2022 Clinical practice guidelines for central precocious puberty of Korean children and adolescents

Article information

Ann Pediatr Endocrinol Metab. 2023;28(3):168-177
Publication date (electronic) : 2023 September 19
doi : https://doi.org/10.6065/apem.2346168.084
Su Jin Kim1orcid_icon, Ji Hyun Kim2, Yong Hee Hong3, In Hyuk Chung4, Eun Byoul Lee5, Eungu Kang6, Jinsup Kim7,*, Aram Yang8, Young-Jun Rhie6, Eun-Gyong Yoo9, Young-Lim Shin3, Jin Ho Choi10, Soo Young Kim11, Jieun Lee,1orcid_icon, Committee of Central precocious puberty of Korean Children and Adolescents on behalf of Korean Society of Pediatric Endocrinology (KSPE)
1Department of Pediatrics, Inha University Hospital, Inha University College of Medicine, Incheon, Korea
2Department of Pediatrics, Dongguk University Ilsan Hospital, Goyang, Korea
3Department of Pediatrics, Soonchunhyang University Bucheon Hospital, Soonchunhyang University School of Medicine, Bucheon, Korea
4Department of Pediatrics, National Health Insurance Service Ilsan Hospital, Goyang, Korea
5Department of Pediatrics, Catholic Kwandong University International St. Mary’s Hospital, Incheon, Korea
6Department of Pediatrics, Korea University College of Medicine, Seoul, Korea
7Department of Pediatrics, Hanyang University Medical Center, Hanyang University College of Medicine, Seoul, Korea
8Department of Pediatrics, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
9Department of Pediatrics, CHA Bundang Medical Center, CHA University, Seongnam, Korea
10Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
11Department of Family Medicine, Kangdong Sacred Heart Hospital, Hallym University College of Medicine, Seoul, Korea
Address for correspondence: Jieun Lee Department of Pediatrics, Inha University Hospital, Inha University College of Medicine, Northwest Gyeonggi Regional Center for Rare Disease, 27 Inhang-ro, Jung-gu, Incheon 22332, Korea Email: anicca@inha.ac.kr
*Current affiliation: Department of Clinical Development at Novel Pharma, Inc.
Received 2023 August 10; Accepted 2023 September 19.

Abstract

The Committee of Central Precocious Puberty of Korean Pediatrics and Adolescents of the Korean Society of Pediatric Endocrinology has newly developed evidence-based 2022 clinical practice guidelines for central precocious puberty in Korean children and adolescents. These guidelines provide the grade of recommendations, which includes both the strength of recommendations and the level of evidence. In the absence of sufficient evidence, recommendations are based on expert opinion. These guidelines have been revised and supplement the previous guidelines "Clinical Guidelines for Precocious Puberty 2011," and are drawn from a comprehensive review of the latest domestic and international research and the grade of recommendation appropriate to the domestic situation. This review summarizes the newly revised guidelines into 8 key questions and 27 recommendations and consists of 4 sections: screening, diagnosis, treatment, and long-term outcome of central precocious puberty.

Highlights

· Central precocious puberty accounts for the largest number of outpatient pediatric endocrine diseases, and is also a disease of high social interest. The newly revised "Clinical Practice Guidelines for Central Precocious Puberty 2022" has been revised and supplements the previous edition. The revisions present the level of evidence based on the latest domestic and international research and the grade of recommendation appropriate to the domestic situation.

Introduction

Precocious puberty (PP) is defined as the onset of secondary sexual characteristics earlier than 2 to 2.5 standard deviations (SDs) of the mean. In general, PP is the onset of puberty in girls younger than 8 years old and boys younger than 9 years old, according to the criteria laid down by Marshall et al. in 1969 [1]. In epidemiological studies in Korea, a higher prevalence and incidence of central PP (CPP) have been reported. A study that analyzed 2004–2010 data reported a prevalence of 57.6 per 100,000 (females 55.9; males 1.7) and an incidence rate of 15.9 per 100,000 (females 15.3; males 0.6) [2]. However, in a study that analyzed 2008–2014 data, the prevalence (193.2 per 100,000) and incidence (122.8 per 100,000) of CPP increased steeply each year [3]. The Korean Society of Pediatric Endocrinology (KSPE) developed "Clinical Guidelines for Precocious Puberty 2011" to standardize domestic CPP treatment and improve medical quality [4]. Now, 10 years after the publication of the first edition, the need to update the clinical practice guideline (CPG) to reflect the latest clinical research has emerged, and the Committee of CPP of Korean Children and Adolescents of KSPE was formed. The newly revised "Clinical Practice Guidelines for Central Precocious Puberty 2022" has been revised and supplements the previous edition. The revisions present the level of evidence based on the latest domestic and international research and the grade of recommendation appropriate to the domestic situation. This newly revised CPG uses 8 key questions (KQs) to summarize 4 sections: screening, diagnosis, treatment, and long-term outcome of CPP.

Development of CPGs

The final decision of recommendation was made through the deliberation process of the committee and the review process of external experts. The level of evidence was modified according to the classification of the research design, and based on the SIGN level of evidence system (Table 1). In principle, all recommendations are based on evidence to determine the grade of recommendation. The grades of recommendation are defined as 4 grades through the blind voting methods of the committee by evaluating the degree of benefit and harm of the intervention based on evidence. The grade of the recommendation does not indicate the strength but denotes the generality of the recommendation. In the recommendation level, "Strong" means that most patients who are provided with sufficient information choose the intervention because the desirable effects are greater than the undesirable effects. "Conditional" means that it is uncertain whether the favorable effects of the intervention outweigh the undesirable effects, so that a fully informed patient can choose another intervention. Table 2 shows the 4-grade notations and meanings of the grade of recommendation.

Levels of evidence

Grades of recommendation

Section 1: Screening for CPP

KQ 1. When should pubertal progression and CPP be carefully monitored?

