Puberty is the onset of reproductive capability in humans accompanied by the development of secondary sexual characteristics and accelerated bone maturation. Central precocious puberty (CPP) is puberty that occurs at an unusually early age. Unusually early is defined for CPP diagnostic purposes as earlier than 8 years of age in girls and earlier than 9 years of age in boys (Bradley et al., 2020). It is usually idiopathic and is more prevalent in girls (Rosenfield et al., 2000). The prevalence of CPP was 193.2 per 100,000 persons (girls, 410.6; boys, 10.9) in an Asian country (Kim et al., 2019). In patients with CPP, levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and sex hormones dramatically increase at an early age.

Although the increase of these hormones is the same as that during the normal process of puberty, timing of the increase of these hormones is inappropriately early, which is a distinct condition in CPP. CPP has several adverse effects, such as shorter final height as a result of early bone maturation, having difficulties in social life and psychosocial/behavioral sequelae due to an early menarche (De Sanctis et al., 2019). Moreover, CPP has been associated with several psychological problems that can have significant long-term impacts. These problems include depression, substance abuse, eating disorders, body dissatisfaction, externalizing behavior, risky sexual behavior, abortion, and certain aspects of academic achievement (Udry, 1979; Graber et al., 1997; Stice et al., 2001; Graber et al., 2004). Given the significant impact that these psychological problems can have on an individual’s subsequent life, it is essential to understand the causal relationships and mechanisms underlying CPP and its associated negative outcomes (Soriano-Guillen and Argente, 2019). While intracranial tumors are involved in some CPP cases, most CPP cases showed no abnormalities on MRI imaging as qualitative image analysis (Cantas-Orsdemir et al., 2018). Regarding quantitative analysis, several reports suggest that pituitary volume is significantly higher in CPP patients than in age-matched non-CPP controls (NC; Sharafuddin et al., 1994; Wu et al., 2020) as the pituitary gland is a hormone-producing site. However, pituitary changes are unlikely to be directly related to psychiatric symptoms because it is not a site responsible for higher nervous functions. Moreover, the reports have focused on pituitary imaging and not a comprehensive quantitative analysis of the entire brain.

Recently, there has been an increasing emphasis on detailed investigations of changes in brain morphology as a means of enhancing our understanding of neurological disorders (Shiohama et al., 2019a,b, 2020). This is particularly relevant in the case of CPP because female patients with CPP exhibit a heightened vulnerability to psychiatric disorders in comparison to typically developing children. Our hypothesis posited that this association might stem from the early and excessive exposure of the brain to sex hormones, resulting in distinct structural modifications within the cerebral cortex that deviate from the normative trajectory of brain maturation. To substantiate this hypothesis, our investigation aimed to comprehensively examine and characterize the structural aspects of the brains of CPP patients, utilizing region- and surface-based measurements obtained through advanced structural MRI techniques.

We analyzed surface and voxel measurements from structural brain MRI scans of patients with CPP and age-matched controls. Thorough regional analyses and surface cortical maps found that the cortical thickness of the precuneus area of the right hemisphere was significantly higher in the CPP than in the NC group. The volume of the right precuneus and global cortical thickness showed age-dependent downward trends in both groups, suggesting the increased thickness of the right precuneus in the CPP group was not simply due to the acceleration of global brain development resulting from early sexual hormone increases. A previous observation study reported that the thinner right rostral middle frontal cortex in the CPP group as compared with that in the NC was a distinct feature of CPP (Yang et al., 2019).

