Combining Pituitary Height and Basal LH for Diagnosing Idiopathic Central Precocious Puberty: A Retrospective Study of 130 Girls

Combining Pituitary Height and Basal LH for Diagnosing Idiopathic Central Precocious Puberty: A Retrospective Study of 130 Girls | 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 Combining Pituitary Height and Basal LH for Diagnosing Idiopathic Central Precocious Puberty: A Retrospective Study of 130 Girls Xu Zhang, Haiming Cai, Cuimei Zhang, Xiaochun Shen, Jinshui He This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6208100/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 Background The gonadotropin-releasing hormone (GnRH) stimulation test is the gold standard for diagnosing central precocious puberty (CPP), but it is invasive and inconvenient. Pituitary height measured on MRI may provide a complementary non-invasive marker. Objective To evaluate the diagnostic performance of pituitary height for distinguishing idiopathic central precocious puberty (ICPP) from premature thelarche (PT) and to assess whether combining pituitary height with baseline luteinizing hormone (LH) improves accuracy. Methods This retrospective study included 130 girls under 8 years presenting with breast development. Pituitary height was measured on sagittal and coronal T1-weighted MRI. Baseline and stimulated gonadotropins were also measured. Diagnostic accuracy was evaluated using ROC analysis, and logistic regression assessed the predictive contribution of pituitary height. Results Pituitary height was significantly greater in the ICPP group (5.61 ± 1.00 mm) than in the PT group (4.15 ± 0.75 mm; p < 0.001). Pituitary height correlated positively with baseline LH (r = 0.35), peak LH (r = 0.28), and peak LH/FSH ratio (r = 0.26). Logistic regression indicated that each 0.1 mm increase in pituitary height raised the ICPP likelihood 18-fold (P < 0.001). The ROC analysis for pituitary height showed an AUC of 0.915, with a 4.7 mm cutoff providing 90% sensitivity and 86.5% specificity. Combining pituitary height with baseline LH levels improved diagnostic accuracy, yielding an AUC of 0.92, sensitivity of 95%, and specificity of 82%. Conclusion MRI-measured pituitary height, especially when combined with baseline LH, provides a non-invasive, effective diagnostic alternative to the GnRH stimulation test for ICPP. Central Precocious Puberty Premature Thelarche MRI Pituitary Height Figures Figure 1 Figure 2 Introduction Central precocious puberty (CPP) is a prevalent pediatric endocrine disorder characterized by the premature activation of the hypothalamic-pituitary-gonadal axis (HPGA). This early activation results in the accelerated development of internal and external genitalia and the emergence of secondary sexual characteristics in girls younger than 8 and boys younger than 9 (ref 1 ). The incidence of CPP is estimated to range between 1 in 10,000 and 1 in 5,000, with a markedly higher prevalence in girls—occurring 5 to 20 times more frequently than in boys 2 , 3 . Diagnostic criteria for CPP in girls include early onset of secondary sexual characteristics such as breast development, pubic hair growth, and menarche before the age of 8, accompanied by elevated serum gonadotropin and sex hormone levels consistent with puberty 4 , 5 . Additional features may include advanced bone age and accelerated growth, with palpable breast nodules being the most commonly observed clinical manifestation 6 . The pituitary gland, a crucial component of the endocrine system, is located beneath the hypothalamus and plays an essential role in regulating neuroendocrine functions. It achieves this by responding to hypothalamic releasing hormones and secreting various trophic hormones. This regulatory function is particularly significant during childhood sexual development, mediated through the HPGA 7 – 9 . During puberty, the pituitary gland undergoes notable morphological changes, often expanding upward beyond the sella turcica and adopting a more spherical shape 10 . These changes are more pronounced in females, where the pituitary size can increase up to 10 mm, reflecting physiological hypersecretion. Variations in pituitary size are particularly evident in the vertical diameter during puberty, with relatively smaller alterations in the sagittal and coronal diameters 10 . The sagittal diameter is considered the most reliable measurement due to its consistent midpoint positioning, whereas the coronal diameter may vary with different imaging planes. Studies have demonstrated significant differences in pituitary height between children diagnosed with CPP and their age-matched peers, correlating with characteristic pubertal changes 11 . The GnRH stimulation test remains a cornerstone in the diagnosis of CPP, distinguishing it from peripheral precocious puberty 7 , 12 . In 2015, the "Diagnosis and Treatment Consensus on Central Precocious Puberty" identified the GnRH stimulation test as the gold standard for CPP diagnosis, widely implemented in clinical settings. Nevertheless, this test is associated with several limitations 13 : (1) The challenge of sourcing natural GnRH has led to the use of GnRH analogs, which, due to their more potent stimulatory effect, require laboratories to establish diagnostic thresholds—posing difficulties for primary care institutions. (2) The "priming effect" of GnRH analogs may accelerate the progression of sexual development. (3) The test necessitates multiple blood draws, which can cause significant discomfort and psychological distress in children. Advancements in magnetic resonance imaging (MRI) technology offer a non-invasive diagnostic alternative 14 – 16 . MRI-based pituitary measurements have the potential to mitigate some limitations associated with the GnRH stimulation test. This study aims to assess differences in pituitary height between patients with premature thelarche (PT) and those with idiopathic central precocious puberty (ICPP). Furthermore, it evaluates the diagnostic utility of pituitary height in identifying ICPP and explores the potential of integrating baseline LH levels with pituitary height measurements for enhanced diagnostic accuracy. Methods Subjects This study comprised 130 female children who presented with breast enlargement at the Pediatric Department of Fujian Medical University Affiliated Zhangzhou Hospital between February 2020 and December 2021. Diagnoses were established based on the "Diagnosis and Treatment Guidelines for Precocious Puberty (Trial)" issued by the Ministry of Health of the People's Republic of China (2010) and the revised "Diagnosis and Treatment Consensus for Central Precocious Puberty" by the Endocrinology and Metabolism Group of the Chinese Pediatric Society (2015). The diagnostic criteria for central precocious puberty (CPP) included the early onset of secondary sexual characteristics, such as breast development before the age of 8, accelerated growth surpassing typical rates for children, bone age exceeding chronological age by one year or more, enlarged gonads with increased uterine and ovarian volume on pelvic ultrasound, and the presence of multiple ovarian follicles