Recommendation 1-1. Consider careful observation for CPP in children with obesity (Randomized controlled study. Do, Conditional)

Childhood obesity can cause hyperandrogenemia and insulin resistance, which can accelerate puberty [5]. The association between obesity and CPP is well-established in girls [6]. Although controversial in boys, a recent large-scale cohort study conducted in Denmark reported that obesity in boys is associated with early puberty [7]. However, in children with obesity, only bone age (BA) can be advanced without other physical changes of puberty, so it is necessary to differentiate it from CPP [8].

Recommendation 1-2. Consider careful observation for CPP in children born SGA or with IUGR (Randomized controlled study. Do, Conditional)

In the case of children who are small for gestational age (SGA) or have intrauterine growth retardation (IUGR), there has been controversy over whether the onset of puberty is earlier than in peers or within the normal range [9,10]. In children born SGA, BA may be delayed at the onset of puberty, but caution is needed as BA can advance rapidly as puberty progresses [11]. More research is needed on the onset and progression of puberty in preterm or full-term infants with SGA or IUGR [12].

Recommendation 1-3. Consider careful observation for CPP, if there is a family history of early puberty (Nonrandomized controlled study. Do, Conditional)

Several genes such as kisspeptin (KISS1), kisspeptin receptor (KISS1R), makorin ring finger protein 3, (MKRN3), and deltalike homolog 1 (DLK1) have been reported to be associated with CPP [13]. Some studies have reported a close relationship between the age of onset of puberty in parents and their children [14]. Therefore, history taking for parental puberty timing and progression should be conducted.

Section 2: Diagnosis of CPP

KQ 2. What tests are performed to diagnose CPP and how are they interpreted?

Recommendation 2-1. BA measurement is recommended for the diagnosis of CPP (Nonrandomized controlled study. Do, Strong)

When secondary sexual characteristics appear early and BA is beyond the chronological age (CA), BA measurement is helpful in diagnosing CPP and predicting adult height (PAH) [15,16]. However, significant advanced BA (difference of more than 2 SDs from the CA) does not confirm CPP. Therefore, BA should be used as an auxiliary tool to help diagnose CPP.

Recommendation 2-2. GnRH stimulation test is recommended for the diagnosis of CPP (Nonrandomized controlled study. Do, Strong)

Gonadotropin-releasing hormone (GnRH) stimulation tests are performed to differentiate CPP from normal pubertal variants such as precocious thelarche or precocious adrenarche and to confirm activation of the hypothalamic-pituitarygonadal axis. In Korea, CPP is defined as an increase of 2 to 3 times the baseline value after a luteinizing hormone release hormone (LHRH) stimulation test and a peak luteinizing hormone (LH) >5 IU/L. A short-acting GnRH agonist (triptorelin 0.1 mg) can be used instead of LHRH [17]. The diagnostic criterion is the same as peak LH > 5 IU/L, but it should be noted that the time to reach the peak LH is around 3 hours. In children with obesity, LH suppression may be seen in the GnRH stimulation test, so caution is needed in the interpretation [18].

To diagnose CPP, clinical features such as sexual maturity rate (SMR) Tanner stage II or higher, accelerated growth velocity (GV), and advanced BA should be considered along with the GnRH stimulation test.

Recommendation 2-3. Unstimulated LH measurement can be considered an auxiliary method for the diagnosis of CPP (Nonrandomized controlled study. Do, Conditional)

Random unstimulated LH levels measured by ultrasensitive assays such as immunochemiluminometric assay (ICMA) or electrochemiluminescence immunoassay (ECLIA) are helpful in diagnosing CPP. Recent studies suggested unstimulated LH < 0.3 IU/L (ICMA method) as the pre-pubertal state 19] and unstimulated LH >0.83 IU/L (ICMA method) as the pubertal state [20]. In a domestic study of 803 subjects, unstimulated LH level > 1.1 IU/L (69.1% sensitivity, 50.5%, radioimmunoassay method) was the cutoff point related to pubertal response [21]. In addition, methods for diagnosing CPP using morning unstimulated LH levels have been reported, morning unstimulated LH > 0.11 IU/L (sensitivity 66.7%, specificity of 78.7%, chemiluminescence immunoassay method) [22] and LH > 0.22 IU/L (positive predictive value of 0.9, ECLIA method) [23] have been suggested as meaningful cutoff values. Since suppression of LH levels may occur in children with obesity, care should be taken in interpreting unstimulated LH levels [18].

Recommendation 2-4. Pelvic ultrasonography can be considered an auxiliary tool for the diagnosis of CPP (Randomized controlled study. Do, Conditional)

As the increase in uterine length and ovarian volume in pelvic ultrasound reflects the stimulation of estrogen and gonadotropin, it can be used as an auxiliary diagnostic tool in patients suspected of CPP. In previous studies, a uterine length of 3.5–4 cm or more and an ovarian volume of 2 cm3 or more have been considered appropriate for puberty. However, the results are inconsistent, and pelvic ultrasonography is highly influenced by the examiner [24,25]. A recent meta-analysis including 1,977 girls reported that when the length of the uterus is 3.2 cm or more, it could be used as a supplementary tool to distinguish between CPP and precocious thelarche with a sensitivity of 81.8% and a specificity of 82.0% [26].

Recommendation 2-5. Breast ultrasonography is not recommended for the diagnosis of CPP (Expert opinion. Do not, Strong)

Breast ultrasonography is not recommended because it has no advantages over other testing methods. In addition, there are few related studies, and clinical results are not suitable as a CPP screening method.

KQ 3. When should a brain MRI be performed to identify organic causes in patients with CPP?

