Correlation analysis of pituitary morphometry in boys with idiopathic central precocious puberty or early puberty: implications for diagnosis

Introduction

Precocious puberty (PP) in boys refers to the development of secondary sexual characteristics (Tanner G2 and/or testicular volume ≥4 mL) before 9 years of age. Central precocious puberty (CPP) is caused by activation of the hypothalamic-pituitary-gonadal (HPG) axis. The well-established adverse outcomes of CPP notably include compromised adult height attributable to premature epiphyseal fusion. Furthermore, accumulating evidence indicates that earlier pubertal timing may be linked to psychosocial difficulties and a potentially elevated risk of cardiometabolic conditions in later life. However, population-based evidence supporting these associations remains less robust for boys compared to girls (1-3).

Epidemiological data indicate that the incidence of CPP is 1/5,000–10,000 in girls, while in boys it is approximately 1/5 to 1/10 of that in girls (4,5). Notably, studies have demonstrated a rising trend in the incidence of PP among boys, with a faster growth rate compared to girls (6,7). Approximately 90% of CPP cases in girls are idiopathic, and boys with CPP have a higher prevalence of organic central nervous system (CNS) lesions (8-10). Thus, many experts recommend performing brain magnetic resonance imaging (MRI) scans in all boys with CPP to rule out organic CNS causes. Recent studies have found a significant increase in the proportion of idiopathic central precocious puberty (ICPP) among etiological factors in boys. However, research on male ICPP remains limited, and existing male studies have typically included smaller patient cohorts.

Boys with pubertal onset between 9–11 years should be classified as early puberty (EP) rather than PP. In clinical practice, however, intervention may be indicated for late-recognized cases of early maturation (e.g., presentation at age 10 with advanced signs like voice breaking due to previously undetected pubertal progression), requiring concurrent evaluation for pathological etiologies. The utility of routine brain MRI in all such cases remains debated.

MRI morphological indicators have been increasingly recognized as auxiliary diagnostic markers for CPP. Sharafuddin et al. demonstrated that individuals with CPP exhibit greater pituitary height compared to those in the normal population (11,12). Additionally, it has been observed that pituitary volume (PV) tends to increase with age and correlates with hormonal levels (13). Wu et al. conducted MRI examinations on 258 girls to explore the discriminative value of pituitary morphology for CPP and premature thelarche, and found that PV is a predictive marker for ICPP, with a sensitivity of 54.10% and a specificity of 72.20% at a cutoff value of 196.01 mm³ (14). However, research on the morphological characteristics of the pituitary in male children with CPP remains limited, with existing studies often constrained by small sample sizes and the lack of standardized measurement methods.

Therefore, utilizing pituitary MRI data from boys with CPP/EP at our institution, this study aims to investigate the diagnostic potential of pituitary morphometry for differentiating idiopathic CPP from EP in male populations. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-391/rc).

Methods

Subjects

This retrospective study included patients diagnosed with ICPP and EP at the Department of Endocrinology, Children’s Hospital Capital Institute of Pediatrics, Beijing, between January 2015 and December 2024. Patients with incomplete clinical data or incomplete pituitary morphological indicators were excluded. A total of 118 boys were ultimately included. The control group consisted of 236 normal children matched for age and gender during the same period. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of the Capital Center for Children’s Health (No. SHERLLM2025027). Written informed consent was waived due to the retrospective nature of the study.

Detection indicators

The data of the patients recorded in the hospital’s information management system were retrospectively analyzed. Information on patients’ age, height, weight, testicular volume, body mass index (BMI), bone age, serum basal luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, insulin-like growth factor 1 (IGF-1), anti-Müllerian hormone (AMH), peak LH and FSH levels following a gonadotropin-releasing hormone (GnRH) stimulation test, pituitary/brain MRI results at diagnosis, and ultrasonic testicular volume was collected.

