Hypothalamic-superior frontal gyrus functional connectivity alterations and luteinizing hormone correlations in girls with central precocious puberty

Article information

Ann Pediatr Endocrinol Metab. 2026;31(2):129-137

Publication date (electronic) : 2026 April 30

doi : https://doi.org/10.6065/apem.2550194.097

Hongqiang Cai^1,2,*, Lianzi Su^1,2, Xiyan Chen^1,2,*, Moran Yang^1,2, Jiajia Xu^1,2, Yanqi Shan^1,2, Ru Zhao^1,2, Longsheng Wang^1,2, Yue Yu^,3, Liwei Zou^1,2,4

¹Department of Radiology, the Second Affiliated Hospital of Anhui Medical University, Hefei, China

²Medical Image Research Center, Anhui Medical University, Hefei, China

³Department of Pediatrics, the Second Affiliated Hospital of Anhui Medical University, Hefei, China

⁴Key Laboratory of Population Health Across Life Cycle (Anhui Medical University), Ministry of Education, Hefei, China

Address for correspondence: Liwei Zou Department of Radiology, the Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China Email: zouliwei@ahmu.edu.cn

Address for co-correspondence: Yue Yu Department of Pediatrics, the Second Affiliated Hospital of Anhui Medical University, Hefei, Anhui Province, China Email: landuoeryu@163.com

*These authors contributed equally to this study as co-first authors.

Received 2025 June 5; Revised 2025 August 20; Accepted 2025 August 29.

Abstract

Highlights

· Girls with central precocious puberty show enhanced functional connectivity between right lateral hypothalamus and right superior frontal gyrus that borderline correlates with peak LH levels, while connectivity to fusiform/supramarginal gyri decreases.

· Left lateral hypothalamus displays increased coupling with right cuneus, revealing hemisphere-specific hypothalamic-cortical network alterations linked to central premature pubertal activation.

· These lateral hypothalamic connectivity shifts, absent in medial hypothalamus, provide novel neuroendocrine insights.

Introduction

Precocious puberty is clinically defined as the premature development of secondary sexual traits and somatic growth. This condition is categorized into 2 primary subtypes: central precocious puberty (CPP), resulting from premature activation of the hypothalamuspituitary-gonadal (HPG) axis; and peripheral precocious puberty (PPP), which develops without involvement of HPG axis regulation [1]. This disorder clinically presents with accelerated sexual maturation (diagnostic criteria: <8 years in females, <9 years in males). It is marked by abnormally early surges in gonadotropin levels followed by downstream activation of sex steroid pathways (estrogen/androgen synthesis) [2].

In diagnostic protocols, the gonadotropin-releasing hormone (GnRH) provocation test is widely recognized as the most reliable method for confirming CPP. Luteinizing hormone (LH) levels peaking above 5 IU/L during this procedure, owing to their elevated diagnostic accuracy, serve as a robust indicator of HPG axis activation [3]. Recent studies have demonstrated a rising incidence of CPP in girls [4], which coincides with increased reports of mental health concerns, such as anxiety and social adjustment difficulties, in this population.

CPP is associated with adverse outcomes, including risk-taking behaviors in adolescents, short stature and obesity in adulthood, and elevated risks of diabetes and premenopausal breast cancer in later life [5]. Furthermore, adolescents with CPP are more likely to experience psychological challenges, such as anxiety, depression, irritability, aggression, and medicine abuse, which may persist into adulthood [6-9]. The neuroendocrine mechanisms linking CPP to these physical and psychological consequences remain poorly understood.

Recent advances in resting-state functional magnetic resonance imaging (rs-fMRI) have enabled its application in neuroendocrine research by capturing spontaneous low-frequency blood oxygen level-dependent (BOLD) signal fluctuations [10]. Functional connectivity (FC) is typically assessed using Pearson correlation between seed-region time series and whole-brain voxels. Given the central role of the hypothalamus in endocrine and behavioral regulation, it has attracted particular interest in CPP research [11]. However, owing to its small size and complex subnuclear anatomy, careful region of interest (ROI) definition is necessary, such as the bilateral lateral and medial subregions described by Baroncini et al. [12,13].

