 and GH\u003csub\u003emax\u003c/sub\u003e remained non-significant (r\u0026thinsp;=\u0026thinsp;0.071, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"4. Discussion","content":"\u003cp\u003eElucidating the relationship between peripubertal adenohypophyseal morphometric changes and the GH-IGF-1 axis holds significant clinical implications. This study revealed that adenohypophysis volume (aPV) and height (aPH) were regulated by GH-IGF1 axis during peripubertal development. The robust-to-moderate correlations between adenohypophysis morphology and growth factors (IGF-1 and IGFBP-3 levels) remained significant even after controlling for anthropometric confounders such as age, height, and body weight. These findings suggested that IGF-1 may play a more prominent role in influencing adenohypophyseal growth dynamics than the association between aPV and GHmax.\u003c/p\u003e\u003cp\u003eAdenohypophysis size serves a critical morphological biomarker in the evaluation of growth-related endocrinopathies (GHD, ISS, CPP) \u003csup\u003e[\u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]\u003c/sup\u003e. Although initial analyses revealed \u003csup\u003e[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]\u003c/sup\u003eno direct correlation between adenohypophysis volume and GH levels, and no significant volume differences between GHD and ISS cohorts, subsequent multivariate adjustment for anthropometric confounders (age, gender, height, and weight) revealed a significant GH-adenohypophysis association, particularly in obese pediatric population \u003csup\u003e[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]\u003c/sup\u003e.Our previous studies demonstrated the diagnostic utility of adenohypophyseal parameters, with volumetric assessment (aPV) achieving robust discrimination between incomplete and central precocious puberty (AUC\u0026thinsp;=\u0026thinsp;0.829 and 0.828)\u003csup\u003e[\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]\u003c/sup\u003e, while radiomic profiling enabled moderately accurate prediction of hypothalamic-pituitary-gonadal (HPG) axis activation (AUC\u0026thinsp;=\u0026thinsp;0.78) \u003csup\u003e[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]\u003c/sup\u003e. Collectively, these findings highlighted the clinical significance of adenohypophyseal tissue architecture and its dynamic remodeling in response to hormonal fluctuations in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) during pubertal development. Additionally, we also had built a prediction model using adenohypophysis MRI features, age, and BMI had great potential in differentiation between GHD and ISS (AUC\u0026thinsp;=\u0026thinsp;0.862) \u003csup\u003e[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]\u003c/sup\u003e. In alignment with these insights, our observed significant correlations between aPh/aPV and IGF-1/IGFBP-3 \u0026ndash;after controlling for anthropometric confounders\u0026ndash; further substantiate the involvement of adenohypophyseal in modulating the GH-IGF-1 axis.\u003c/p\u003e\u003cp\u003eFrom a diagnostic perspective, adenohypophysis volumetry exhibits distinct clinical correlation: reduced volume in conjunction with low IGF-1 levels is indicative of growth hormone deficiency (GHD), whereas a normal or enlarged volume may indicate ISS \u003csup\u003e[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/sup\u003e. Mechanistic studies have shown that ablation of the IGF-1 receptor paradoxically upregulates GH mRNA expression \u003csup\u003e[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/sup\u003e, implying the presence of a negative feedback mechanism within the GH-IGF axis. This bidirectional regulatory circuits entails GH-stimulated IGF-1 synthesis, which subsequently modulates adenohypophyseal secretory function \u003csup\u003e[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]\u003c/sup\u003e. Out adjusted analyses further confirm a persistent between aPV and IGF1 correlation (r\u0026thinsp;=\u0026thinsp;0.252), independent of age and weight, with IGFBP-3 exerting a secondary stabilizing effect on IGF-1 (r\u0026thinsp;=\u0026thinsp;0.166).