Recommendation 3-1. Brain MRI is recommended for girls younger than 6 years of age who have been diagnosed with CPP, and for girls older than 6 years who have neurologic signs and symptoms suggesting a CNS abnormality (Randomized controlled study. Do, Strong)

Recommendation 3-2. Brain MRI is selectively considered for girls with an onset of puberty between the age of 6 and 8 years who have no neurological signs or symptoms suspicious of CNS abnormality (Nonrandomized controlled study. Do, Conditional)

Recommendation 3-3 Brain MRI is recommended for boys diagnosed with CPP (Nonrandomized controlled study. Do, Conditional)

In girls, the prevalence of central nervous system (CNS) abnormalities decreases with age [27]. In a meta-analysis of 1,853 girls diagnosed with CPP, the incidence of brain magnetic resonance imaging (MRI) abnormalities was 7% overall, however, it was 25% in the group of girls that were younger than 6 years old and 3% in the 6 to 8 years old group. The most common brain MRI abnormality was hypothalamic hamartomas, and brain tumors were 1.6% of all age groups [27]. In a domestic study that analyzed brain MRIs of 317 girls diagnosed with CPP, 91.8% were normal and 8.2% discovered benign findings of the CNS (Rathke cleft cyst, pineal cyst, suspected pituitary hyperplasia, etc.), but there were no pathological CNS lesions [28]. Clinical factors that can predict abnormal findings on brain MRI in patients diagnosed with CPP have not yet been identified, but puberty onset before the age of 6 was reported as the most likely predictor [27].

In boys, the incidence of brain MRI abnormalities has been reported higher than that of girls, but recent studies have shown that the incidence of idiopathic CPP is increasing in boys, especially in boys recently diagnosed with CPP. In a study of 100 boys diagnosed with CPP, brain MRI abnormalities were found in 26%, most of which were diagnosed under the age of 7 years. When the diagnosis period was 2003–2005, the frequency of idiopathic CPP was 33.3%, but it showed a tendency to increase to 81.6% in 2012–2014 [29]. In a domestic study that analyzed 138 boys diagnosed with CPP (average age at diagnosis, 9.51±0.56 years), brain MRI abnormalities were found in 7%, and no lesions requiring treatment were observed [30]. Recently, several studies have reported that the incidence of idiopathic CPP in boys has increased, but it should be considered that the average age at the time of diagnosis is 8 years or older in some studies. Further studies such as a meta-analysis or systematic review will be needed to predict the organic causes of CPP in boys.

Section 3: Treatment of CPP

KQ 4. What are the indications and considerations for treatment in patients with CPP?

Recommendation 4-1. An observation period of 3 to 6 months is recommended to evaluate the tempo of pubertal progression in patients with suspected CPP (Randomized controlled study. Do, Strong)

Most patients with suspected CPP do not require treatment due to early or transient pubertal development; therefore, periodic observation is required to determine treatment [31]. Before treating CPP, the following should be discussed with parents and the patient to decide whether to treat or observe [32]; (1) The decision on GnRH agonist treatment in patients with CPP depends on the age, rapid pubertal progression, SMR, accelerated GV, advanced BA, and loss of PAH. In general, slow progressive-precocious puberty (SP-PP) is not considered to change the stage of SMR during an observation period of 6 months or more [33]. In SP-PP, the BA progression and GV are not too fast, and the age of menarche may not be too early.

(2) In patients with CPP who are above average in height and do not have severely advanced BA, final adult height (FAH) is likely to be within the normal range and GnRH agonist treatment may not improve FAH significantly.

(3) The results of studies on height gain according to CPP treatment are diverse [34], some studies have shown that girls treated for CPP after the age of 8 years do not show significant increases in FAH, and some may show decreases [35-37].

Recommendation 4-2. Treatment is recommended for rapid progressive-precocious puberty (Randomized controlled study. Do, Strong)

Rapid progressive-precocious puberty is associated with highly accelerated pubertal development, premature menarche, and loss of FAH if untreated [38,39]. In a recent meta-analysis, treatment with a GnRH agonist in patients aged 6.3 to 9 years showed an increase in FAH of 3.2 cm. Among these patients, those with an average increase of 5.1 cm started treatment before the age of 8 years old, but those with an average increase of 2.5 cm started after the age of 8 years old [40]. There are few long-term data on FAH in boys because the prevalence is lower than in girls, but the average increase in FAH after GnRH agonist treatment was 6.2±8.7 cm, and the effect was better when the age at the start of treatment was younger [41].

In contrast, treatment is not generally recommended for early puberty or SP-PP because the FAH without treatment is similar to the median parental height [42]. In addition, if BA has progressed significantly at the time of diagnosis, the height gain after treatment may be insignificant.

Recommendation 4-3. Treatment is considered for girls with CPP that are at high risk for psychosocial stress due to early menarche (Nonrandomized controlled study. Do, Conditional)

Early breast development and menarche can cause discomfort and psychological stress in girls, which can lead to problems such as depression, anxiety, and behavioral disorders [43]. However, it is difficult to identify the correlation between psychiatric problems and CPP clearly, and in long-term followup studies of patients with CPP, there was no significant difference in the level of psychosocial well-being in adulthood compared to the general population [44]. There are concerns about psychosocial stress due to CPP, but behavioral problems may be less common than expected [45].

KQ 5. What is the treatment for CPP?

Recommendation 5-1. GnRH agonist is recommended as a standard treatment of CPP (Nonrandomized controlled study. Do, Strong)

Recommendation 5-2. Leuprolide or triptorelin is recommended according to the usage and dosage approved in Korea (Randomized controlled study. Do, Strong)

Recommendation 5-3. Since there is no difference in the effects of GnRH agonists with different administration intervals, it is recommended to select a drug according to the situation (Randomized controlled study. Do, Strong)

Currently, there are various GnRH agonist formulations with different doses and durations of action. The GnRH agonists approved for use in the treatment of CPP in Korea are summarized in Table 3. In the case of leuprolide, the dosage determined by body weight used in the past is not recommended due to a lack of evidence [38]. In recent domestic studies comparing the effects of 4-week and 3-month formulations of leuprolide or triptorelin, there was no difference in the effect between the formulations [46,47].

