I. Clinical diagnosis
Based on the time of appearance of secondary sexual signs, symptoms, signs and laboratory tests, we first determine whether the child is CPP.
Precocious puberty is classified into central precocious puberty (GnRH-dependent, true, complete precocious puberty), peripheral precocious puberty (non-GnRH-dependent, pseudo-precocious puberty) and incomplete precocious puberty (partial precocious puberty) according to whether HPGA function is initiated early.
The diagnosis of CPP is subject to the following criteria.
(1) Early appearance of secondary sexual characteristics: the development of secondary sexual characteristics appears before the age of 8 years in girls and 9 years in boys. The first manifestation is the appearance of breast nodules in girls and increased testicular volume in boys.
(2) Accelerated linear growth: annual growth rate is higher than normal children.
(3) Premature bone age: bone age is 1 year or more above the actual age.
(4) Enlarged gonads: pelvic ultrasound shows increased volume of the girl’s uterus and ovaries, and multiple follicles >4 mm in diameter are visible in the ovaries; testicular volume I >4 ml in boys.
(5) HPGA function is initiated, and serum gonadotropins and sex hormones reach pubertal levels.
The following issues should also be noted in the clinical diagnosis process.
1. Age definition of precocious puberty: Precocious puberty refers to the development of secondary sexual characteristics in girls before the age of 8 and in boys before the age of 9. Recent surveys around the world have shown that the age of mammary gland development shows a clear trend of advancement, but the age of menarche is only slightly advanced, and there are racial and geographical differences. The Lawson Wilkins Pediatric Endocrine Society in the United States recommends defining the age of precocious puberty as <7 years for Caucasian girls and <6 years for African-American girls, but there is controversy. The timing of the onset of sexual development has been associated with genetic, environmental, and obesity factors. Therefore, it has been proposed that the age definition of precocious puberty should be based on the criteria of different countries and different races. The previous age criteria are still widely used at home and abroad.
Therefore, some scholars suggest that the age definition of precocious puberty should be made according to the criteria of different countries and different races. At present, the previous age criteria are still widely used at home and abroad. Obesity and other factors are related. Therefore, some scholars suggest that the age definition of precocious puberty should be based on the criteria of different countries and different races. At present, the previous age criteria are still widely used at home and abroad. <-->Obesity and other factors are related. Therefore, some scholars suggest that the age definition of precocious puberty should be based on the criteria of different countries and different races. At present, the previous age criteria are still widely used at home and abroad. <-->
2, the order and process of sexual development: sexual development is a continuous process and has a certain pattern. CPP is due to the early initiation of HPGA function, and the order of sexual development is basically the same as that of normal children. The sequence of pubertal development in girls is: breast development, pubic hair, external genital changes, axillary hair growth, and menstruation. In boys, sexual development is first manifested by the increase in testicular volume (≥4 ml marks the beginning of puberty), followed by the growth and thickening of the penis, the growth of pubic hair, axillary hair and low voice, beard, and the appearance of spermatorrhea. There are significant individual differences in the rate of sexual development. The general process of sexual development can last 3-4 years, and the progression of each Tanner stage in girls lasts about 1 year. In boys, the progression of Tanner’s stages is similar to that of girls, but the time from the beginning of testicular enlargement to ejaculation is slightly longer than that of girls.
In the diagnosis of precocious puberty, it is easier to diagnose children who show signs of sexual development before the typical defined age (8 years for girls and 9 years for boys), but while the age of onset of sexual development is important, the sequence and progression of sexual development should also be considered, as abnormal sequence or progression of sexual development can be different manifestations of precocious puberty. The abnormal sequence or process of sexual development can be a different manifestation of precocious puberty. It has important implications for further diagnosis and management.
When the sequence of sexual development is abnormal, we should pay attention to exclude peripheral precocious puberty and incomplete precocious puberty. Among them, incomplete precocious puberty is also called pubertal variants, including simple premature breast development.
When the sexual development process is abnormal, the following conditions should be alerted:
(1) Slowly progressive precocious puberty: some children show signs of sexual development before the defined age (7-8 years), but the sexual development process and bone age progress slowly, and linear growth remains at the corresponding percentile.