\u003c/p\u003e\u003cp\u003eConventional MRI methods utilizing ellipsoid approximations are constrained by geometric assumptions that limit diagnostic precision \u003csup\u003e[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]\u003c/sup\u003e. In contrast, the 3D CUBE sequence offers accurate volumetric assessment of the adenohypophysis by mitigating shape-related artifacts. This advancement is particularly advantageous in the evaluation of pediatric growth disorders, where 3D volumetry facilitates more sensitive detection of developmental anomalies in suspected GHD cases. The notably stronger correlation observed between aPV and IGF-1/IGFBP-3 levels (r\u0026thinsp;=\u0026thinsp;0.609 and 0.560, respectively) compared to aPV-GHmax association (r\u0026thinsp;=\u0026thinsp;0.083\u0026ndash;0.212) implied that integrating volumetric MRI with IGF-1 profiling could optimize diagnostic accuracy while minimizing dependence on invasive GH stimulation protocols.\u003c/p\u003e\u003cp\u003eOverall, our findings substantiate that adenohypophyseal enlargement during puberty primarily reflects IGF-1 mediated trophic effects on the gland rather than direct GH secretory activity. This revised paradigm refines the conventional understanding of GH-IGF-1 axis regulation, repositioning the adenohypophysis as both a secretory gland and a target organ responsive to IGF-1 signaling.\u003c/p\u003e\u003cp\u003e\u003cb\u003eLimitations\u003c/b\u003e:\u003c/p\u003e\u003cp\u003eThis study emplyed a single-center design with limited sample diversity (n\u0026thinsp;=\u0026thinsp;380 cases), a broad age range (3\u0026ndash;12 years), and lacked stratification by pubertal stage, thereby limiting its statistical power for subgroup analyses of peripubertal children. Moreover, methodological limitations constrained diagnostic efficacy, including the absence of multimodal diagnostic algorithms that integrate additional serum biomarkers and longitudinal growth velocity data, and the lack of validation in genetic syndromes affecting GH-IGF1 axis. Finally, mechanistic gaps remain; further investigation using animal models is necessary to elucidate the cellular mechanisms by which IGF-1 mediates adenohypophyseal growth, as well as the temporal dynamics between hormonal changes (GH, IGF-1, and IGFBP-3) and volumetric alterations\u003c/p\u003e"},{"header":"5. Conclussion","content":"\u003cp\u003ePeripubertal adenohypophysis enlargement predominately represents an IGF-1 mediated target organ response rather than secretory hyperplasia. MRI-derived 3D CUBE volumetry demonstrated considerable promise as a non-invasive biomarker for assessing GH-IGF1 axis function, warranting further validation in multicenter cohorts.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eaPH: Adenohypophyseal height;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eaPV: Adenohypophyseal volume;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGH: Growth hormone;\u003c/p\u003e\n\u003cp\u003eGH\u003csub\u003emax\u003c/sub\u003e: Peak growth hormone concentration;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eGHD: Growth hormone deficiency;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIGF-1: Insulin-like growth factor 1;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIGFBP-3: Insulin-like growth factor binding protein 3;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eHtSDS: Height standard deviation score;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eBMI: Body mass index;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eISS: Idiopathic short stature;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eMRI: Magnetic resonance imaging;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIRB: Institutional Review Board.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was approved by the Institutional Review Boards (IRB) of Tongji Hospital (IRB No. TJ-RB202303157) in accordance with the ethical principles of the Declaration of Helsinki.\u0026nbsp;Written informed consent was obtained from the legal guardians of all participants under 16 years of age.