larger than 4 mm in diameter. Elevated gonadotropin and sex hormone levels consistent with puberty indicated activation of the hypothalamic-pituitary-gonadal axis. Idiopathic central precocious puberty (ICPP) was diagnosed after secondary causes were excluded. Diagnosis of premature thelarche (PT) was defined as incomplete precocious puberty, characterized by isolated breast development without other signs of sexual maturation, no accelerated growth or advanced bone age, absence of vaginal bleeding, and mildly elevated baseline estradiol and FSH levels. Clinical trial number: not applicable. Data Collection Collected data included the age of onset, age at presentation, presence or absence of menstruation, age at menarche, and disease duration. Physical examination parameters included height, weight, body mass index (BMI), and Tanner staging (Yeh et al., 2021). Hormonal assessments measured serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol (E2) using Beckman Coulter assays (USA). The GnRH stimulation test involved administering a subcutaneous injection of leuprorelin at a dose of 2.5 µg/kg to fasting patients before 8 a.m. Blood samples (2 ml) were collected at baseline (0 min) and at 30- and 60-minutes post-injection for LH and FSH measurements. MRI Magnetic resonance imaging (MRI) scans were performed using a 1.5T MRI system (Area, Siemens Healthcare, Erlangen, Germany) equipped with a 16-channel head coil. T2-weighted imaging (T2WI) provided whole-brain structural images in the transverse plane with a TR/TE of 500/11 ms, a matrix size of 224 × 320 mm, a field of view (FOV) of 18.8 × 25.0 cm, and a slice thickness of 1 mm. T1-weighted imaging (T1WI) was conducted in sagittal and coronal planes with a TR/TE of 1600/98 ms, a matrix size of 218 × 256 mm, an FOV of 14 × 14 cm, and a slice thickness of 2.5 mm, focusing on the sellar region. Pituitary gland height and diameter measurements were taken along the pituitary stalk in both sagittal and coronal sections. Data Analysis Quantitative variables with normal distribution were reported as mean ± standard deviation (x ± s), and comparisons between two independent samples were conducted using the t-test. For variables not following a normal distribution, data were presented as medians with interquartile ranges, and the Wilcoxon rank-sum test was employed for group comparisons. Spearman correlation analysis was utilized to assess the relationship between pituitary height and sex hormone levels. Logistic regression analysis, adjusted for age as a confounding variable, was performed to evaluate the influence of pituitary height on the likelihood of ICPP in girls with early breast development, with odds ratios (ORs) serving as relative risk indicators. The diagnostic efficacy of pituitary height and baseline LH levels for ICPP was assessed using receiver operating characteristic (ROC) curve analysis, with the area under the curve (AUC) as the metric for diagnostic performance. All statistical analyses were conducted using SPSS 25.0 software, with a significance threshold of P < 0.05. Ethics Approval Statement This study was approved by the Ethics Committee of the Affiliated Hospital of Zhangzhou, Fujian Medical University. Written informed consent was obtained from all participants’ parents or legal guardians and they were all consented to participate. Results Comparison of Hormones The study analyzed 112 female participants, divided into two groups: 52 in the premature thelarche (PT) group and 60 in the idiopathic central precocious puberty (ICPP) group. The mean age of the PT group was 7.20 ± 0.82 years, while the mean age of the ICPP group was 7.40 ± 1.12 years. The age difference between the groups was not statistically significant (t = 0.9876, P = 0.326). Hormone level comparisons revealed that the PT group had a median baseline LH level of 0.20 (0.10, 0.30) mIU/ml, baseline FSH of 2.91 (1.33, 4.55) mIU/ml, peak FSH of 16.75 (9.44, 20.13) mIU/ml, peak LH of 2.95 (1.83, 3.95) mIU/ml, and an LH peak/FSH peak ratio of 0.20 (0.14, 0.3). In contrast, the ICPP group exhibited higher levels, with a median baseline LH of 0.80 (0.33, 1.38) mIU/ml, baseline FSH of 4.77 (2.74, 6.35) mIU/ml, peak FSH of 17.20 (14.81, 23.44) mIU/ml, peak LH of 16.40 (11.60, 26.90) mIU/ml, and an LH peak/FSH peak ratio of 1.10 (0.83, 1.49). The Wilcoxon rank-sum test showed significant differences between the two groups for all hormone levels except for estradiol (E2) (P < 0.0001) (Table 1 ). Table 1 Comparison of hormones between PT and ICPP group Variants PT Median (IQR) ICPP Median (IQR) P Basal LH(mIU/ML) 0.20 (0.10, 0.30) 0.8 (0.33, 1.38) < 0.001 Basal FSH(mIU/ML) 2.91 (1.33, 4.55) 4.77 (2.74, 6.35) < 0.001 Max FSH(mIU/ML) 16.75 (9.44, 20.13) 17.20 (14.81, 23.44) < 0.001 Max LH(mIU/ML) 2.95 (1.83, 3.95) 16.40 (11.60, 26.90) < 0.001 Max LH/FSH 0.20 (0.14, 0.3) 1.1 (0.83, 1.49) < 0.001 E2(pg/ml) 26.50 (10.75, 34.00) 33.00 (24.00, 54.50) 0.075 Comparison of Pituitary Height The average pituitary height was 4.15 ± 0.75 mm in the PT group and 5.61 ± 1.0 mm in the ICPP group. An independent two-sample t-test revealed a statistically significant difference in pituitary height between the two groups (P < 0.001), with the ICPP group displaying a greater pituitary height ( Figure. 1 ). Correlation of Pituitary Height with Basal LH, Peak LH, and LH/FSH Ratio Positive correlations were observed between pituitary height and baseline LH, peak LH, and the LH/FSH peak ratio. Spearman correlation coefficients were 0.35 (P = 0.006), 0.28 (P = 0.03), and 0.26 (P = 0.04), respectively, indicating that increased pituitary height was associated with higher baseline LH, peak LH, and LH/FSH ratio levels. Diagnostic Value of Pituitary Height in ICPP Logistic regression analysis, adjusted for age, demonstrated a strong association between pituitary height and ICPP, with an odds ratio (OR) of 18 (P < 0.001, Fig. 2 A). This analysis suggested that for every 0.1-millimeter increase in pituitary height, the likelihood of developing ICPP increased by 18 times in girls with early breast development. The diagnostic efficacy of pituitary height was further evaluated using receiver operating characteristic (ROC) curve analysis. The area under the curve (AUC) for pituitary height in diagnosing ICPP was 0.915 (95% CI: 0.85, 0.96) (Fig. 2 B), with a P-value of < 0.001. An optimal cutoff value of 4.7 mm yielded a sensitivity of 90% and a specificity of 86.5%, signifying high diagnostic accuracy. Baseline LH levels were also assessed for diagnostic performance through ROC curve analysis, which revealed an AUC of 0.83 (95% CI: 0.75, 0.90) (Fig. 2 B), with a significant P-value of < 0.001. The optimal cutoff value was 0.3 mIU/ml, providing a sensitivity of 75% and a specificity of 87%. When combining pituitary height and baseline LH levels, the diagnostic test showed an improved sensitivity of 95%, specificity of 82%, and an AUC of 0.92 (95% CI: 0.86, 0.97) (Fig. 2 B), with a P-value of < 0.001. These results indicate that the combined use of pituitary height and baseline LH levels constitutes a highly effective diagnostic approach for ICPP. Discussion This