The BMI was calculated by dividing weight in kilograms by height in meters squared. Bone age was assessed using the Greulich-Pyle scale. Testicular volume was measured using the Prader orchidometer, and high-frequency ultrasonography (ARIETTA70, ALOKA, Tokyo, Japan) was also performed, with volume calculated using the formula V = length (L) × width (W) × height (H) × 0.71 (15).

MRI was performed using a 3.0-T MRI scanner (Ingenia 3.0T MRI, Philips Healthcare, Best, The Netherlands) with the following scanning parameters: T1-weighted imaging (T1WI) sequence with a repetition time/echo time (TR/TE) ratio of 2.19, and a slice thickness of 1 mm. The PV was calculated by measuring the length, height, and width of the pituitary gland in millimeters. The length and height were measured on the midline sagittal thin section from the posterior wall to the anterior wall, while the width was measured on the thin coronal section from the anterior part of the pituitary stalk to the entrance. The volume was calculated using the Di Chiro formula: PV=½ × L × H × W (16).

The clinical diagnostic basis for the ICPP

Boys diagnosed with ICPP meet the criteria for CPP and exhibit normal findings on pituitary MRI. The diagnostic criteria for CPP are as follows: (I) testicular enlargement occurs before the age of 9.0 years; (II) testicular volume is ≥4 mL; (III) serum levels of gonadotropins and sex hormones reach puberty level; (IV) bone age is advanced by ≥1 year compared to chronological age; (V) linear growth velocity is accelerated. Laboratory criteria for CPP diagnosis include a basal LH level >5 IU/L or a peak LH level >5 IU/L after GnRH stimulation test, with a peak LH/FSH ratio >0.6. For the GnRH stimulation test, triptorelin (0.1 mg/m²) is administered subcutaneously, and blood samples are taken at 0, 30, 60, and 90 minutes to measure LH and FSH levels.

The clinical diagnostic basis for the EP

Diagnostic criteria for EP in boys are as follows: typically, within the first 1–2 years of puberty, our study selects boys who exhibit testicular volume enlargement or voice change between the ages of 9.0 and 11.0 years.

Control group data source

The control group was based on the normal pediatric pituitary database established by our hospital, which includes pituitary MRI measurement data from 236 healthy boys [2:1 per-case age-match; median 9.00 (8.00, 10.00) years]. The measurement methods were consistent with those used in this study.

Statistical analysis

Statistical analysis was conducted using R software (version 4.2.0). Normality of continuous variables was assessed using the Shapiro-Wilk test and Q-Q plots. Non-normally distributed variables were analyzed using non-parametric methods. Pearson and Spearman correlation coefficients were used for normally and non-normally distributed variables, respectively. Logistic regression analysis was employed to evaluate the association between pituitary morphology and PP, with age adjustment. The model’s significance and non-linear relationships were assessed using the likelihood ratio test (LRT). Odds ratios (ORs) and their 95% confidence intervals (95% CIs) were calculated. Restricted cubic splines (RCS) analysis was used to explore non-linear relationships, and optimal cutoff values for pituitary parameters were determined. All tests were two-sided with a significance level of α=0.05. Data are presented as mean ± standard deviation or median [interquartile range].

Results

Clinical baseline characteristics of the case group

As shown in Table 1, height and IGF-1 followed normal distributions, whereas other indicators were non-normally distributed. The median age at presentation was 9.86 years. Obesity was present in 24.6% (29/118) of patients, and overweight in 11.9% (14/118).

Comparison of pituitary MRI results between the case and control groups

Pituitary morphology differed significantly between the case and control groups. The case group exhibited greater median dimensions than controls for all parameters: length (6.70 vs. 6.40 mm; P=0.04), width (11.80 vs. 10.90 mm; P<0.001), height (5.00 vs. 4.70 mm; P=0.03), and volume (201.50 vs. 165.58 mm³; P<0.001) (Table 2, Figure 1).

