· Amid growing global concern over early puberty, pubertal evaluations at King Chulalongkorn Memorial Hospital, Bangkok have become more frequent. Among 583 Thai girls assessed between 2018 and 2022, most had central precocious puberty (CPP) with higher body mass index z-scores than normal pubertal variants, and most CPP cases received gonadotropin-releasing-hormone agonists. The impact of obesity on puberty underscores the need for preventive weight management and updated country-specific healthcare guidelines for young girl with signs of early puberty.

Puberty marks a critical period of physical, psychological, and social development in adolescents, characterized by the onset of secondary sexual characteristics, growth acceleration, and reproductive maturation. In recent years, there has been growing concern over a potential trend towards earlier puberty onset among girls, prompting extensive investigations into the prevalence, characteristics, and management of early puberty [1,2]. Early onset of puberty has significant implications for both individual health outcomes and public health systems.

Globally, the age at onset of puberty has decreased in the last century. The age of breast development has decreased nearly 3 months per decade from 1977 to 2013 [2]. In Thailand, a study of schoolgirls in the southern region highlighted a decline in the age of thelarche and menarche by 0.2 and 0.3 years, respectively, over the period from 1994 to 2012 [3]. The coronavirus disease 2019 (COVID-19) pandemic has further intensified interest in this area, as disruptions of daily routines, lifestyle changes, and environmental factors have led to speculation about potential impacts on pubertal timing. Previous studies have shown that the emergence of the COVID-19 pandemic was associated with increases in both precocious puberty cases and pubertal progression rates [4,5].

Precocious puberty, characterized by the appearance of secondary sexual characteristics in girls before the age of 8 years or menarche before 9 years, may be gonadotropin-releasing-hormone (GnRH)-dependent or may occur without activation of the hypothalamic-pituitary-gonadal (HPG) axis, as observed in premature thelarche, adrenarche, normal variant puberty, or GnRH-independent precocious puberty [6]. Studies of Caucasian populations have documented a notable rise in the annual incidence of GnRH-dependent precocious puberty and normal variant puberty over the past 2 decades: GnRH-dependent precocious puberty escalated six-fold, while premature thelarche and premature adrenarche surged by 33-fold and 18-fold, respectively [7].

In Thailand, like many other regions, changes in pubertal timing appear to be occurring. However, comprehensive data regarding the prevalence and characteristics of early puberty, especially in Thai girls, remain limited. Previous studies have predominantly focused on Western populations, resulting in data gaps regarding pubertal development in Asian cohorts. This study aimed to elucidate the prevalence, characteristics, and treatment of a substantial cohort of Thai girls experiencing early puberty and evaluated at King Chulalongkorn Memorial Hospital, a large tertiary center in Bangkok, Thailand, between 2018 and 2022.

In this large single tertiary center study of 583 Thai girls with signs of early puberty, we observed a significant annual increase in the evaluation of these signs, where were particularly notable in 2020. This surge coincided with the COVID-19 pandemic lockdown, during which Thailand introduced measures to limit outdoor activities and mandated school closures from March 2020 to October 2021. Interestingly, we found a higher prevalence of GnRH-dependent precocious puberty than of the normal pubertal variant. Reports from various centers have also suggested an increase in the occurrence of precocious puberty and rapidly progressive early puberty in girls following the COVID-19 pandemic [10,11].

Proposed mechanisms for the increase in precocious puberty during the COVID-19 pandemic encompass multiple factors. First, direct effects of COVID-19 infection, such as inflammation of the olfactory bulb, disruption of the blood-brain barrier, and cytokine storms, has been reported [5]. Second, pandemic-related lifestyle changes, including reduced physical activity, increased sedentary time [12], limited access to healthy food, food insecurity, and altered family eating patterns [13] (e.g., increased consumption of processed foods and high-calorie snacks), may have contributed to childhood obesity and early pubertal onset [14]. Third, increased indoor time and the expanded use of disinfectants during the pandemic elevated household exposure to endocrine-disrupting chemicals [15], potentially influencing pubertal timing. Finally, Thailand's 2019 reimbursement approval of GnRH analogs for CPP and increased public knowledge of this condition may have heightened parental awareness, resulting in more children undergoing evaluations for puberty-related concerns. While our study included limited information regarding the history of COVID-19 infection and other relevant factors in the subjects, the higher proportion of overweight/obese children and elevated BMI among girls with CPP compared to those with normal puberty variants suggests a potential link between obesity and the rising incidence of CPP during the pandemic.

Obesity has been linked to earlier thelarche onset and faster pubertal progression in girls, primarily due to the interaction between the HPG axis and leptin, an adipokine correlated with body fat [14,16,17]. Leptin influences the kisspeptin system, a crucial regulator of pubertal timing [17]. Overweight or obese girls tend to enter puberty earlier and reach menarche at younger ages than normal-weight peers [18,19]. For every 1-ng/mL increase in serum leptin, menarche occurs approximately one month earlier [20]. Obesity-related factors like insulin resistance and hyperinsulinemia also accelerate epiphyseal growth plate maturation, leading to advanced bone age and rapid physical maturation [17]. Encouraging healthy weight management may mitigate the risk of early puberty onset and rapid pubertal progression in girls.

In the postpandemic period from 2021 to 2022, the number of girls diagnosed with GnRH-dependent precocious puberty remained stable, while cases of normal pubertal variant gradually increased, becoming a significant reason for medical visits to endocrine clinics. The observed shift suggests a potential alteration in the dynamics of pubertal development among girls during this timeframe. It is crucial to closely monitor and conduct follow-up assessments to gain better understanding of the underlying factors driving these trends. Prioritizing the development of tools to screen puberty status, along with promotion of public education, is essential to optimize outpatient healthcare resources.