study confirms that pituitary height is significantly elevated in girls with ICPP and correlates closely with both baseline and stimulated LH levels. Combining these measures produced superior diagnostic performance, highlighting the value of integrating imaging and hormonal data in clinical practice. Among the indicators, basal LH levels—closely linked to pubertal activation—have been proposed as potential predictors for CPP. Currently, basal LH is the primary single-factor predictor in clinical practice. Studies employing chemiluminescent immunoassay for LH detection have indicated a cutoff value of > 0.3 IU/L, which yields sensitivities ranging from 35–79% with 100% specificity 19 . However, basal LH cutoff thresholds have varied considerably from 0.10 to 0.83 IU/L, demonstrating consistent specificity but variable sensitivity, which can result in missed diagnoses. While an LH cutoff of > 0.83 IU/L might enhance predictive performance, it does not entirely exclude CPP in girls with lower basal LH levels 20 . Advanced predictive models using machine learning algorithms such as XGBoost and random forest have been developed to improve diagnostic accuracy 14 . While these multifactorial models show high sensitivity and specificity, their complexity may hinder routine clinical use 15 , 21 , 22 . Pituitary gland height and morphology change significantly from infancy to adolescence, closely reflecting age-related endocrine activity 23 . In infancy, the hypothalamic-pituitary-gonadal axis (HPGA) exhibits high activity, resulting in increased estrogen levels and a more prominent pituitary gland. As the central nervous system exerts an inhibitory effect on GnRH secretion, this activity decreases, leading to a flattening of the pituitary gland's upper border. Minimal morphological changes are observed during childhood, characterized by slow linear growth. During puberty, reduced inhibitory control allows for increased GnRH pulse secretion, driving rapid pituitary development and enhanced gonadotropin release. This change is particularly marked in adolescent girls, where the pituitary gland adopts a more spherical shape indicative of pubertal activation 24 . ICPP is primarily driven by premature activation of the HPGA, manifesting as characteristic pubertal changes in the pituitary gland 25 . Assessing these changes is critical for diagnosing ICPP. MRI serves as an effective method for evaluating pituitary size and morphology, providing a valuable diagnostic reference for ICPP 11 , 16 , 22 , 23 . In a study conducted by Pérignon et al., MRI measurements of pituitary height in girls under the age of 8 with early breast development revealed that classical CPP cases presented with pituitary heights exceeding normal pubertal ranges, distinguishing them from milder cases that exhibited typical pituitary heights 26 . Lurie et al. also affirmed that pituitary height is a reliable marker for overall pituitary size 27 . Positive correlations were found between pituitary height and baseline LH (Spearman correlation coefficient of 0.35, P = 0.006), peak LH (0.28, P = 0.03), and the LH/FSH peak ratio (0.26, P = 0.04), supporting the utility of pituitary height as a diagnostic marker for ICPP. The AUC for basal LH in diagnosing ICPP was 0.83 (95% CI: 0.75, 0.90), indicating good discriminative capability with an optimal cutoff of 0.3 mIU/ml, yielding 75% sensitivity and 87% specificity. The variability in LH levels, due to its pulsatile nature and differences in assay methodologies, contributes to diagnostic challenges, as approximately 50% of Tanner stage 1 girls may present with prepubertal basal LH levels 20 . Our findings suggest that a pituitary height of > 4.7 mm, in conjunction with basal LH > 0.3 mIU/ml, offers significant diagnostic value. The combination of these parameters provided a sensitivity of 95%, specificity of 82%, and an AUC of 0.92 (95% CI: 0.86, 0.97, P < 0.001), indicating a robust diagnostic approach for ICPP. Limitations We acknowledge that 2.5 mm slice thickness limits resolution, compared to modern 3D volumetric imaging. Additionally, contrast-enhanced imaging, which would allow exclusion of microadenomas, was not performed. However, these limitations reflect real-world practice in many pediatric units, making these findings relevant to routine clinical care. To enhance generalizability, future multi-center studies should validate these thresholds across populations and imaging systems. Combining MRI with pelvic ultrasound could further strengthen the diagnostic algorithm. Conclusion Combining pituitary height with baseline LH offers a sensitive, non-invasive diagnostic approach for distinguishing ICPP from PT. This strategy is especially valuable in primary care settings where full stimulation testing may be impractical. Future research should validate this approach using prospective, multi-center cohorts with optimized imaging. Declarations Data availability The raw data in the manuscript are available upon request. All requests for data will be reviewed by the Ethical Review Committee for Biomedical Research at the hospital and that data sharing will be conducted in compliance with relevant ethical guidelines and regulations. Acknowledgements The authors gratefully thank the parents and children who have been generous with their time for participating in our research. Consent to Publish & Conflict of Interest Statement All the authors are consented to publish the paper and declare no competing interests. Funding This research received no specific grant from any funding agency, commercial entity, or not-for-profit organization. Authors’ Contributions Study design: Xu Zhang, Jinshui He. Data collection: Haiming Cai, Cuimei Zhang. Data analysis: Xiaochun Shen, Jinshui He. Manuscript drafting: Xu Zhang, Jinshui He. All authors reviewed and approved the final manuscript. References Nebesio TD, Eugster EA. Current Concepts in Normal and Abnormal Puberty. Curr Probl Pediatr Adolesc Health Care. 2007;37:50–72. Lee PA et al. Efficacy of Leuprolide Acetate 1-Month Depot for Central Precocious Puberty (CPP): Growth Outcomes During a Prospective, Longitudinal Study. Int J Pediatr Endocrinol 2011, 7 (2011). Soriano-Guillén L, et al. Central Precocious Puberty in Children Living in Spain: Incidence, Prevalence, and Influence of Adoption and Immigration. J Clin Endocrinol Metabolism. 2010;95:4305–13. Fuqua JS. Treatment and Outcomes of Precocious Puberty: An Update. J Clin Endocrinol Metabolism. 2013;98:2198–207. Marshall WA, Tanner JM. Variations in the Pattern of Pubertal Changes in Boys. Arch Dis Child. 1970;45:13–23. Marshall WA, Tanner JM. 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Size, shape, and appearance of the normal female pituitary gland. Am J Roentgenol. 1984;143:377–81. Latronico AC, Brito VN, Carel J-C. Causes, diagnosis, and treatment of central precocious puberty. Lancet Diabetes Endocrinol. 2016;4:265–74. Pérignon F, Brauner R, Argyropoulou M, Brunelle F. Precocious puberty in girls: pituitary height as an index of hypothalamo-pituitary activation. J Clin Endocrinol Metab. 