The precuneus is located in the posteromedial cortex of the parietal lobe, which is numerous complex tasks, including visuospatial processing, episodic memory recall, and self-processing operation, i.e., the sense of volition (Cavanna and Trimble, 2006). The precuneus is also involved in the network governing consciousness of the self (Cavanna and Trimble, 2006; Cheng et al., 2018). Puberty is a crucial period for the development of neurocognitive functions (Laube et al., 2020) and the functions of the precuneus are affected by age in adolescents (Killanin et al., 2020). The specific alterations to the precuneus seen in patients with CPP in this study may be related to some of the functions under its control, which show rapid development during puberty. Cortical thickness in the precuneus tends to thin with age in normal adolescent females (Levman et al., 2017), while our findings indicate a thicker cortex in CPP. This suggests that age-related maturation of precuneus function may be affected or altered in CPP. A previous study revealed differences in the brain architecture between CPP and NC in the anterior, middle frontal lobe, with decreased cortical thickness in that region in patients with CPP. The same study also found a significant correlation between cortical thickness and estrogen levels on the basis of surface-based measurements (Yang et al., 2019). However, our study did not see any substantial differences between groups in the cortical thicknesses, volumes, and surface areas of the frontal cortex. The ages of participants may explain this disparity. Patients in our study investigated were older and further into puberty. Our data may indicate features that appear later in puberty in patients with CPP than those identified in the previous report. Animal studies have shown that prolonged exposure to higher levels of estrogen can affect neurons differently from short-term exposure (Woolley, 2007). Our study indicates that other frontal area thicknesses can be indicative of CPP.

Regarding mechanisms, estrogen is a candidate that induces alterations in brain morphology, such as those observed in our study. CPP causes activation of the hypothalamus–pituitary–adrenal (HPA) axis at an inappropriately early age. Increased estrogen levels are an outcome of this and induce the pubescent changes observed in female patients with CPP. GnRH stimulation tests of our patients with CPP verified both increased estrogen level increases and HPA axis activation. Estrogen receptors are expressed throughout the body, including the synapses of the prefrontal cortex. Nevertheless, the effects of estrogen on neurons are debated. Some studies have reported adverse effects on gray matter (Herting et al., 2014; Brouwer et al., 2015), leading to decreased prefrontal cortex volume. By contrast, other research has shown estrogen to have favorable effects on the survival of neurons, the development of dendritic spines, and the formation of synapses (Romeo, 2003). In the present study, the correlation between estrogen levels in the LH-RH test and right precuneus thickness in CPP was 0.17, which was not statistically significant. Estrogen levels exhibit diurnal and daily variations, making it challenging to establish a clear relationship with a single value. Hence, the fundamental mechanisms involved in estrogen-induced alterations to brain morphology require further investigation.

There were several limitations to this study. First, the number of participants was limited. However, patients had similar CPP etiologies and ages of onset. This homogeneity between patients facilitated a detailed evaluation of brain morphology. Further analysis with a larger sample of patients will be required to confirm our results. Second, since this is a cross-sectional study, it does not allow us to infer causal effects. Finally, no psychological scales were administered to our patients with CPP to reveal whether the alterations in brain morphology related to the altered moods and sensitivity observed in patients with CPP. Further prospective studies are warranted to elucidate the effects of brain structure changes in CPP on psychological development. Despite its limitations, we think that this study adds to our understanding of the effects of CPP on brain structure.

Patients with CPP showed specific morphological brain changes compared with NC. Sex steroids may be involved in the observed structural brain differences in patients with CPP. The features of brain morphology in CPP identified in this study could contribute to further understanding the association between CPP and detrimental psychological outcomes.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Chiba University Hospital’s Institutional Review Board. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.

SY: conceptualization, methodology, writing—original draft, and writing—review and editing. TT: conceptualization, methodology, writing—original draft, formal analysis, data curation, validation, and writing review and editing. TS: conceptualization, methodology, formal analysis, data curation, validation, and writing—review and editing. RT and YK: data curation, validation, and writing—review and editing. SH, HY, and HH: writing—review and editing. All authors contributed to the article and approved the submitted version.

This study was supported by the Foundation for Growth Science in Japan, the Japan Society for the Promotion of Science (grant number KAKEN JP21K07694), National Center of Neurology and Psychiatry [grant number: Intramural Research Grant for Neurological and Psychiatric Disorders (3–10)], and Japan Agency for Medical Research and Development (grant number: the Practical Research Project for Rare/Intractable Diseases JP21ek0109498).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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