Figure 1 Violin plots of pituitary metrics for the case and control groups. Group 1 represents the case group, and Group 0 represents the control group. (A) Pituitary length. (B) Pituitary height. (C) Pituitary width. (D) Pituitary volume.

Correlation between age and pituitary morphology

The relationship between age and four pituitary metrics was assessed. Age was found to be positively correlated with pituitary length, width, height, and volume, with a stronger correlation with PV (Corr =0.290, P<0.001). Among the four pituitary morphology metrics, pituitary height and volume showed a strong correlation (Corr =0.757, P<0.001; case group Corr =0.731, P<0.001; control group Corr =0.780, P<0.001) (Figure 2).

Figure 2 Correlation matrix between pituitary parameters. The intensity of color indicates the strength of the correlation coefficient. Corr represents the correlation coefficient. Group 0 represents the control group, and Group 1 represents the case group. Significance levels are indicated as follows: *, P<0.05; **, P<0.01; ***, P<0.001.

Correlation between pituitary morphology and clinical and laboratory findings

According to Spearman correlation analysis, pituitary length was positively correlated with LH (r=0.42, P<0.001). Pituitary width was positively correlated with height (r=0.33, P<0.001), LH (r=0.30, P=0.01), and ultrasound testicular volume (r=0.30, P=0.01). Pituitary height was positively correlated with LH (r=0.43, P<0.001), testosterone (r=0.41, P<0.001), average testicular volume (r=0.41, P<0.001), ultrasound testicular volume (r=0.44, P<0.001), IGF-1 (r=0.45, P<0.001), and bone age (r=0.24, P=0.04). PV was positively correlated with LH (r=0.64, P<0.001), testosterone (r=0.37, P<0.001), average testicular volume (r=0.37, P<0.001), ultrasound testicular volume (r=0.47, P<0.001), IGF-1 (r=0.38, P<0.001), and bone age (r=0.30, P=0.01) (Figure 3, Tables 3,4).

Figure 3 Correlation heatmap for the case group. Blue indicates positive correlation, red indicates negative correlation, and × indicates no correlation. The intensity of the color represents the strength of the correlation. AMH, anti-Müllerian hormone; E2, estradiol levels; FSH, follicle-stimulating hormone; IGF-1, insulin-like growth factor 1; LH, luteinizing hormone; uTV, ultrasound testicular volume.

RCS

To investigate the relationship between pituitary morphology and the diagnosis of ICPP/EP in boys, this study utilized RCS for modeling analysis. The results showed that pituitary width and volume were significantly associated with the risk of ICPP/EP onset (width: P=0.001; volume: P=0.050), with no evidence of nonlinearity (both P-nonlinear >0.05). No significant associations were found for pituitary length or height (length: P=0.052; height: P=0.80). The analysis demonstrated an increasing risk of ICPP/EP with greater pituitary width, showing an optimal cutoff at 13 mm, while a similar rising risk trend was observed for PV with an optimal cutoff at 240 mm³ (Figure 4).

Figure 4 RCS of pituitary morphology. The solid lines indicate the risk of ICPP/EP associated with statistical indicators, and the shaded areas represent the 95% CIs. (A) Pituitary length, (B) Pituitary width, (C) Pituitary height, (D) Pituitary volume. CI, confidence interval; EP, early puberty; ICPP, idiopathic central precocious puberty; RCS, restricted cubic spline.

Multivariate analysis

This study utilized logistic regression to investigate the association between pituitary morphometry and the risk of ICPP/EP in boys. The results indicated that pituitary length was significantly positively correlated with the risk of ICPP/EP onset (OR =1.279, 95% CI: 1.064–1.538, P=0.009), but after adjusting for age, there was no statistically significant difference in the risk of ICPP/EP. After adjusting for age, pituitary width and volume were significantly associated with the risk of ICPP/EP (pituitary width, OR =1.297, 95% CI: 1.126–1.494, P<0.001; PV, OR =1.132, 95% CI: 1.023–1.253, P=0.02). Moreover, for every 1 mm increase in pituitary width, the risk of ICPP/EP increased by 29.7%. For every 30 mm³ increase in PV, the risk of ICPP/EP increased by 13.2%. Pituitary height did not show a statistically significant difference in the risk of ICPP/EP onset (Table 5).