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u0026nbsp;(No identifiable personal/clinical images compromising anonymity are included. Figure 1 displays anonymized MRI scans without patient identifiers.)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData is provided within the manuscript or supplementary information files. The datasets generated and/or analyzed during this study are available from the corresponding author upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study has received funding from the Hubei Provincial Natural Science Foundation of China (grant number: 2023AFB862).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWriting \u0026ndash; Original Draft:\u0026nbsp;\u003c/strong\u003eJianjian Cai, Longbiao Cai, Chengdong Peng, Dong Liu\u003cstrong\u003e; Conceptualization \u0026amp; Methodology:\u0026nbsp;\u003c/strong\u003eWeiyin Vivian Liu\u003cstrong\u003e; Investigation, Data Curation \u0026amp; Formal Analysis:\u0026nbsp;\u003c/strong\u003eQin Liu, Yunyun Zhao, Tian Tian; \u003cstrong\u003eVisualization:\u0026nbsp;\u003c/strong\u003eXianrong Kong, Guojun Ding (Figures 1-3); \u003cstrong\u003eWriting \u0026ndash; Review \u0026amp; Editing:\u0026nbsp;\u003c/strong\u003eAll authors\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eJianjian Cai and Longbiao Cai authors contributed equally to this work.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eTian W, Qi H, Wang Z, Qiao S, Wang P, Dong J, Wang H. Hormone supply to the pituitary gland: A comprehensive investigation of female‑related tumors (Review). Int J Mol Med. 2022 Oct;50(4):122.\u003c/li\u003e\n\u003cli\u003eGusmao DO, de Sousa ME, Tavares MR, Donato J. Increased GH Secretion and Body Growth in Mice Carrying Ablation of IGF-1 Receptor in GH-releasing Hormone Cells. Endocrinology. 2022 Oct11;163(11):bqac151.\u003c/li\u003e\n\u003cli\u003ePagani S, Bozzola E, Acquafredda G, Terlizzi V, Raia V, Majo F, Villani A, Bozzola M. GH-IGF-1 Axis in Children with Cystic Fibrosis. Clin Med Res. 2019 Dec;17(3-4):82-89.\u003c/li\u003e\n\u003cli\u003eBerryman DE, Glad CA, List EO, Johannsson G. The GH/IGF-1 axis in obesity: pathophysiology and therapeutic considerations. Nat Rev Endocrinol. 2013 Jun;9(6):346-56.\u003c/li\u003e\n\u003cli\u003ePerry RJ, Farquharson C, Ahmed SF. The role of sex steroids in controlling pubertal growth. Clin Endocrinol (Oxf). 2008 Jan;68(1):4-15.\u003c/li\u003e\n\u003cli\u003eHan X, Xiu J, Huang Z, Zhang J, Zhang Z, Dong Y, Yuan X, Liu Q. Three-dimensional magnetic resonance volumetry of the pituitary gland is effective in detecting short stature in children. Exp Ther Med. 2014 Aug;8(2):551-556.\u003c/li\u003e\n\u003cli\u003eFehrenbach U, Jadan A, Auer TA, Kreutz K, Geisel D, Ziagaki A, Bobbert T, Wiener E. Obesity and pituitary gland volume - a correlation study using three-dimensional magnetic resonance imaging. Neuroradiol J. 2020 Oct;33(5):400-409.\u003c/li\u003e\n\u003cli\u003eKessler M, Tenner M, Frey M, Noto R. Pituitary volume in children with growth hormone deficiency, idiopathic short stature and controls. J Pediatr Endocrinol Metab. 2016 Oct 1;29(10):1195-1200.\u003c/li\u003e\n\u003cli\u003eRisi R, Masieri S, Poggiogalle E, Watanabe M, Caputi A, Tozzi R, Gangitano E, Masi D, Mariani S, Gnessi L, Lubrano C. Nickel Sensitivity Is Associated with GH-IGF1 Axis Impairment and Pituitary Abnormalities on MRI in Overweight and Obese Subjects. Int J Mol Sci. 2020 Dec 20;21(24):9733.\u003c/li\u003e\n\u003cli\u003ePellini C, di Natale B, De Angelis R, Bressani N, Scotti G, Triulzi F, Chiumello G. Growth hormone deficiency in children: role of magnetic resonance imaging in assessing aetiopathogenesis and prognosis in idiopathic hypopituitarism. Eur J Pediatr. 1990 May;149(8):536-41.\u003c/li\u003e\n\u003cli\u003eRamalho D, Ara\u0026uacute;jo A, Rocha G, Duarte-Ribeiro F. Secukinumab, Pituitary Enlargement and Panhypopituitarism: Are They Related? Eur J Case Rep Intern Med. 2021 Dec 31;8(12):003099.\u003c/li\u003e\n\u003cli\u003e\u0026Scaron;těchovsk\u0026aacute; K, Tůma T, Masopust V, Kos\u0026aacute;k M. Diferenci\u0026aacute;ln\u0026iacute; diagnostika zvět\u0026scaron;en\u0026iacute; hypof\u0026yacute;zy [Differential diagnosis of pituitary enlargement]. Vnitr Lek. 2022 Winter;68(1):58-63.