Gonadotropin-releasing hormone agonist formulations approved for use in central precocious puberty treatment in Korea

Recommendation 5-4. GnRH antagonists or aromatase inhibitors are not recommended due to insufficient evidence of their effectiveness (Nonrandomized controlled study. Do not, Strong)

Neither GnRH antagonists nor aromatase inhibitors are approved for the treatment of CPP. In girls with CPP, it has been reported that LH inhibition is faster when anastrozole (aromatase inhibitor) is added or when a GnRH antagonist is combined with a GnRH agonist at the beginning of treatment, but mid- to long-term clinical results have not been reported [48]. Therefore, evidence for the use of GnRH antagonists or aromatase inhibitors in patients with CPP is insufficient.

KQ 6. What are the precautions for GnRH agonist treatment in patients with CPP?

Recommendation 6-1. Consider maintaining GnRH agonist treatment if there are minor adverse effects that may occur temporarily during administration (Others. Do, Conditional)

Systemic symptoms such as a headache or hot flashes may occur after the administration of a GnRH agonist, but these are usually transient and do not affect treatment [49]. Allergic or local adverse effects occur infrequently [38]. In a domestic study, four of 621 patients (0.6%) with CPP who received a GnRH agonist developed local adverse effects such as aseptic abscesses [50]. If local reactions persist, changing to another formulation is recommended. After the initiation of GnRH agonist treatment, transient withdrawal bleeding may occur. But if it persists for more than 2 months, other causes should be considered [51].

Recommendation 6-2. Immediate evaluation and treatment are recommended when SCFE, pseudotumor cerebri, or anaphylaxis occurs during GnRH agonist treatment (Others. Do, Strong)

Risk factors for slipped capital femoral epiphysis (SCFE) are obesity, male sex, growth spurt, and prior radiation therapy. Since SCFE has been reported during or after treatment with a GnRH agonist, evaluation and treatment are required when complaining of pain [50,52,53]. There are few case reports of pseudotumor cerebri after the administration of a GnRH agonist, which were improved after the discontinuation of the GnRH agonist and treatment with acetazolamide and V-P shunt [54,55]. Anaphylactic reaction after the administration of a GnRH agonist is rare but requires immediate treatment, and it has also been reported in domestic studies [50,56].

Recommendation 6-3. GH combination treatment is considered optional when the growth rate is severely reduced during treatment or the prognosis for FAH is poor (Nonrandomized controlled study. Do, Conditional)

In a meta-analysis including 1,268 patients, an untreated group, a group treated with the GnRH agonist alone, and a growth hormone (GH) combination treatment group were compared [57]. The GH combination treatment group was 1 cm taller than the GnRH agonist monotherapy group and 3.3 cm taller than the untreated group. In a domestic study of 166 patients with CPP, the average age at the start of treatment was 7.89 years, and additional height gain was reported in a GH combination therapy group compared to a GnRH agonist monotherapy group [58]. However, GH combined therapy can cause stress related to long-term self-injections for patients and a burden of cost for parents. Furthermore, differences in effects and adverse effects according to GH treatment may occur depending on the patient's situation and should be selectively considered when the prognosis for FAH is poor. It is recommended that pediatric endocrinologists, patients, and families fully discuss the benefits, risks, and costs of GH combination therapy to determine treatment [48].

KQ 7. What are the appropriate periodic evaluation and treatment lengths for GnRH agonists in patients with CPP?

Recommendation 7-1. It is recommended to evaluate the effects of GnRH agonist treatment every 3 to 6 months (Nonrandomized controlled study. Do, Strong)

Recommendation 7-2. If treatment failure is suspected, reevaluation should be considered sooner (Nonrandomized controlled study. Do, Conditional)

The effect of a GnRH agonist can be seen after 2 to 6 months of treatment, and when it is effective, the progression of secondary sexual characteristics stops and the GV decreases to pre-pubertal levels [59,60]. On physical examination, it is important that the SMR of the breast/testis does not progress, but pubic hair may not change or may be progressed by normal adrenal cortex maturation [49]. Measurement of basal or stimulated LH, estradiol/testosterone, and BA are also considered. It is helpful to measure BA every 6 months to one year [61]. According to some studies, treatment failure can be considered if basal LH > 0.6 IU/L, or estradiol > 30 pg/mL (girls)/testosterone > 30 ng/dL (boys), and stimulated LH > 4 IU/L [20,62]. However, several studies have shown that measurements of basal or stimulated LH or estradiol/testosterone alone are not helpful in determining treatment effectiveness, and an increase in results compared to pre-pubertal levels does not necessarily indicate treatment failure [63]. Therefore, it is necessary to evaluate treatment effects on the overall condition of the patient, including laboratory tests and physical examinations. Treatment failure is determined by a combination of SMR and BA progression, lack of slowing down GV, and unsuppressed hormonal testing, in which a case re-evaluation of treatment effect is required.

Recommendation 7-3. It is recommended to determine when to discontinue GnRH agonist treatment by considering several factors including CA, BA, recovery of puberty, and FAH (Nonrandomized controlled study. Do, Conditional)

Based on BA, GnRH agonist treatment until 12 to 12.5 years in girls and 13 to 14 years in boys is the most helpful for FAH [41,64-66]. In general, the longer the treatment period, the higher FAH, but in girls who are treated with GnRH agonist after a CA of 13 years, no further increase in FAH is observed and even a negative correlation may be shown [38,67,68]. In girls with CPP, menarche is predicted after an average of 12 to 18 months after the completion of treatment and may begin after a few months or be delayed as long as 2 years [58,69]. It is recommended that the discontinuation of GnRH agonist treatment be decided after providing information about the FAH and pubertal progression to the guardians and patients, as well as an achievement of appropriate BA or CA.

Recommendation 7-4. Consider evaluating pubertal recovery and growth after the GnRH agonist treatment (Expert opinion. Do, Conditional)

After GnRH agonist treatment, regular follow-up is recommended until the FAH is reached and the recovery of gonadal function is confirmed (for girls, until menarche).

Section 4: Long-term outcome of CPP

KQ 8. Is the treatment with a GnRH agonist associated with an increased risk of other diseases in the long term?