Discussion

This study analyzed pituitary morphology indicators in boys and found that those with ICPP/EP had significantly larger pituitary length, width, height, and volume compared to the control group. Basal LH levels were moderately to strongly correlated with pituitary width, height, and volume; testicular volume was positively correlated with pituitary width, height, and volume; while IGF-1 was only correlated with pituitary height and volume. These pituitary indicators may therefore serve as potential imaging biomarkers for diagnosing ICPP/EP in boys. Logistic regression analysis and RCS curve plotting revealed significant correlations between pituitary width and volume and the risk of ICPP/EP onset, with diagnostic cutoff values of 13 mm and 240 mm³, respectively.

In clinical practice, pituitary width is commonly measured using the coronal view through pituitary MRI. Previous clinical applications of the coronal view have primarily focused on diagnosing pituitary tumors, assessing tumor invasiveness, and diagnosing pituitary inflammation, especially for the diagnosis of pituitary microadenomas, where the coronal view is superior to the sagittal view for detection (17). For MRI studies on children with sexual precocity, past research has concentrated on etiological exploration. In recent years, studies concerning pituitary morphometric indicators have achieved some advancements in the differential diagnosis of PP and premature thelarche development in girls. However, due to the lack of uniformity in the definition of pituitary morphometric indicators across various studies, or the consideration of only certain aspects of these indicators, the diagnostic value of pituitary width in the diagnosis of PP in girls remains to be determined. Previous studies indicated that the sagittal view of imaging is convenient and precise (18), and some researchers have suggested that pituitary height is a better reflection of pituitary development, whereas length is only moderately associated with the development of the cranial base (19). Consequently, in studies of pituitary function, height is often utilized as an indicator. Numerous studies have demonstrated a positive correlation between pituitary height and peak LH, estradiol, and IGF-1 levels in girls (14,20), and that pituitary height and volume have a greater diagnostic value for CPP in girls (14,20,21). However, the findings of this study do not fully align with those previous results. In this research, pituitary height was positively correlated with LH, testosterone, testicular volume, IGF-1, and bone age, but it showed no statistical significance in the risk of ICPP/EP onset in boys, which may reflect sex-specific differences.

Previous animal studies have demonstrated that elevated levels of sex steroids (both exogenous and endogenous) and gonadotropins correlate with increased pituitary cell proliferation (22,23). In human studies, a noticeable increase in PV occurs during puberty, which is more pronounced in girls than in boys, and sex-specific differences are also evident in pituitary height and volume (21,24,25). From an anatomical perspective, the anterior pituitary is divided into the tuberal, intermediate, and distal sections, with the distal section being a crucial part of the anterior lobe and the key area for clinical measurement of pituitary height. It is noteworthy that the weight of the adenohypophysis in females is approximately 20% higher than in males on average, primarily due to the relatively larger volume of the distal section in females. In the cell composition of the anterior pituitary gland, somatropes that secrete growth hormone (GH) account for 40% to 50%, and these cells are mainly distributed in the lateral parts of the anterior pituitary; concurrently, gonadotropes that secrete LH and FSH account for 10% to 15% of the total number of cells in the anterior pituitary, and these cells are widely scattered throughout the entire anterior lobe (26,27). Since the lateral parts are the main distribution areas of somatropes, the size of the distal part of the pituitary, that is, the pituitary height, may have a more significant correlation with the secretion of GH. In this study, the correlation between pituitary height and IGF-1 levels is stronger, thus in developing boys, pituitary height may be more significantly associated with the secretion of GH (16,28). In a study on healthy children, it was further found that the increase in LH, estradiol (in girls), and testosterone levels during puberty is associated with a larger PV (13). In contrast, the relationship between FSH and PV is independent of puberty and is only related to PV in girls during puberty (13). This may be because LH and FSH are differentially regulated by distinct peptides, especially in boys, where FSH is more closely related to inhibin B secreted by Sertoli cells in the testes (29). Inhibin B levels increase earlier and more rapidly in boys than in girls, thus FSH levels in boys are more significantly inhibited (29). This can also explain why, in this study, neither basal FSH nor FSH levels after stimulation were related to the four morphological indicators of the pituitary, nor were they significantly correlated with testicular size or penile length. These sex-specific differences in pituitary indicators and differences in hormone secretion mechanisms may explain why pituitary height was not significantly related to the risk of PP/EP in boys, while it had greater diagnostic value for PP in girls.