Studies have revealed distinct FC alterations in CPP. In a CPP group compared to a PPP group, Chen et al. [14] reported reduced FC between the bilateral insulae and the right middle frontal gyrus (MFG), as well as between the left fusiform gyrus (FFG) and the right amygdala. Higher basal and peak estradiol (E2) levels correlated with increased resting-state FC of the bilateral insulae. Qin et al. [15] revealed increased FC in CPP subjects between the right posterior cerebellar lobe and the bilateral medial prefrontal gyri/posterior cingulate cortex. Strengthened connectivity was also observed between the left cerebellum posterior lobe and the bilateral MFG and bilateral precuneus. Concurrently, they observed attenuated FC between the left superior occipital gyrus and right calcarine.

Previous studies have identified functional abnormalities in multiple brain regions of CPP patients, including the frontal lobe, FFG, insula, posterior cerebellum, and parietal lobe. However, these findings were derived from whole-brain FC analyses, which lacked targeted investigation of hypothalamic involvement in CPP. The present study addressed this gap by focusing on the hypothalamus as the primary ROI. We investigated hypothalamic FC patterns in girls with CPP and analyzed their associations with hormone levels to elucidate the neuroendocrine mechanisms underlying the disorder.

Methods

5. FC analysis

In this study, a ROI analysis approach was employed. In accordance with prior methodologies [13], the hypothalamus was subdivided into lateral and medial regions, resulting in 4 ROIs (left/right hemispheres; detailed in Table 1). For each region, spherical seed ROIs with a 2-mm radius were used for seed-to-voxel whole-brain analysis. Individual FC maps were generated by computing Pearson correlations between the time course of each seed region and the time courses of all whole-brain voxels. These subject-specific FC maps were then Fisher z-transformed to produce z-value maps for subsequent group-level analyses.

Table 1.

Coordinate information of hypothalamic region of interests

Results

1. Results of demographic analysis of the 2 groups

Compared to the non-CPP group, girls with CPP exhibited a significantly higher chronological age (P=0.008) and bone age (P=0.022), along with a lower PH (P=0.016). No statistically significant differences were observed in the other demographic or clinical characteristics, including height, weight, blood pressure, maternal height, or PH. Table 2 summarizes the demographic characteristics of all participants.

Table 2.

Demographic differences between the 2 groups

2. Results of analysis of hormone levels associated with GnRH stimulation experiments

Compared to the non-CPP group, the CPP patients exhibited significantly higher baseline FSH (P<0.001), baseline LH (P<0.001), peak FSH (P=0.028), peak LH (P<0.001), and peak LH/FSH ratios (P<0.001). Significant differences persisted after log10 transformation for baseline FSH (P<0.001), baseline LH (P<0.001), peak FSH (P=0.028), peak LH (P<0.001), and peak LH/FSH ratios (P<0.001). Table 3 summarizes the statistical outcomes of the hormonal profiles obtained via the GnRH stimulation test.

Table 3.

Differences in hormone levels associated with GnRH stimulation experiments between the 2 groups

3. Results of FC analysis between hypothalamus and brain based on hypothalamic ROI coordinates in girls with CPP

As depicted in Supplementary Table 1 and Fig. 1, the CPP group exhibited greater FC between the right lateral hypothalamus and right superior frontal gyrus (SFG) relative to the non-CPP group. In addition, the CPP group showed diminished FC linking the right lateral hypothalamus to both the right FFG and right supramarginal gyrus (SMG). Meanwhile, the CPP group displayed amplified FC between the left lateral hypothalamus and the right cuneus (CUN). However, FC analyses revealed no significant differences between the medial hypothalamus and other regions.

Fig. 1.

Graph of hypothalamic FC differences (P<0.05 [FWER]) between the CPP group compared to the non-CPP group. Increased FC: between the LH. R and the SFG. R (cluster size=58); between the LH. L and the CUN. R (cluster size=44). Decreased FC: between the LH. R and the FFG. R (cluster size=52); between the LH. R and the SMG. R (cluster size=53). In the visualization: Blue dots represent seed points; green dots denote regions with enhanced FC; and red dots represent regions with diminished FC. Lines connecting points are uniform in color and thickness, denoting connections between seed points and brain regions without conveying directionality or connectivity strength. FC, functional connectivity; FWER, family-wise error rate; CPP, central precocious puberty; LH. L, left lateral hypothalamus; LH. R, right lateral hypothalamus; SFG. R, right superior frontal gyrus; CUN. R, right cuneus; FFG. R, right fusiform gyrus; SMG. R, right supramarginal gyrus.