Recommendation 8-1. GnRH agonist treatment does not affect reproductive function nor increase the risk of PCOS in patients with CPP (Randomized controlled study. Do not, Strong)

Evidence that GnRH agonist treatment is associated with reduced fertility or increased infertility is lacking. The reproductive function returns to normal with menarche and regular ovulatory menstruation after GnRH agonist treatment in most girls, except in some cases with structural abnormalities of the pituitary gland [70]. In studies that compare the group with CPP who received GnRH agonist treatment, the group with CPP who did not receive treatment, and a control group, all 3 groups gave birth without problems, and there was no difference in the rate of spontaneous pregnancy between groups [71,72]. Although there are limited data on reproductive function in males treated with a GnRH agonist for CPP, testosterone, gonadotropins, and semen analysis have been reported to be in the normal range [73]. The evidence that polycystic ovary syndrome (PCOS) occurs more frequently in patients with CPP compared to normal controls is not clear, and in a recent meta-analysis, the incidence of PCOS was no different between GnRH-treated and untreated groups [74,75]. Therefore, long-term evaluation and monitoring for reproductive function or PCOS in patients with CPP are not recommended.

Recommendation 8-2. GnRH agonist treatment does not affect metabolic disease, bone health, or mental health in patients with CPP (Randomized controlled study. Do not, Strong)

It has been reported that body fat increases at the beginning of treatment with a GnRH agonist, but there is no difference in body mass index (BMI) after treatment [76]. In long-term studies, the body weights of patients with CPP were similar to that of the general population regardless of treatment, and high BMI at diagnosis was associated with overweight or obesity in adulthood. Therefore, GnRH agonist treatment does not appear to have any long-term effects on obesity in adulthood. [71,75]. In previous studies, it was reported that patients with CPP had higher bone mineral density (BMD) than peers at the time of diagnosis and that BMD decreased during GnRH agonist treatment [77,78]. However, BMD in late adolescence after treatment was within the normal range, and it does not appear to affect BMD in the long term [78,79].

Some studies have reported that prolonged exposure to estrogen in girls with early puberty may be associated with an increased risk of breast cancer, obesity, type 2 diabetes, cardiovascular disease, and other malignancies [80]. However, these studies have limitations in that they did not adjust confounding factors such as obesity and exposure to other endocrine disruptors, so further research is needed on the effects of GnRH agonist treatment on these diseases. Taken together, long-term evaluation and monitoring for metabolic disease, bone health, or mental health in patients with CPP is not recommended.

Conclusion

CPP is one of the most common pediatric endocrine diseases, and it is of high social interest due to its increasing prevalence and incidence every year. The second edition of 2022 CPGs for the CPP of Korean children and adolescents has been revised and supplements the previous edition based on the latest domestic and international research. These guidelines will help pediatricians standardize the diagnosis and management of CPP in Korean children and adolescents.

Notes

Conflicts of interest

No potential conflict of interest relevant to this article was reported.

Funding

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Author contribution

Conceptualization: SJK, JL; Data curation: SJK, JHK, YHH, IHC, EBL, EK, JK, AY; Methodology: SJK, JHK, YHH, IHC, EBL, EK, JK, AY, SYK, JL; Project administration: SJK, JL; Writing - original draft: SJK; Writing - review & editing: SJK, JHK, YHH, IHC, EBL, EK, JK, AY, YR, EGY, YLS, JHC, JL

Acknowledgements

The authors greatly appreciate the members of the Committee of Central Precocious Puberty of Korean Children and Adolescents and the Korean Society for Pediatric Endocrinology for their support in developing and publishing these guidelines.