1992;75:1170–2. Lurie SN et al. In Vivo Assessment of Pituitary Gland Volume with Magnetic Resonance Imaging: The Effect of Age*. The Journal of Clinical Endocrinology & Metabolism 71, 505–508 (1990). Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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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-6208100","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":438357764,"identity":"424e811d-625d-4647-b1b1-e46fb8f3a2e8","order_by":0,"name":"Xu Zhang","email":"","orcid":"","institution":"Affiliated Hospital of Zhangzhou, Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xu","middleName":"","lastName":"Zhang","suffix":""},{"id":438357765,"identity":"3e4d2765-c658-45c3-9f0b-da47c7b19606","order_by":1,"name":"Haiming Cai","email":"","orcid":"","institution":"Affiliated Hospital of Zhangzhou, Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Haiming","middleName":"","lastName":"Cai","suffix":""},{"id":438357766,"identity":"9a590c0f-56fe-4126-9a0c-259c1357cada","order_by":2,"name":"Cuimei Zhang","email":"","orcid":"","institution":"Affiliated Hospital of Zhangzhou, Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Cuimei","middleName":"","lastName":"Zhang","suffix":""},{"id":438357767,"identity":"4419706a-56b0-464b-9190-86012d9632b5","order_by":3,"name":"Xiaochun Shen","email":"","orcid":"","institution":"Affiliated Hospital of Zhangzhou, Fujian Medical University","correspondingAuthor":false,"prefix":"","firstName":"Xiaochun","middleName":"","lastName":"Shen","suffix":""},{"id":438357768,"identity":"2b4243a8-2f7d-4d4e-a07c-b043888625bb","order_by":4,"name":"Jinshui He","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyUlEQVRIiWNgGAWjYBACxmYGBmYGBgkGAwbmAwc+/CBNC1viwZk9RNrEDCIMGHiMD3OwEaO8nffw58I2CwZz9p4Phxl4GOT5xQ4QchhfmvTMNgkGy56zGw4XWDAYzpydQEgLjxkzL1CLwY3cDYdn8DAkGNwmrMX4M1jL/TcPDvOwEafFQBpiCw8D0VrMpHnOAbWcSTMABrIEYb8Y9p8x/sxTVsdgcPzw4w8fftjI80sT0tIAoeuhtAR+5SAgT1jJKBgFo2AUjHgAAHZePlv0u31WAAAAAElFTkSuQmCC","orcid":"","institution":"Affiliated Hospital of Zhangzhou, Fujian Medical University","correspondingAuthor":true,"prefix":"","firstName":"Jinshui","middleName":"","lastName":"He","suffix":""}],"badges":[],"createdAt":"2025-03-12 03:23:08","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6208100/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6208100/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":80581482,"identity":"8547d27b-0820-4f4d-aeab-9060e7a751c5","added_by":"auto","created_at":"2025-04-14 23:21:12","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":36628,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eMeasurement of pituitary height on mid-sagittal T1-weighted MRI.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe pituitary height was measured perpendicular to the sellar floor at the point of maximal gland height (dashed line). This technique follows established pediatric imaging guidelines for pituitary assessment. In patients with idiopathic central precocious puberty (ICPP), the pituitary height was significantly greater compared to patients with premature thelarche (PT), reflecting physiological hypertrophy of the gland associated with early activation of the hypothalamic-pituitary-gonadal axis.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6208100/v1/5fd3e87c5ae7adacdc95ea7b.png"},{"id":80581484,"identity":"c6cb9222-1fee-494d-bf99-e50f665e0184","added_by":"auto","created_at":"2025-04-14 23:21:12","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":61271,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eReceiver operating characteristic (ROC) curves for distinguishing idiopathic central precocious puberty (ICPP) from premature thelarche (PT).\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe ROC curve demonstrates the diagnostic performance of pituitary height alone (AUC = 0.915), baseline luteinizing hormone (LH) alone (AUC = 0.83), and the combined model of pituitary height and baseline LH (AUC = 0.92). Combining both markers achieved optimal sensitivity and specificity, supporting the value of an integrated imaging-endocrine approach for the early diagnosis of ICPP.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6208100/v1/8ef10ed86a0510ef92c3d91e.png"},{"id":82884116,"identity":"bfd16882-b6d7-4d37-9e20-aeab3dae5fb0","added_by":"auto","created_at":"2025-05-16 11:31:47","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":704634,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6208100/v1/5371e4eb-659f-418e-bef2-d3eabfeee181.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Combining Pituitary Height and Basal LH for Diagnosing Idiopathic Central Precocious Puberty: A Retrospective Study of 130 Girls","fulltext":[{"header":"Introduction","content":"\u003cp\u003eCentral precocious puberty (CPP) is a prevalent pediatric endocrine disorder characterized by the premature activation of the hypothalamic-pituitary-gonadal axis (HPGA). This early activation results in the accelerated development of internal and external genitalia and the emergence of secondary sexual characteristics in girls younger than 8 and boys younger than 9 (ref\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e). The incidence of CPP is estimated to range between 1 in 10,000 and 1 in 5,000, with a markedly higher prevalence in girls\u0026mdash;occurring 5 to 20 times more frequently than in boys\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Diagnostic criteria for CPP in girls include early onset of secondary sexual characteristics such as breast development, pubic hair growth, and menarche before the age of 8, accompanied by elevated serum gonadotropin and sex hormone levels consistent with puberty \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Additional features may include advanced bone age and accelerated growth, with palpable breast nodules being the most commonly observed clinical manifestation \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe pituitary gland, a crucial component of the endocrine system, is located beneath the hypothalamus and plays an essential role in regulating neuroendocrine functions. It achieves this by responding to hypothalamic releasing hormones and secreting various trophic hormones. This regulatory function is particularly significant during childhood sexual development, mediated through the HPGA\u003csup\u003e\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e. During puberty, the pituitary gland undergoes notable morphological changes, often expanding upward beyond the sella turcica and adopting a more spherical shape \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. These changes are more pronounced in females, where the pituitary size can increase up to 10 mm, reflecting physiological hypersecretion. Variations in pituitary size are particularly evident in the vertical diameter during puberty, with relatively smaller alterations in the sagittal and coronal diameters\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. The sagittal diameter is considered the most reliable measurement due to its consistent midpoint positioning, whereas the coronal diameter may vary with different imaging planes. Studies have demonstrated