\u003c/li\u003e\n\u003cli\u003eOh JS, Sohn B, Choi Y, Song K, Suh J, Kwon A, Kim HS. The influence of pituitary volume on the growth response in growth hormone-treated children with growth hormone deficiency or idiopathic short stature. Ann Pediatr Endocrinol Metab. 2024 Apr;29(2):95-101.\u003c/li\u003e\n\u003cli\u003eJ. S. Oh, B. Sohn, Y. Choi, et al. (2024) The influence of pituitary volume on the growth response in growth hormone-treated children with growth hormone deficiency or idiopathic short stature. Ann Pediatr Endocrinol Metab 29:95-101.\u003c/li\u003e\n\u003cli\u003eTien RD, Kucharczyk J, Bessette J, Middleton M. MR imaging of the pituitary gland in infants and children: changes in size, shape, and MR signal with growth and development. AJR Am J Roentgenol. 1992 May;158(5):1151-4.\u003c/li\u003e\n\u003cli\u003eKim, M.S.; Sung, K.J. MR Measurement of Normal Pituitary Gland Height on Midsagittal Section: Age and Sex Differentiation. J. Korean Radiol. Soc. 1992, 28, 523\u0026ndash;526.\u003c/li\u003e\n\u003cli\u003eBonczar M, Wysiadecki G, Ostrowski P, Michalczak M, Plutecki D, Wilk J, Michalik W, Walocha J, Balawender K, Iskra T, Lusina D, Koziej M, Radek M, Żytkowski A. The Morphology of the Pituitary Gland: A Meta-Analysis with Implications for Diagnostic Imaging. Brain Sci. 2023 Jan 2;13(1):89.\u003c/li\u003e\n\u003cli\u003eLiu D, Lv W, Liu WV, Tian T, Qin Y, Li Y, Liu Q, Cai J, Gao S, Ding G, Zhao Y, Zhou Y, Xie Y, Zhu W. MRI Radiomics Features of Adenohypophysis Determine the Activation of Hypothalamic-Pituitary-Gonadal Axis in Peri-Puberty Children. J Magn Reson Imaging. 2024 May;59(5):1769-1776.\u003c/li\u003e\n\u003cli\u003eKara \u0026Ouml;, Esen I, Tepe D, G\u0026uuml;lleroğlu NB, Tayfun M. Relevance of Pituitary Gland Magnetic Resonance Imaging Results with Clinical and Laboratory Findings in Growth Hormone Deficiency. Med Sci Monit. 2018 Dec 30;24:9473-9478.\u003c/li\u003e\n\u003cli\u003eDumrongpisutikul N, Chuajak A, Lerdlum S. Pituitary height at magnetic resonance imaging in pediatric isolated growth hormone deficiency. Pediatr Radiol. 2018 May;48(5):694-700.\u003c/li\u003e\n\u003cli\u003eShu K, Wang K, Zhang R, Wang C, Cai Z, Liu K, Lin H, Zeng Y, Cao Z, Lai C, Yan Z, Lu Y. Pituitary MRI Radiomics Improves Diagnostic Performance of Growth Hormone Deficiency in Children Short Stature: A Multicenter Radiomics Study. Acad Radiol. 2024 Sep;31(9):3783-3792.\u003c/li\u003e\n\u003cli\u003eAkkus G, S\u0026ouml;z\u0026uuml;tok S, Odabaş F, Onan B, Evran M, Karagun B, Sert M, Tetiker T. Pituitary Volume in Patients with Primary Empty Sella and Clinical Relevance to Pituitary Hormone Secretion: A Retrospective Single Center Study. Curr Med Imaging. 2021;17(8):1018-1024.\u003c/li\u003e\n\u003cli\u003eLi X, Zhou B, Yao Y, Wang G, Meng H. Reduced Growth Hormone Predicts Worsening Adipose Tissue Insulin Resistance in Adults with Obesity. Obes Facts. 2023;16(4):401-410.\u003c/li\u003e\n\u003cli\u003eScacchi M, Pincelli AI, Cavagnini F. Growth hormone in obesity. Int J Obes Relat Metab Disord. 1999 Mar;23(3):260-71.\u003c/li\u003e\n\u003cli\u003eLiu D, Liu WV, Zhang L, Qin Y, Li Y, Ding G, Zhou Y, Xie Y, Chen P, Zhu W. Diagnostic value of adenohypophyseal MRI features in female children with precocious puberty. Clin Radiol. 2024 Mar;79(3):179-188.\u003c/li\u003e\n\u003cli\u003eCai L, Cao X, Cai J, Liu Q, Zhao Y, Kong X, Ding G, Tian T, Liu WV, Liu D. Pituitary MRI features in identifying idiopathic short stature from growth hormone deficiency in children with short stature. Eur Radiol. 2025 Apr 11. \u003c/li\u003e\n\u003cli\u003eCheng Y, Li W, Gui R, Wang C, Song J, Wang Z, Wang X, Shen Y, Wang Z, Hao L. Dual Characters of GH-IGF1 Signaling Pathways in Radiotherapy and Post-radiotherapy Repair of Cancers. Front Cell Dev Biol. 2021 Jun 9;9:671247. \u003c/li\u003e\n\u003cli\u003eHu B, Li H, Zhang X. A Balanced Act: The Effects of GH-GHR-IGF1 Axis on Mitochondrial Function. Front Cell Dev Biol. 2021 Mar 18;9:630248.\u003c/li\u003e\n\u003cli\u003eAl-Samerria S, Radovick S. The Role of Insulin-like Growth Factor-1 (IGF-1) in the Control of Neuroendocrine Regulation of Growth. Cells. 