References

1. Marshall WA, Tanner JM. Variations in pattern of pubertal changes in girls. Arch Dis Child 1969;44:291–303.
2. Kim SH, Huh K, Won S, Lee KW, Park MJ. A significant increase in the incidence of central precocious puberty among Korean girls from 2004 to 2010. PLoS One 2015;10e0141844.
3. Kim YJ, Kwon A, Jung MK, Kim KE, Suh J, Chae HW, et al. Incidence and prevalence of central precocious puberty in Korea: an epidemiologic study based on a national database. J Pediatr 2019;208:221–8.
4. 2011 Clinical Practice Guideline for Korean Children and Adolescents Seoul (Korea): Korean Society of Pediatric Endocrinology, 2011.
5. McCartney CR, Blank SK, Prendergast KA, Chhabra S, Eagleson CA, Helm KD, et al. Obesity and sex steroid changes across puberty: evidence for marked hyperandrogenemia in pre- and early pubertal obese girls. J Clin Endocrinol Metab 2007;92:430–6.
6. Li W, Liu Q, Deng X, Chen Y, Liu S, Story M. Association between obesity and puberty timing: a systematic review and meta-analysis. Int J Environ Res Public Health 2017;14:1266.
7. Brix N, Ernst A, Lauridsen LLB, Parner ET, Arah OA, Olsen J, et al. Childhood overweight and obesity and timing of puberty in boys and girls: cohort and sibling-matched analyses. Int J Epidemiol 2020;49:834–44.
8. de Groot CJ, van den Berg A, Ballieux B, Kroon HM, Rings E, Wit JM, et al. Determinants of advanced bone age in childhood obesity. Horm Res Paediatr 2017;87:254–63.
9. Deng X, Li W, Luo Y, Liu S, Wen Y, Liu Q. Association between small fetuses and puberty timing: a systematic review and meta-analysis. Int J Environ Res Public Health 2017;14:1377.
10. Darendeliler F. IUGR: Genetic influences, metabolic problems, environmental associations/triggers, current and future management. Best Pract Res Clin Endocrinol Metab 2019;33:101260.
11. Verkauskiene R, Petraitiene I, Albertsson Wikland K. Puberty in children born small for gestational age. Horm Res Paediatr 2013;80:69–77.
12. Suikkanen J, Nurhonen M, Cole TJ, Paalanne M, Matinolli HM, Tikanmaki M, et al. Preterm birth and subsequent timing of pubertal growth, menarche, and voice break. Pediatr Res 2022;92:199–205.
13. Shim YS, Lee HS, Hwang JS. Genetic factors in precocious puberty. Clin Exp Pediatr 2022;65:172–81.
14. Wohlfahrt-Veje C, Mouritsen A, Hagen CP, Tinggaard J, Mieritz MG, Boas M, et al. Pubertal onset in boys and girls is influenced by pubertal timing of both parents. J Clin Endocrinol Metab 2016;101:2667–74.
15. Li W, Liu Q, Deng X, Chen Y, Liu S, Story M. Association between obesity and puberty timing: a systematic review and meta-analysis. Int J Environ Res Public Health 2017;14:1266.
16. Xu YQ, Li GM, Li Y. Advanced bone age as an indicator facilitates the diagnosis of precocious puberty. J Pediatr (Rio J) 2018;94:69–75.
17. Freire AV, Escobar ME, Gryngarten MG, Arcari AJ, Ballerini MG, Bergada I, et al. High diagnostic accuracy of subcutaneous Triptorelin test compared with GnRH test for diagnosing central precocious puberty in girls. Clin Endocrinol (Oxf) 2013;78:398–404.
18. Lee HY, Lee YJ, Ahn MB, Cho WK, Suh BK. The effect of overweight on the luteinizing hormone level after gonadorelin stimulation test in girls with idiopathic central precocious puberty. Ann Pediatr Endocrinol Metab 2018;23:215–9.
19. Neely EK, Wilson DM, Lee PA, Stene M, Hintz RL. Spontaneous serum gonadotropin concentrations in the evaluation of precocious puberty. J Pediatr 1995;127:47–52.
20. Houk CP, Kunselman AR, Lee PA. Adequacy of a single unstimulated luteinizing hormone level to diagnose central precocious puberty in girls. Pediatrics 2009;123:e1059–63.
21. Lee HS, Park HK, Ko JH, Kim YJ, Hwang JS. Utility of Basal luteinizing hormone levels for detecting central precocious puberty in girls. Horm Metab Res 2012;44:851–4.
22. Kang YS, Yoo DY, Chung IH, Yoo EG. Diurnal variation of gonadotropin levels in girls with early stages of puberty. Ann Pediatr Endocrinol Metab 2017;22:183–8.
23. Lee DM, Chung IH. Morning basal luteinizing hormone, a good screening tool for diagnosing central precocious puberty. Ann Pediatr Endocrinol Metab 2019;24:27–33.
24. Sathasivam A, Rosenberg HK, Shapiro S, Wang H, Rapaport R. Pelvic ultrasonography in the evaluation of central precocious puberty: comparison with leuprolide stimulation test. J Pediatr 2011;159:490–5.
25. Wen X, Wen D, Zhang H, Zhang H, Yang Y. Observational study pelvic ultrasound a useful tool in the diagnosis and differentiation of precocious puberty in Chinese girls. Medicine (Baltimore) 2018;97e0092.
26. Nguyen NN, Huynh LBP, Do MD, Yang TY, Tsai MC, Chen YC. Diagnostic accuracy of female pelvic ultrasonography in differentiating precocious puberty from premature thelarche: a systematic review and meta-analysis. Front Endocrinol (Lausanne) 2021;12:735875.
27. Cantas-Orsdemir S, Garb JL, Allen HF. Prevalence of cranial MRI findings in girls with central precocious puberty: a systematic review and meta-analysis. J Pediatr Endocrinol Metab 2018;31:701–10.
28. Yoon JS, So CH, Lee HS, Lim JS, Hwang JS. Prevalence of pathological brain lesions in girls with central precocious puberty: possible overestimation? J Korean Med Sci 2018;33e329.
29. Alikasifoglu A, Vuralli D, Gonc EN, Ozon A, Kandemir N. Changing etiological trends in male precocious puberty: evaluation of 100 cases with central precocious puberty over the last decade. Horm Res Paediatr 2015;83:340–4.
30. Yoon JS, So CH, Lee HS, Lim JS, Hwang JS. The prevalence of brain abnormalities in boys with central precocious puberty may be overestimated. PLoS One 2018;13e0195209.
31. Zhu SY, Du ML, Huang TT. An analysis of predictive factors for the conversion from premature thelarche into complete central precocious puberty. J Pediatr Endocrinol Metab 2008;21:533–8.
32. Kaplowitz PB, Backeljauw PF, Allen DB. Toward more targeted and cost-effective gonadotropin-releasing hormone analog treatment in girls with central precocious puberty. Horm Res Paediatr 2018;90:1–7.
33. Massart F, Federico G, Harrell JC, Saggese G. Growth outcome during GnRH agonist treatments for slowly progressive central precocious puberty. Neuroendocrinology 2009;90:307–14.
34. Franzini IA, Yamamoto FM, Bolfi F, Antonini SR, Nunes-Nogueira VS. GnRH analog is ineffective in increasing adult height in girls with puberty onset after 7 years of age: a systematic review and meta-analysis. Eur J Endocrinol 2018;179:381–90.
35. Bertelloni S, Massart F, Miccoli M, Baroncelli GI. Adult height after spontaneous pubertal growth or GnRH analog treatment in girls with early puberty: a meta-analysis. Eur J Pediatr 2017;176:697–704.
36. Magiakou MA, Manousaki D, Papadaki M, Hadjidakis D, Levidou G, Vakaki M, et al. The efficacy and safety of gonadotropin-releasing hormone analog treatment in childhood and adolescence: a single center, long-term follow-up study. J Clin Endocrinol Metab 2010;95:109–17.
37. Guaraldi F, Beccuti G, Gori D, Ghizzoni L. Management of endocrine disease: long-term outcomes of the treatment of central precocious puberty. Eur J Endocrinol 2016;174:R79–87.
38. Bangalore Krishna K, Fuqua JS, Rogol AD, Klein KO, Popovic J, Houk CP, et al. Use of gonadotropin-releasing hormone analogs in children: update by an international consortium. Horm Res Paediatr 2019;91:357–72.
39. Calcaterra V, Klersy C, Vinci F, Regalbuto C, Dobbiani G, Montalbano C, et al. Rapid progressive central precocious puberty: diagnostic and predictive value of basal sex hormone levels and pelvic ultrasound. J Pediatr Endocrinol Metab 2020;33:785–91.
40. Park HK, Choo MS, Shim YS. Adult height after gonadotropin-releasing hormone agonist treatment in girls with early puberty: a meta-analysis. Clin Endocrinol (Oxf) 2020;93:135–45.
41. Bertelloni S, Mul D. Treatment of central precocious puberty by GnRH analogs: long-term outcome in men. Asian J Androl 2008;10:525–34.
42. Kaplowitz PB. Treatment of central precocious puberty. Curr Opin Endocrinol Diabetes Obes 2009;16:31–6.
43. Menk TAS, Inacio M, Macedo DB, Bessa DS, Latronico AC, Mendonca BB, et al. Assessment of stress levels in girls with central precocious puberty before and during long-acting gonadotropin-releasing hormone agonist treatment: a pilot study. J Pediatr Endocrinol Metab 2017;30:657–62.
44. Copeland W, Shanahan L, Miller S, Costello EJ, Angold A, Maughan B. Outcomes of early pubertal timing in young women: a prospective population-based study. Am J Psychiatry 2010;167:1218–25.