significant differences in pituitary height between children diagnosed with CPP and their age-matched peers, correlating with characteristic pubertal changes\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe GnRH stimulation test remains a cornerstone in the diagnosis of CPP, distinguishing it from peripheral precocious puberty\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. In 2015, the \"Diagnosis and Treatment Consensus on Central Precocious Puberty\" identified the GnRH stimulation test as the gold standard for CPP diagnosis, widely implemented in clinical settings. Nevertheless, this test is associated with several limitations\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e: (1) The challenge of sourcing natural GnRH has led to the use of GnRH analogs, which, due to their more potent stimulatory effect, require laboratories to establish diagnostic thresholds\u0026mdash;posing difficulties for primary care institutions. (2) The \"priming effect\" of GnRH analogs may accelerate the progression of sexual development. (3) The test necessitates multiple blood draws, which can cause significant discomfort and psychological distress in children.\u003c/p\u003e \u003cp\u003eAdvancements in magnetic resonance imaging (MRI) technology offer a non-invasive diagnostic alternative\u003csup\u003e\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e. MRI-based pituitary measurements have the potential to mitigate some limitations associated with the GnRH stimulation test. This study aims to assess differences in pituitary height between patients with premature thelarche (PT) and those with idiopathic central precocious puberty (ICPP). Furthermore, it evaluates the diagnostic utility of pituitary height in identifying ICPP and explores the potential of integrating baseline LH levels with pituitary height measurements for enhanced diagnostic accuracy.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eSubjects\u003c/h2\u003e \u003cp\u003eThis study comprised 130 female children who presented with breast enlargement at the Pediatric Department of Fujian Medical University Affiliated Zhangzhou Hospital between February 2020 and December 2021. Diagnoses were established based on the \"Diagnosis and Treatment Guidelines for Precocious Puberty (Trial)\" issued by the Ministry of Health of the People's Republic of China (2010) and the revised \"Diagnosis and Treatment Consensus for Central Precocious Puberty\" by the Endocrinology and Metabolism Group of the Chinese Pediatric Society (2015). The diagnostic criteria for central precocious puberty (CPP) included the early onset of secondary sexual characteristics, such as breast development before the age of 8, accelerated growth surpassing typical rates for children, bone age exceeding chronological age by one year or more, enlarged gonads with increased uterine and ovarian volume on pelvic ultrasound, and the presence of multiple ovarian follicles larger than 4 mm in diameter. Elevated gonadotropin and sex hormone levels consistent with puberty indicated activation of the hypothalamic-pituitary-gonadal axis. Idiopathic central precocious puberty (ICPP) was diagnosed after secondary causes were excluded. Diagnosis of premature thelarche (PT) was defined as incomplete precocious puberty, characterized by isolated breast development without other signs of sexual maturation, no accelerated growth or advanced bone age, absence of vaginal bleeding, and mildly elevated baseline estradiol and FSH levels. Clinical trial number: not applicable.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eData Collection\u003c/h3\u003e\n\u003cp\u003eCollected data included the age of onset, age at presentation, presence or absence of menstruation, age at menarche, and disease duration. Physical examination parameters included height, weight, body mass index (BMI), and Tanner staging (Yeh et al., 2021). Hormonal assessments measured serum levels of luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol (E2) using Beckman Coulter assays (USA). The GnRH stimulation test involved administering a subcutaneous injection of leuprorelin at a dose of 2.5 \u0026micro;g/kg to fasting patients before 8 a.m. Blood samples (2 ml) were collected at baseline (0 min) and at 30- and 60-minutes post-injection for LH and FSH measurements.\u003c/p\u003e\n\u003ch3\u003eMRI\u003c/h3\u003e\n\u003cp\u003eMagnetic resonance imaging (MRI) scans were performed using a 1.5T MRI system (Area, Siemens Healthcare, Erlangen, Germany) equipped with a 16-channel head coil. T2-weighted imaging (T2WI) provided whole-brain structural images in the transverse plane with a TR/TE of 500/11 ms, a matrix size of 224 \u0026times; 320 mm, a field of view (FOV) of 18.8 \u0026times; 25.0 cm, and a slice thickness of 1 mm. T1-weighted imaging (T1WI) was conducted in sagittal and coronal planes with a TR/TE of 1600/98 ms, a matrix size of 218 \u0026times; 256 mm, an FOV of 14 \u0026times; 14 cm, and a slice thickness of 2.5 mm, focusing on the sellar region. Pituitary gland height and diameter measurements were taken along the pituitary stalk in both sagittal and coronal sections.\u003c/p\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eData Analysis\u003c/h2\u003e \u003cp\u003eQuantitative variables with normal distribution were reported as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (x\u0026thinsp;\u0026plusmn;\u0026thinsp;s), and comparisons between two independent samples were conducted using the t-test. For variables not following a normal distribution, data were presented as medians with interquartile ranges, and the Wilcoxon rank-sum test was employed for group comparisons. Spearman correlation analysis was utilized to assess the relationship between pituitary height and sex hormone levels. Logistic regression analysis, adjusted for age as a confounding variable, was performed to evaluate the influence of pituitary height on the likelihood of ICPP in girls with early breast development, with odds ratios (ORs) serving as relative risk indicators. The diagnostic efficacy of pituitary height and baseline LH levels for ICPP was assessed using receiver operating characteristic (ROC) curve analysis, with the area under the curve (AUC) as the metric for diagnostic performance. All statistical analyses were conducted using SPSS 25.0 software, with a significance threshold of P\u0026thinsp;\u0026lt;\u0026thinsp;0.05.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eEthics Approval Statement\u003c/h3\u003e\n\u003cp\u003e This study was approved by the Ethics Committee of the Affiliated Hospital of Zhangzhou, Fujian Medical University. Written informed consent was obtained from all participants\u0026rsquo; parents or legal guardians and they were all consented to participate.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eComparison of Hormones\u003c/h2\u003e \u003cp\u003eThe study analyzed 112 female participants, divided into two groups: 52 in the premature thelarche (PT) group and 60 in the idiopathic central precocious puberty (ICPP) group. The mean age of the PT group was 7.20\u0026thinsp;\u0026plusmn;\u0026thinsp;0.82 years, while the mean age of the ICPP group was 7.40\u0026thinsp;\u0026plusmn;\u0026thinsp;1.12 years. The age difference between the groups was not statistically significant (t\u0026thinsp;=\u0026thinsp;0.9876, P\u0026thinsp;=\u0026thinsp;0.326).