4. Correlation results of hypothalamic FC and GnRH excitation test in CPP girls

Fig. 2 shows that elevated peak LH concentrations exhibited borderline significant correlation with enhanced FC between the right lateral hypothalamic and the right SFG (correlation coefficient [r]=0.362, P=0.050) in the CPP group. The results of correlation analyses of analysis of covariance were the following: age (r=0.224, P=0.122), bone age (r=0.158, P=0.216), and father’s height (r=0.216, P=0.139). Under this analytical approach, no significant correlations were observed between FC and the other parameters.

Fig. 2.

Correlation analysis between FC values and peak LH levels in the CPP group. The seed is the LH. R. The x-axis represents log-transformed peak LH values; the y-axis denotes FC between the LH. R and the SFG. R. All FC values underwent Fisher z-transformation. Enhanced FC values were borderline significantly correlated with peak LH levels (r=0.362, P=0.050). FC, functional connectivity; peak LH, peak luteinizing hormone; CPP, central precocious puberty; LH. R, right lateral hypothalamus; SFG. R, right superior frontal gyrus.

Discussion

The experimental data revealed that CPP-diagnosed girls demonstrated elevated baseline FSH and LH concentrations, along with heightened FSH peaks, LH peaks, and LH/FSH ratio peaks compared with agematched controls of girls without CPP. Enhanced FC was detected between the right lateral hypothalamic area and the right SFG in the CPP subjects, exhibiting borderline significant correlation with peak LH concentrations. In contrast, diminished connectivity patterns emerged between the right lateral hypothalamus and the right FFG/SMG. However, greater connectivity was evident between the left lateral hypothalamic region and the right CUN. Comparative analysis of medial hypothalamic connections demonstrated no statistically significant alterations in FC across examined cerebral areas.

Our findings highlight the critical association between CPP and the lateral hypothalamus, a region integral to the regulation of motivation, metabolism, motor function, and social behavior. The left lateral hypothalamus is implicated in learning, sustained motivation, reward processing, and aggression suppression [17-19], while the right lateral hypothalamus modulates motor control, interference inhibition, and social interaction [17-20]. In the CPP subjects, peak LH levels were borderline significantly correlated with FC in the right lateral hypothalamus. According to one report, androgen exposure reduces mean diffusivity in the lateral hypothalamus [21]. Furthermore, females with depression exhibit elevated lateral hypothalamic hypocretin-1 levels, with estrogen receptors being colocalized alongside hypocretin neurons in this region [22]. Additionally, estrogen-regulated kisspeptin neurons in the lateral septum project extensively to GnRH neurons [23], which could reflect a potential interplay between the lateral hypothalamus, sex hormones, and GnRH signaling in CPP pathogenesis.

Our studies found FC between the right lateral hypothalamic region and right SFG among the CPP subjects. The right SFG is involved in cognitive regulation, emotional processing, and behavioral functioning [24,25]. In the study of Yi et al. [24] the right SFG showed increased FC with the left middle occipital cortex. The right SFG also exhibited heightened FC with the bilateral superior occipital gyri. No similar associations were found for the left SFG. Investigations by Xie et al. [26] found increased amplitude of low-frequency fluctuations within the right SFG among individuals exhibiting HPG axis activation, with these neural oscillations demonstrating positive correlations with the prolactin concentrations. Yu et al. [27] observed reduced regional homogeneity (ReHo) values in the bilateral orbital and medial SFG of CPP girls. In their study, the ReHo values of right orbital pars of SFG positively correlated with baseline/peak E2 levels; however, it was inversely associated with perceptual reasoning and Wechsler Intelligence Scale scores. Recent studies have indicated that the lateral hypothalamus connects to the medial aspect of the SFG [28,29]. In CPP patients, FC between the right lateral hypothalamus and right SFG showed a trend-level correlation with peak LH levels (r=0.362, P=0.050). This association should be interpreted cautiously, as it suggests a potential, but not robust, link.