2021 Oct 5;10(10):2664. \u003c/li\u003e\n\u003cli\u003eChen LH, Xie T, Lei Q, Gu YR, Sun CZ. A review of complex hormone regulation in thyroid cancer: novel insights beyond the hypothalamus-pituitary-thyroid axis. Front Endocrinol (Lausanne). 2024 Jul 22;15:1419913.\u003c/li\u003e\n\u003cli\u003eRomero CJ, Pine-Twaddell E, Sima DI, Miller RS, He L, Wondisford F, Radovick S. Insulin-like growth factor 1 mediates negative feedback to somatotroph GH expression via POU1F1/CREB binding protein interactions. Mol Cell Biol. 2012 Nov;32(21):4258-69.\u003c/li\u003e\n\u003cli\u003eChen J, Wang X, He C, Wei S. MRI Findings of Pituitary Gland in Growth Hormone-Deficient Children and Their Correlation with Growth Hormone Peak during Growth Hormone Stimulation Tests. Contrast Media Mol Imaging. 2022 Aug 10;2022:3111585. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Diagnosis, Adenohypophysis, Growth Hormone, Insulin-like growth factor 1, Insulin-like growth factor binding protein 3","lastPublishedDoi":"10.21203/rs.3.rs-7069926/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7069926/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e\u003cp\u003eTo explore the regulatory mechanisms of adenohypophysis height and volume growth in peripubertal children via the correlation between magnetic resonance characteristics (height and volume) of the adenohypophysis and the GH-IGF-1 axis.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eIncluded were 380 children (aged 3\u0026ndash;12) suspected of growth disorders from 2020\u0026ndash;2024. Participants underwent pituitary MRI, serological tests, and GH stimulation tests. Adenohypophysis height (aPH) and volume (aPV), along with Insulin-like Growth Factor 1(IGF-1), Insulin-like growth factor binding protein 3. (IGFBP-3), and GHmax levels, were measured. Pearson and partial correlation analyses assessed relationships among these variables.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003ePearson analysis revealed stronger correlations of aPV with IGF-1 (r\u0026thinsp;=\u0026thinsp;0.609, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and IGFBP-3 (r\u0026thinsp;=\u0026thinsp;0.560, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) than with GHmax (r\u0026thinsp;=\u0026thinsp;0.083, p\u0026thinsp;=\u0026thinsp;0.105). Similarly, aPH correlated more closely with IGF-1 (r\u0026thinsp;=\u0026thinsp;0.490, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and IGFBP-3 (r\u0026thinsp;=\u0026thinsp;0.448, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) than with GHmax (r\u0026thinsp;=\u0026thinsp;0.111, p\u0026thinsp;=\u0026thinsp;0.031). Partial correlation analysis, adjusting for age, height, and weight, showed improved but still weaker correlations between aPV, aPH and GHmax (r\u0026thinsp;=\u0026thinsp;0.212, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01; r\u0026thinsp;=\u0026thinsp;0.155, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) compared to IGF-1 (r\u0026thinsp;=\u0026thinsp;0.252\u0026ndash;0.254, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), suggesting confounding effects of growth-related factors.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003e3D CUBE-retrieved enlarged volume and increased height of adenohypophysis during adolescence more likely attributed to the GH-IGF-1 axis rather than hormone secretion.\u003c/p\u003e","manuscriptTitle":"MRI-derived morphological metrics unveiling GH-IGF-1 axis in modulation of adenohypophyses during peripubertal development","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-01 10:17:32","doi":"10.21203/rs.3.rs-7069926/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"3d62301d-5371-4668-9e15-2d07ac572b8e","owner":[],"postedDate":"September 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-07T04:08:19+00:00","versionOfRecord":[],"versionCreatedAt":"2025-09-01 10:17:32","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7069926","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7069926","identity":"rs-7069926","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}