\u003c/p\u003e \u003cp\u003eHormone level comparisons revealed that the PT group had a median baseline LH level of 0.20 (0.10, 0.30) mIU/ml, baseline FSH of 2.91 (1.33, 4.55) mIU/ml, peak FSH of 16.75 (9.44, 20.13) mIU/ml, peak LH of 2.95 (1.83, 3.95) mIU/ml, and an LH peak/FSH peak ratio of 0.20 (0.14, 0.3). In contrast, the ICPP group exhibited higher levels, with a median baseline LH of 0.80 (0.33, 1.38) mIU/ml, baseline FSH of 4.77 (2.74, 6.35) mIU/ml, peak FSH of 17.20 (14.81, 23.44) mIU/ml, peak LH of 16.40 (11.60, 26.90) mIU/ml, and an LH peak/FSH peak ratio of 1.10 (0.83, 1.49). The Wilcoxon rank-sum test showed significant differences between the two groups for all hormone levels except for estradiol (E2) (P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\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\u003eComparison of hormones between PT and ICPP group\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=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" 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\u003eVariants\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePT\u003c/p\u003e \u003cp\u003e\u003cem\u003eMedian (IQR)\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eICPP\u003c/p\u003e \u003cp\u003e\u003cem\u003eMedian (IQR)\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBasal LH(mIU/ML)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.20 (0.10, 0.30)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.8 (0.33, 1.38)\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\u003eBasal FSH(mIU/ML)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.91 (1.33, 4.55)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4.77 (2.74, 6.35)\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\u003eMax FSH(mIU/ML)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e16.75 (9.44, 20.13)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e17.20 (14.81, 23.44)\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\u003eMax LH(mIU/ML)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e2.95 (1.83, 3.95)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16.40 (11.60, 26.90)\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\u003eMax LH/FSH\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0.20 (0.14, 0.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.1 (0.83, 1.49)\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\u003eE2(pg/ml)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e26.50 (10.75, 34.00)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e33.00 (24.00, 54.50)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.075\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eComparison of Pituitary Height\u003c/h3\u003e\n\u003cp\u003eThe average pituitary height was 4.15\u0026thinsp;\u0026plusmn;\u0026thinsp;0.75 mm in the PT group and 5.61\u0026thinsp;\u0026plusmn;\u0026thinsp;1.0 mm in the ICPP group. An independent two-sample t-test revealed a statistically significant difference in pituitary height between the two groups (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), with the ICPP group displaying a greater pituitary height (\u003cb\u003eFigure. 1\u003c/b\u003e).\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eCorrelation of Pituitary Height with Basal LH, Peak LH, and LH/FSH Ratio\u003c/h2\u003e \u003cp\u003ePositive correlations were observed between pituitary height and baseline LH, peak LH, and the LH/FSH peak ratio. Spearman correlation coefficients were 0.35 (P\u0026thinsp;=\u0026thinsp;0.006), 0.28 (P\u0026thinsp;=\u0026thinsp;0.03), and 0.26 (P\u0026thinsp;=\u0026thinsp;0.04), respectively, indicating that increased pituitary height was associated with higher baseline LH, peak LH, and LH/FSH ratio levels.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eDiagnostic Value of Pituitary Height in ICPP\u003c/h2\u003e \u003cp\u003eLogistic regression analysis, adjusted for age, demonstrated a strong association between pituitary height and ICPP, with an odds ratio (OR) of 18 (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001, Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA). This analysis suggested that for every 0.1-millimeter increase in pituitary height, the likelihood of developing ICPP increased by 18 times in girls with early breast development.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eThe diagnostic efficacy of pituitary height was further evaluated using receiver operating characteristic (ROC) curve analysis. The area under the curve (AUC) for pituitary height in diagnosing ICPP was 0.915 (95% CI: 0.85, 0.96) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB), with a P-value of \u0026lt;\u0026thinsp;0.001. An optimal cutoff value of 4.7 mm yielded a sensitivity of 90% and a specificity of 86.5%, signifying high diagnostic accuracy.\u003c/p\u003e \u003cp\u003eBaseline LH levels were also assessed for diagnostic performance through ROC curve analysis, which revealed an AUC of 0.83 (95% CI: 0.75, 0.90) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB), with a significant P-value of \u0026lt;\u0026thinsp;0.001. The optimal cutoff value was 0.3 mIU/ml, providing a sensitivity of 75% and a specificity of 87%.\u003c/p\u003e \u003cp\u003eWhen combining pituitary height and baseline LH levels, the diagnostic test showed an improved sensitivity of 95%, specificity of 82%, and an AUC of 0.92 (95% CI: 0.86, 0.97) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB), with a P-value of \u0026lt;\u0026thinsp;0.001. These results indicate that the combined use of pituitary height and baseline LH levels constitutes a highly effective diagnostic approach for ICPP.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis study confirms that pituitary height is significantly elevated in girls with ICPP and correlates closely with both baseline and stimulated LH levels. Combining these measures produced superior diagnostic performance, highlighting the value of integrating imaging and hormonal data in clinical practice.