45. Wojniusz S, Callens N, Sutterlin S, Andersson S, De Schepper J, Gies I, et al. Cognitive, emotional, and psychosocial functioning of girls treated with pharmacological puberty blockage for idiopathic central precocious puberty. Front Psychol 2016;7:1053.
46. Chung LY, Kang E, Nam HK, Rhie YJ, Lee KH. Efficacy of triptorelin 3-month depot compared to 1-month depot for the treatment of Korean girls with central precocious puberty in single tertiary center. J Korean Med Sci 2021;36e219.
47. Jeon MJ, Choe JW, Chung HR, Kim JH. Short-term efficacy of 1-month and 3-month gonadotropin-releasing hormone agonist depots in girls with central precocious puberty. Ann Pediatr Endocrinol Metab 2021;26:171–7.
48. Torres-Tamayo M, Zurita-Cruz JN, Aguilar-Herrera BE, Miranda-Lora AL, Calzada-Leon R, Rivera-Hernandez AJ, et al. Adjuvant interventions in the treatment of precocious puberty: clinical guideline for the diagnosis and treatment of precocious puberty. Bol Med Hosp Infant Mex 2020;77(Supl 1):26–8.
49. Carel JC, Eugster EA, Rogol A, Ghizzoni L, Palmert MR; ESPE-LWPES GnRH Analogs Consensus Conference Group, et al. Consensus statement on the use of gonadotropin-releasing hormone analogs in children. Pediatrics 2009;123:e752–62.
50. Lee JW, Kim HJ, Choe YM, Kang HS, Kim SK, Jun YH, et al. Significant adverse reactions to long-acting gonadotropinreleasing hormone agonists for the treatment of central precocious puberty and early onset puberty. Ann Pediatr Endocrinol Metab 2014;19:135–40.
51. Yeshaya A, Kauschansky A, Orvieto R, Varsano I, Nussinovitch M, Ben-Rafael Z. Prolonged vaginal bleeding during central precocious puberty therapy with a long-acting gonadotropin-releasing hormone agonist. Acta Obstet Gynecol Scand 1998;77:327–9.
52. Inman M, Hursh BE, Mokashi A, Pinto T, Metzger DL, Cummings EA. Occurrence of slipped capital femoral epiphysis in children undergoing gonadotropin-releasing hormone agonist therapy for the treatment of central precocious puberty. Horm Res Paediatr 2013;80:64–8.
53. De Sanctis V, Soliman AT, Di Maio S, Soliman N, Elsedfy H. Long-term effects and significant Adverse Drug Reactions (ADRs) associated with the use of Gonadotropin-Releasing Hormone analogs (GnRHa) for central precocious puberty: a brief review of literature. Acta Biomed 2019;90:345–59.
54. Gul U, Kacar Bayram A, Kendirci M, Hatipoglu N, Okdemir D, Gumus H, et al. Pseudotumour cerebri presentation in a child under the gonadotropin-releasing hormone agonist treatment. J Clin Res Pediatr Endocrinol 2016;8:365–7.
55. Omar AA, Nyaga G, Mungai LNW. Pseudotumor cerebri in patient on leuprolide acetate for central precocious puberty. Int J Pediatr Endocrinol 2020;2020:22.
56. Luchinger AB, Mijatovic V, Rustemeyer T, Hompes PG. Anaphylactic reaction to different gonadotropin-releasing hormone agonists for the treatment of endometriosis. Am J Med Sci 2011;341:240–2.
57. Gu Q, Luo Y, Ye J, Shen X. Comparative efficacy and safety of three current clinical treatments for girls with central precocious puberty: a network meta-analysis. Endocr Pract 2019;25:717–28.
58. Kim MS, Koh HJ, Lee GY, Kang DH, Kim SY. Comparing adult height gain and menarcheal age between girls with central precocious puberty treated with gonadotropinreleasing hormone agonist alone and those treated with combined growth hormone therapy. Ann Pediatr Endocrinol Metab 2019;24:116–23.
59. Klein KO, Dragnic S, Soliman AM, Bacher P. Predictors of bone maturation, growth rate and adult height in children with central precocious puberty treated with depot leuprolide acetate. J Pediatr Endocrinol Metab 2018;31:655–63.
60. Zurita-Cruz JN, Torres-Tamayo M, Aguilar-Herrera BE, Miranda-Lora AL, Rivera-Hernandez AJ, Calzada-Leon R, et al. Monitoring during the treatment of precocious puberty: clinical guideline for the diagnosis and treatment of precocious puberty. Bol Med Hosp Infant Mex 2020;77(Supl 1):29–34.
61. Lazar L, Phillip M. Pubertal disorders and bone maturation. Endocrinol Metab Clin North Am 2012;41:805–25.
62. Brito VN, Latronico AC, Arnhold IJ, Mendonca BB. A single luteinizing hormone determination 2 hours after depot leuprolide is useful for therapy monitoring of gonadotropin-dependent precocious puberty in girls. J Clin Endocrinol Metab 2004;89:4338–42.
63. Lee PA, Klein K, Mauras N, Neely EK, Bloch CA, Larsen L, et al. Efficacy and safety of leuprolide acetate 3-month depot 11.25 milligrams or 30 milligrams for the treatment of central precocious puberty. J Clin Endocrinol Metab 2012;97:1572–80.
64. Lazar L, Padoa A, Phillip M. Growth pattern and final height after cessation of gonadotropin-suppressive therapy in girls with central sexual precocity. J Clin Endocrinol Metab 2007;92:3483–9.
65. Brito VN, Latronico AC, Cukier P, Teles MG, Silveira LF, Arnhold IJ, et al. Factors determining normal adult height in girls with gonadotropin-dependent precocious puberty treated with depot gonadotropin-releasing hormone analogs. J Clin Endocrinol Metab 2008;93:2662–9.
66. Eugster EA. Treatment of central precocious puberty. J Endocr Soc 2019;3:965–72.
67. Shim YS, Lim KI, Lee HS, Hwang JS. Long-term outcomes after gonadotropin-releasing hormone agonist treatment in boys with central precocious puberty. PLoS One 2020;15e0243212.
68. Carel JC, Roger M, Ispas S, Tondu F, Lahlou N, Blumberg J, et al. Final height after long-term treatment with triptorelin slow release for central precocious puberty: importance of statural growth after interruption of treatment. French study group of Decapeptyl in Precocious Puberty. J Clin Endocrinol Metab 1999;84:1973–8.
69. Wu V, Zhao V, Issa R, Wilkes M, Wallach E, Rapaport R, et al. Clinical findings influencing time to menarche post gonadotropin-releasing hormone agonist therapy in central precocious puberty. Ann Pediatr Endocrinol Metab 2021;26:185–91.
70. Heger S, Partsch CJ, Sippell WG. Long-term outcome after depot gonadotropin-releasing hormone agonist treatment of central precocious puberty: final height, body proportions, body composition, bone mineral density, and reproductive function. J Clin Endocrinol Metab 1999;84:4583–90.
71. Lazar L, Lebenthal Y, Yackobovitch-Gavan M, Shalitin S, de Vries L, Phillip M, et al. Treated and untreated women with idiopathic precocious puberty: BMI evolution, metabolic outcome, and general health between third and fifth decades. J Clin Endocrinol Metab 2015;100:1445–51.
72. Martinerie L, de Mouzon J, Blumberg J, di Nicola L, Maisonobe P, Carel JC, et al. Fertility of women treated during childhood with Triptorelin (depot formulation) for central precocious puberty: the PREFER study. Horm Res Paediatr 2020;93:529–38.
73. Bertelloni S, Baroncelli GI, Ferdeghini M, Menchini-Fabris F, Saggese G. Final height, gonadal function and bone mineral density of adolescent males with central precocious puberty after therapy with gonadotropinreleasing hormone analogues. Eur J Pediatr 2000;159:369–74.
74. Lazar L, Meyerovitch J, de Vries L, Phillip M, Lebenthal Y. Treated and untreated women with idiopathic precocious puberty: long-term follow-up and reproductive outcome between the third and fifth decades. Clin Endocrinol (Oxf) 2014;80:570–6.
75. Luo X, Liang Y, Hou L, Wu W, Ying Y, Ye F. 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;94:786–96.
76. Yoon JW, Park HA, Lee J, Kim JH. The influence of gonadotropin-releasing hormone agonists on anthropometric change in girls with central precocious puberty. Korean J Pediatr 2017;60:395–402.
77. van der Sluis IM, Boot AM, Krenning EP, Drop SL, de Muinck Keizer-Schrama SM. Longitudinal follow-up of bone density and body composition in children with precocious or early puberty before, during and after cessation of GnRH agonist therapy. J Clin Endocrinol Metab 2002;87:506–12.
78. Park HK, Lee HS, Ko JH, Hwang IT, Lim JS, Hwang JS. The effect of gonadotrophin-releasing hormone agonist treatment over 3 years on bone mineral density and body composition in girls with central precocious puberty. Clin Endocrinol (Oxf) 2012;77:743–8.
79. Antoniazzi F, Zamboni G, Bertoldo F, Lauriola S, Tato L. Bone development during GH and GnRH analog treatment. Eur J Endocrinol 2004;151 Suppl 1:S47–54.
80. Prentice P, Viner RM. Pubertal timing and adult obesity and cardiometabolic risk in women and men: a systematic review and meta-analysis. Int J Obes (Lond) 2013;37:1036–43.