Differentiating between girls with slow-progressive precocious puberty and those with rapidly progressive precocious puberty is important for management but can be challenging at their initial presentation. In 2020, Calcaterra et al. [21] proposed that combination of at least 3 of the following criteria has a specificity of 85% and a sensitivity of 58% in identifying rapidly progressive precocious puberty: basal LH ≥0.2 IU/L, E2 level ≥50 pmol/L, uterine longitudinal diameter ≥3.5 cm, transverse uterine diameter ≥1.5 cm, and ovarian volume ≥2 cm3. Several studies have also pinpointed key factors that distinguish the 2 groups, encompassing variations in height velocity, the progression of puberty, bone age, and hormonal profiles. In our study, when comparing GnRH-dependent precocious puberty with slow-progressive precocious puberty, we found a significantly higher BMI z-score in the former group but found no significance differences in hormonal profiles. These findings are consistent with those of previous studies [16-19,22] and underscore the significant impact of obesity on both the timing of puberty onset and the rate of pubertal progression in girls. Moreover, early puberty onset or menarche may potentially serve as surrogate indicators of future metabolic syndrome and noncommunicable diseases [19,20].

Among the 413 girls diagnosed with GnRH-dependent precocious puberty in our cohort, only one had a serious organic CNS cause of CPP, specifically an opticohypothalamic glioma. This case required further treatment with chemotherapy. Pituitary microadenoma and RCC were the most common MRI findings, but their association with GnRH-dependent precocious puberty is uncertain. A neuroimaging study of 112 Italian girls diagnosed with precocious puberty [23] between 2005 and 2019 found RCCs in 5 girls (4.5%) as compared with 1.2% in our study. Other reports indicate that the overall RCC detection ranges from 0.2%–12.1% [24,25]. In China, a large cohort of 221 patients aged 5 to 82 years who were diagnosed with RCC between 2019 and 2021 showed common symptoms such as dizziness and headaches, despite the benign nature of RCC. Endocrinopathies such as central hypothyroidism and growth hormone deficiency were also prevalent, with CPP found in 8 patients [25]. Another study of 91 children and adolescents diagnosed with RCC between 2006 and 2015 reported that 59.3% exhibited endocrinopathy, including early puberty (34%) and short stature (13%). Diagnosis of CPP was mainly reported in children aged 7–12 years (48.8%) and those younger than 7 years (46.2%) [26]. The mechanisms underlying the association between RCC and CPP remain unclear; however, continuous monitoring of CNS symptoms and other pituitary hypo/hyperfunction in these patients is warranted.

Previous studies reported the prevalence of pathologic GnRH-dependent precocious puberty was approximately 8% in girls with CPP under 6 years, suggesting MRI for girls with CPP under the age of 6 [6]. In our study, only a few girls aged less than 6–8 years had serious CNS issues. Individuals who did not undergo brain and pituitary MRI, either due to parental concerns regarding the procedure or financial limitations, underwent close monitoring. None of these individuals displayed signs of CNS abnormalities or pituitary hormone deficiency during their follow-up assessments. These findings suggest the need to reconsider and update the age threshold for MRI in CPP cases.

Currently, GnRH analogs are the preferred treatment for children with GnRH-dependent precocious puberty. Treatment objectives encompass halting physical maturation, preventing early menarche, slowing skeletal maturation, enhancing final adult height, addressing psychosocial or behavioral consequences, and alleviating parental anxiety [6,15]. Since 2019, Thailand's universal healthcare system has covered triptorelin and leuprorelin (11.25 mg injection, 3 months), improving treatment accessibility for girls with low predicted final adult height or psychosocial issues related to early puberty or menstruation. Our study showed that nearly all girls with GnRH-dependent precocious puberty received GnRH analog treatment, primarily through injections for 3 months. Treatment indications primarily focused on failure to achieve the predicted final adult height, with additional reasons including psychosocial problems and significant anxiety associated with early puberty. According to the Thai Key Performance Index report published by the Ministry of Public Health, the overall health expenditure per capita for the years 2020–2021 ranged from 278 to 355 United States dollar (USD) annually [25]. Notably, the average cost of a 3-month supply of GnRH agonist formula was approximately 240 USD per dose, totaling approximately 956 USD per person annually, suggesting significant economic impact on Thailand's healthcare system. However, it is crucial to weigh this cost against potential long-term health consequences of untreated CPP when assessing overall cost-effectiveness.

In conclusion, our study highlighted a significant increase in the number of girls exhibiting signs of early puberty, particularly in cases of GnRH-dependent precocious puberty, with a notable surge observed shortly after the COVID-19 pandemic. These findings underscore the importance of updating guidelines to refine healthcare strategies for effective management of this evolving trend in puberty within pediatric endocrinology services. It is essential to recognize the need for ethnicity-specific references for pubertal onset and menarche, given the potential variations across populations. Additionally, while GnRH analog treatment has become more accessible, further evaluation of its cost-effectiveness is essential to optimize resource allocation. The strengths of this study include its substantial sample size and thorough data collection over a 5-year period in a large tertiary center, providing a comprehensive analysis of puberty trends in Thai girls. However, limitations include the inclusion of subjects from a single center and the retrospective design, which may have resulted in some missing data. In Thailand, there is a lack of recent national data on early puberty in Thai girls for the interval since the end of the COVID-19 pandemic. Therefore, a multicenter nationwide study is recommended. Our findings also underscore the importance of addressing obesity as a potential contributor to early puberty. Promoting healthy lifestyles and weight management may mitigate the risk of early puberty onset and rapid pubertal progression in girls and should be emphasized in pediatric healthcare settings.