\u003c/p\u003e \u003cp\u003eAmong the indicators, basal LH levels\u0026mdash;closely linked to pubertal activation\u0026mdash;have been proposed as potential predictors for CPP. Currently, basal LH is the primary single-factor predictor in clinical practice. Studies employing chemiluminescent immunoassay for LH detection have indicated a cutoff value of \u0026gt;\u0026thinsp;0.3 IU/L, which yields sensitivities ranging from 35\u0026ndash;79% with 100% specificity\u003csup\u003e19\u003c/sup\u003e. However, basal LH cutoff thresholds have varied considerably from 0.10 to 0.83 IU/L, demonstrating consistent specificity but variable sensitivity, which can result in missed diagnoses. While an LH cutoff of \u0026gt;\u0026thinsp;0.83 IU/L might enhance predictive performance, it does not entirely exclude CPP in girls with lower basal LH levels\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Advanced predictive models using machine learning algorithms such as XGBoost and random forest have been developed to improve diagnostic accuracy\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. While these multifactorial models show high sensitivity and specificity, their complexity may hinder routine clinical use\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003ePituitary gland height and morphology change significantly from infancy to adolescence, closely reflecting age-related endocrine activity\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. In infancy, the hypothalamic-pituitary-gonadal axis (HPGA) exhibits high activity, resulting in increased estrogen levels and a more prominent pituitary gland. As the central nervous system exerts an inhibitory effect on GnRH secretion, this activity decreases, leading to a flattening of the pituitary gland's upper border. Minimal morphological changes are observed during childhood, characterized by slow linear growth. During puberty, reduced inhibitory control allows for increased GnRH pulse secretion, driving rapid pituitary development and enhanced gonadotropin release. This change is particularly marked in adolescent girls, where the pituitary gland adopts a more spherical shape indicative of pubertal activation\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eICPP is primarily driven by premature activation of the HPGA, manifesting as characteristic pubertal changes in the pituitary gland\u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. Assessing these changes is critical for diagnosing ICPP. MRI serves as an effective method for evaluating pituitary size and morphology, providing a valuable diagnostic reference for ICPP\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e,\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. In a study conducted by P\u0026eacute;rignon et al., MRI measurements of pituitary height in girls under the age of 8 with early breast development revealed that classical CPP cases presented with pituitary heights exceeding normal pubertal ranges, distinguishing them from milder cases that exhibited typical pituitary heights\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e. Lurie et al. also affirmed that pituitary height is a reliable marker for overall pituitary size\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003ePositive correlations were found between pituitary height and baseline LH (Spearman correlation coefficient of 0.35, P\u0026thinsp;=\u0026thinsp;0.006), peak LH (0.28, P\u0026thinsp;=\u0026thinsp;0.03), and the LH/FSH peak ratio (0.26, P\u0026thinsp;=\u0026thinsp;0.04), supporting the utility of pituitary height as a diagnostic marker for ICPP. The AUC for basal LH in diagnosing ICPP was 0.83 (95% CI: 0.75, 0.90), indicating good discriminative capability with an optimal cutoff of 0.3 mIU/ml, yielding 75% sensitivity and 87% specificity. The variability in LH levels, due to its pulsatile nature and differences in assay methodologies, contributes to diagnostic challenges, as approximately 50% of Tanner stage 1 girls may present with prepubertal basal LH levels \u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Our findings suggest that a pituitary height of \u0026gt;\u0026thinsp;4.7 mm, in conjunction with basal LH\u0026thinsp;\u0026gt;\u0026thinsp;0.3 mIU/ml, offers significant diagnostic value. The combination of these parameters provided a sensitivity of 95%, specificity of 82%, and an AUC of 0.92 (95% CI: 0.86, 0.97, P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), indicating a robust diagnostic approach for ICPP.\u003c/p\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eWe acknowledge that 2.5 mm slice thickness limits resolution, compared to modern 3D volumetric imaging. Additionally, contrast-enhanced imaging, which would allow exclusion of microadenomas, was not performed. However, these limitations reflect real-world practice in many pediatric units, making these findings relevant to routine clinical care. To enhance generalizability, future multi-center studies should validate these thresholds across populations and imaging systems. Combining MRI with pelvic ultrasound could further strengthen the diagnostic algorithm.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eCombining pituitary height with baseline LH offers a sensitive, non-invasive diagnostic approach for distinguishing ICPP from PT. This strategy is especially valuable in primary care settings where full stimulation testing may be impractical. Future research should validate this approach using prospective, multi-center cohorts with optimized imaging.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe raw data in the manuscript are available upon request. All requests for data will be reviewed by the Ethical Review Committee for Biomedical Research at the hospital and that data sharing will be conducted in compliance with relevant ethical guidelines and regulations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors gratefully thank the parents and children who have been generous with their time for participating in our research.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent to Publish \u0026amp; Conflict of Interest Statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll the authors are consented to publish the paper and declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research received no specific grant from any funding agency, commercial entity, or not-for-profit organization.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudy design: Xu Zhang, Jinshui He.\u003c/p\u003e\n\u003cp\u003eData collection: Haiming Cai, Cuimei Zhang.\u003c/p\u003e\n\u003cp\u003eData analysis: Xiaochun Shen, Jinshui He.\u003c/p\u003e\n\u003cp\u003eManuscript drafting: Xu Zhang, Jinshui He.\u003c/p\u003e\n\u003cp\u003eAll authors reviewed and approved the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eNebesio TD, Eugster EA. Current Concepts in Normal and Abnormal Puberty. Curr Probl Pediatr Adolesc Health Care. 2007;37:50\u0026ndash;72.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLee PA et al. Efficacy of Leuprolide Acetate 1-Month Depot for Central Precocious Puberty (CPP): Growth Outcomes During a Prospective, Longitudinal Study. \u003cem\u003eInt J Pediatr Endocrinol\u003c/em\u003e 2011, 7 (2011).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSoriano-Guill\u0026eacute;n L, et al. Central Precocious Puberty in Children Living in Spain: Incidence, Prevalence, and Influence of Adoption and Immigration. J Clin Endocrinol Metabolism. 2010;95:4305\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFuqua JS. Treatment and Outcomes of Precocious Puberty: An Update. J Clin Endocrinol Metabolism. 2013;98:2198\u0026ndash;207.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMarshall WA, Tanner JM. 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Front Endocrinol. 2018;9:410.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKim MS, Park JS, Sung K. J. MR measurement of normal pituitary gland height on midsagittal section: age and sex differentiation. J Korean Radiol Soc. 1992;28:523.