Article information Continued

Table 1.

Levels of evidence

Notation Classifications based on research design
Randomized controlled study Systematic review, meta-analysis, randomized controlled study
Nonrandomized controlled study Cohort study, cross-sectional study, case-control study
Other Others (case series, etc.)
Expert opinion Expert opinions

Table 2.

Grades of recommendation

Grades of recommendation Significance
Do, Strong It is recommended for most patients.
Do, Conditional It is recommended to selectively use it considering the benefit/harm/cost/preference of the patient.
Do not, Conditional It is recommended to use it as a limitation, considering the benefit/harm/cost/preference of the patient. (It can be used on a limited basis, but caution is required.)
Do not, Strong It is not recommended for most patients.

Table 3.

Gonadotropin-releasing hormone agonist formulations approved for use in central precocious puberty treatment in Korea

Ingredient Dosing interval Brand name
Triptorelin acetate 4 Weeks Decapeptyl depot injection 3.75 mg
Dipherelin PR injection 3.75 mg
Triptorelin pamoate 3 Months Dipherelin PR injection 11.25 mg
6 Months Dipherelin SR injection 22.5 mg
Leuprolide acetate 4 Weeks Lorelin depot injection
Leuplin injection 3.75 mg
Leuplin DPS injection 3.75 mg
Luphere depot injection 3.75 mg
3 Months Leuplin DPS injection 11.25 mg