In the 118 male patients included in this study, the median basal LH was 3.41 IU/L, FSH was 3.32 IU/L, and testosterone was 7.25 nmol/L. Compared with girls (30), boys have higher LH and FSH levels at diagnosis, which suggests that the enlargement of the testes in boys is more subtle than the breast development in girls. This subtlety makes EP in boys less likely to be detected. This may also be one of the reasons for the sex-specific differences in pituitary morphology during puberty. Our previous etiological study found that among boys presenting with PP, 75.6% were diagnosed with CPP, and 24.4% were diagnosed with peripheral precocious puberty (PPP). In the CPP group, 79% were idiopathic CPP, and 21% were pathologic CPP. The top three causes of PPP were congenital adrenal hyperplasia (CAH), germ cell tumors, and familial male-limited PP (31). Therefore, compared with females, male PP has a more insidious onset and a higher probability of being pathologic, highlighting the greater value of early diagnosis in males.

Furthermore, these data indicate that the HPG axis was already activated in most boys at the time of consultation. For such patients, the diagnosis of CPP may not inherently require pituitary MRI. However, it must be emphasized that, given the higher risk of organic intracranial pathologies in boys with CPP, many experts recommend performing brain MRI to exclude underlying CNS disorders. If MRI is undertaken, our proposed pituitary morphometric criteria (width ≥13 mm, volume ≥240 mm³) can thereby provide valuable auxiliary diagnostic reference, particularly in cases where hormonal levels are borderline or clinical presentation is equivocal. This conclusion has undergone preliminary validation within our region. As an initial exploratory study, our findings warrant further verification through external, multi-center research to confirm their generalizability.

In the current research on PP in boys, most studies focus on etiological analyses, with limited research on idiopathic PP. The application of pituitary MRI in studies of PP in boys has also been restricted to the diagnosis of pathologic conditions. This study innovatively analyzes the pituitary size metrics of a large sample of boys with ICPP/EP, providing a basis for the application of pituitary MRI in the diagnosis of ICPP/EP in boys and proposing potential diagnostic cutoff values.

This study has limitations, including its retrospective design and missing hormonal data in controls, which may constrain analytical depth. Future prospective multicenter studies should validate these findings while investigating pituitary morphology correlations with BMI, family history and other factors to establish a reliable diagnostic model for male PP.

Conclusions

The pituitary width and volume of boys with ICPP/EP are positively correlated with basal LH and testicular volume. Compared with healthy children, pituitary width and volume show statistically significant differences in the risk of ICPP/EP onset, and thus have the potential to serve as auxiliary diagnostic indicators for CPP/EP in boys. Moreover, a pituitary width ≥13 mm or a PV ≥240 mm³ is associated with a significantly increased risk of ICPP/EP onset in boys. However, the clinical application of this quantitative criterion based on MRI still requires further clinical validation.

Acknowledgments

We appreciate the support from the patients and their parents.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-391/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-391/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-391/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-391/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of the Capital Center for Children’s Health (No. SHERLLM2025027). Written informed consent was waived due to the retrospective nature of the study.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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