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eArgyropoulou MI, Kiortsis DN. MRI of the hypothalamic-pituitary axis in children. Pediatr Radiol. 2005;35:1045\u0026ndash;55.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCarel J-C, et al. Consensus Statement on the Use of Gonadotropin-Releasing Hormone Analogs in Children. Pediatrics. 2009;123:e752\u0026ndash;62.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLuo X, et al. Long-term efficacy and safety of gonadotropin-releasing hormone analog treatment in children with idiopathic central precocious puberty: A systematic review and meta-analysis. Clin Endocrinol (Oxf). 2021;94:786\u0026ndash;96.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eJiang H, et al. Noninvasive radiomics-based method for evaluating idiopathic central precocious puberty in girls. J Int Med Res. 2021;49:030006052199102.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMohieldin A, Mohamed D, Mahmoud M, Fagiri M, Abukonna A. Effect of Age and Gender Variation in Normal Pituitary Gland Height Using Magnetic Resonance Imaging. \u003cem\u003eBJMMR\u003c/em\u003e 18, 1\u0026ndash;8 (2016).\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYadav P, Singhal S, Chauhan S, Harit S. MRI Evaluation of Size and Shape of Normal Pituitary Gland: Age and Sex Related Changes. \u003cem\u003eJCDR\u003c/em\u003e (2017) \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.7860/JCDR/2017/31034.10933\u003c/span\u003e\u003cspan address=\"10.7860/JCDR/2017/31034.10933\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAbreu AP, Kaiser UB. Pubertal development and regulation. Lancet Diabetes Endocrinol. 2016;4:254\u0026ndash;64.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBadouraki M, Christoforidis A, Economou I, Dimitriadis AS, Katzos G. Evaluation of pelvic ultrasonography in the diagnosis and differentiation of various forms of sexual precocity in girls. Ultrasound Obstet Gynecol. 2008;32:819\u0026ndash;27.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChen M, Eugster EA. Central Precocious Puberty: Update on Diagnosis and Treatment. Pediatr Drugs. 2015;17:273\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePoomthavorn P, Khlairit P, Mahachoklertwattana P. Subcutaneous Gonadotropin-Releasing Hormone Agonist (Triptorelin) Test for Diagnosing Precocious Puberty. Horm Res Paediatr. 2009;72:114\u0026ndash;9.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYeh S-N, et al. Diagnostic evaluation of central precocious puberty in girls. Pediatr Neonatology. 2021;62:187\u0026ndash;94.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNg SM, Kumar Y, Cody D, Smith CS, Didi M. Cranial MRI scans are indicated in all girls with central precocious puberty. Arch Dis Child. 2003;88:414\u0026ndash;8. discussion 414\u0026ndash;418.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDenk CC, Onderoğlu S, Ilgi S, G\u0026uuml;rcan F. Height of normal pituitary gland on MRI: differences between age groups and sexes. Okajimas Folia Anat Jpn. 1999;76:81\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWolpert S, Molitch M, Goldman J, Wood J. Size, shape, and appearance of the normal female pituitary gland. Am J Roentgenol. 1984;143:377\u0026ndash;81.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLatronico AC, Brito VN, Carel J-C. Causes, diagnosis, and treatment of central precocious puberty. Lancet Diabetes Endocrinol. 2016;4:265\u0026ndash;74.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eP\u0026eacute;rignon F, Brauner R, Argyropoulou M, Brunelle F. Precocious puberty in girls: pituitary height as an index of hypothalamo-pituitary activation. J Clin Endocrinol Metab. 1992;75:1170\u0026ndash;2.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eLurie SN et al. In Vivo Assessment of Pituitary Gland Volume with Magnetic Resonance Imaging: The Effect of Age*. \u003cem\u003eThe Journal of Clinical Endocrinology \u0026amp; Metabolism\u003c/em\u003e 71, 505\u0026ndash;508 (1990).\u003c/span\u003e\u003c/li\u003e\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":"Central Precocious Puberty, Premature Thelarche, MRI, Pituitary Height","lastPublishedDoi":"10.21203/rs.3.rs-6208100/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6208100/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe gonadotropin-releasing hormone (GnRH) stimulation test is the gold standard for diagnosing central precocious puberty (CPP), but it is invasive and inconvenient. Pituitary height measured on MRI may provide a complementary non-invasive marker.\u003c/p\u003e\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eTo evaluate the diagnostic performance of pituitary height for distinguishing idiopathic central precocious puberty (ICPP) from premature thelarche (PT) and to assess whether combining pituitary height with baseline luteinizing hormone (LH) improves accuracy.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThis retrospective study included 130 girls under 8 years presenting with breast development. Pituitary height was measured on sagittal and coronal T1-weighted MRI. Baseline and stimulated gonadotropins were also measured. Diagnostic accuracy was evaluated using ROC analysis, and logistic regression assessed the predictive contribution of pituitary height.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003ePituitary height was significantly greater in the ICPP group (5.61\u0026thinsp;\u0026plusmn;\u0026thinsp;1.00 mm) than in the PT group (4.15\u0026thinsp;\u0026plusmn;\u0026thinsp;0.75 mm; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Pituitary height correlated positively with baseline LH (r\u0026thinsp;=\u0026thinsp;0.35), peak LH (r\u0026thinsp;=\u0026thinsp;0.28), and peak LH/FSH ratio (r\u0026thinsp;=\u0026thinsp;0.26). Logistic regression indicated that each 0.1 mm increase in pituitary height raised the ICPP likelihood 18-fold (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The ROC analysis for pituitary height showed an AUC of 0.915, with a 4.7 mm cutoff providing 90% sensitivity and 86.5% specificity. Combining pituitary height with baseline LH levels improved diagnostic accuracy, yielding an AUC of 0.92, sensitivity of 95%, and specificity of 82%.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eMRI-measured pituitary height, especially when combined with baseline LH, provides a non-invasive, effective diagnostic alternative to the GnRH stimulation test for ICPP.\u003c/p\u003e","manuscriptTitle":"Combining Pituitary Height and Basal LH for Diagnosing Idiopathic Central Precocious Puberty: A Retrospective Study of 130 Girls","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-14 23:21:08","doi":"10.21203/rs.3.rs-6208100/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":"ab6c2e46-fc9f-4eb3-a144-bcac3a6cb684","owner":[],"postedDate":"April 14th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-05-16T11:23:31+00:00","versionOfRecord":[],"versionCreatedAt":"2025-04-14 23:21:08","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6208100","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6208100","identity":"rs-6208100","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}