Meanwhile, experimental data revealed altered FC between the right lateral hypothalamic region and right FFG in CPP-affected females. Neuroimaging investigations have demonstrated the critical involvement of the FFG in facial recognition processes, semantic decoding, and nonverbal cognitive functions [30,31]. Neuroimaging comparisons demonstrated diminished FC between the left ventral anterior insula and ipsilateral FFG in somatic depression patients versus non-somatic depression cohorts [32]. Parallel investigations by Chen et al. [14] identified reduced left FFG gray matter density in CPP populations compared to PPP controls, coupled with attenuated connectivity between the left FFG and contralateral amygdala. Our results contrast with those of earlier studies by revealing decreased connectivity between the right FFG and right lateral hypothalamic zone in CPP subjects. This divergence from prior findings involving the left FFG raises the possibility that hemisphere-specific involvement of fusiform regions may contribute to CPP-related neural alterations.

Furthermore, experimental observations revealed impaired FC between the right lateral hypothalamic region and right SMG in CPP-affected female subjects. Anatomically situated within the inferior parietal lobular complex, the SMG is critically engaged in linguistic operations and affective information processing, as established in neuroimaging literature [33,34]. Complementary neurocognitive investigations by Steinbeis et al. [35] demonstrated heightened emotional egocentric bias tendencies in pediatric populations relative to adults. These tendencies were associated with diminished neural activation in the right SMG and compromised connectivity patterns with the left dorsolateral prefrontal cortex. Park et al. [36] observed increased gray matter volume along the SMG in patients with idiopathic CPP (ICPP). The diminished FC between the right SMG and right lateral hypothalamus in CPP girls could reflect right lateral hypothalamic dysregulation impacting the right SMG.

The present study identified increased FC between the left lateral hypothalamus and right CUN in girls with CPP. The right CUN is a key region for visual processing [37]. Adolescents with borderline personality disorder exhibit elevated ReHo in the right CUN [24], while ICPP patients show increased CUN matter volume [36]. The CUN functionally connects with the precuneus. Zhao et al. [38] identified genetic underpinnings of default mode network connectivity involving the precuneus and adjacent cortices. Girls with HPG axis activation exhibit reduced cortical thickness in the right precuneus, which inversely correlates with LH and E2 levels [39]. Conversely, CPP patients demonstrate greater precuneus cortical thickness than non-CPP peers, although both groups have shown age-related declines in precuneus volume and cortical thickness [40]. Enhanced function between the left lateral hypothalamus and the right CUN in CPP subjects may suggest left lateral hypothalamic modulation of right CUN activity. However, a significant limitation of this study and similar CPP neuroimaging studies is the absence of concurrent cognitive or behavioral outcome measures.

CPP is associated with distinct psychological and behavioral challenges. One study demonstrated that girls with precocious puberty often develop distorted perceptions of their body image and breast development, which correlate with elevated depression scores [41]. Adolescents with CPP exhibit greater anxiety and poorer body image [8]. CPP is also linked to increased emotional reactivity, higher heart-rate variability, and slower information processing speeds in adolescents [42]. Intriguingly, these mental health challenges relate to our findings of altered FC in the lateral hypothalamus, right SFG, right FFG, right SMG, and right CUN. While the altered FC patterns observed in this study may contribute to emotional or behavioral outcomes previously reported in CPP, such interpretations remain speculative. Future studies incorporating neuropsychological testing are warranted.

Several limitations warrant consideration when interpreting our findings. First, the cross-sectional design precluded longitudinal assessment of FC changes in CPP patients over time. Second, given the higher prevalence of CPP in girls, our study consisted exclusively of female participants, which limits the generalizability of our results to males. Third, the modest sample size of the CPP group (n=37) may have introduced bias and limited the statistical power of our analyses. We plan to increase the sample size in future research to further validate these findings. Fourth, some of the variables (bone age and father’s height) were not controlled in the FC comparisons; thus, our FC results must be used cautiously when extrapolating the data. Finally, while we linked alterations in FC to emotional, cognitive, and behavioral characteristics, the absence of reported neuropsychological assessments means these interpretations remain speculative in nature and lack direct empirical support. Consequently, these relationships should be considered hypotheses requiring future investigation rather than established conclusions. Despite these limitations, this study integrated hypothalamic ROI mapping and hormonal profiling to demonstrate altered hypothalamic FC in CPP subjects, providing new insights that hormonal dysregulation directly modulates hypothalamus–brain interactions.

In conclusion, abnormal lateral hypothalamus FC patterns in CPP girls, particularly linked to peak LH levels, offer new insights into the neuroendocrine mechanisms underlying CPP.

Supplementary materials

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