(2) Rapidly progressive pubeay: Although some children begin to develop sexually after the defined age, the sexual development process is rapid and the time to progress from one developmental stage to the next is short (<6 months). The growth rate increases, skeletal maturation is rapid, and bone age significantly exceeds the actual age within a short period of time, affecting the final adult height due to early epiphyseal healing. The slow progressive puberty should be followed up and the bone age should be rechecked every six months if necessary, and timely intervention should be given if abnormalities are found. For fast-progressing puberty, it may need to be treated according to the precocious puberty program.
3. Growth acceleration: Growth acceleration can occur during the process of sexual development, generally at the age of 9-10 years for girls and 11-12 years for boys, but with individual and racial differences, and related to the stage of sexual development. In Tanner II-IV, the percentage of girls with accelerated growth was 40%, 30%, and 20%, while the percentage of boys with accelerated growth was 8%, 60%, and 28%, respectively. Growth acceleration even occurs before the onset of mammary gland development in 10% of girls and at the beginning of Tanner V in 4% of boys. If there is a lack of information on the growth rate of the child, growth should be monitored for 3-6 months to further evaluate for accelerated growth and to assess for fast progressive sexual development.
4. Assessment of gonadal development: pelvic ultrasound in girls: uterine length 3.4-4.0 cm, ovarian volume 1-3 ml (ovarian volume = length × width × thickness cm × 0.5233), and multiple follicles ≥4 mm in diameter visible, suggesting pubertal development. Endometrial echo has good specificity but slightly lower sensitivity (42%-87%) and can be used as one of the auxiliary examinations for the differential diagnosis of CPP from normal girls and girls with premature mammary gland development alone, but not as a means of differentiation from other peripheral precocious puberty. Testes in boys: testicular volume ≥ 4 m1 (testicular volume = length × width × thickness cm × 0.71) or testicular length diameter > 2.5 cm suggests pubertal development.
5. Properly assess whether HPGA function is initiated by.
(1) Basal level of luteinizing hormone (LH). LH is more clinically significant than follicle-stimulating hormone (FSH) in the diagnostic process of CPP. However, the significance of basal LH level is limited because LH is pulsatile secretion; its level is affected by the detection method and varies greatly; there is a lack of corresponding normal value information; and about 50% of girls in Tanner 1I stage have basal LH values that can be at prepubertal levels.
(2) GnRH excitation test: GnRH excitation test is the gold standard for the diagnosis of CPP and an important basis for differentiating CPP from peripheral precocious puberty. However, clinically, due to various factors, the diagnosis cannot be made solely based on the results of GnRH excitation test, and the following issues should be noted in the process of result evaluation.
GnRHa is tens of times stronger than natural GnRH, and its peak value occurs at 60-120 min, so it is generally not recommended for use in routine diagnosis. If GnRHa is used instead, there should be each laboratory’s own drug dose and test data.
② Detection methods: The diagnostic threshold values are different when different methods are applied. Immunofluorescence method (IFMA), LH peak >9.6 U/L (boys) or >6.9 U/L (girls); immunochemiluminescence method (ICMA), LH peak ≥5.0 U/L are suggestive of gonadal axis initiation. Therefore, it is inappropriate to use the same threshold value for result evaluation for different assays. Centers and laboratories in a position to do so are advised to establish their own diagnostic cut-off values.
The LH peak/FSH peak is also useful for differentiating between fast-progressive and non-progressive CPP (the LH peak/FSH peak ratio in children with fast-progressive CPP is higher than the LH peak/FSH peak ratio in children with fast-progressive CPP). LH peak/FSH peak ratio is higher).
④In the GnRH excitation test, the basal and peak values of FSH have no significant clinical significance for the diagnosis of precocious puberty.
⑤In addition, the results should be judged in the context of the child’s sexual development status, the progression of sexual characteristics, and the changes in height and bone age. In some children with a short course of disease, the GnRH stimulation test may be false negative when the breast development is early, when there is no obvious growth acceleration, and when the bone age is not significantly advanced. Such children should be closely followed for the development of sex characteristics, growth rate, bone age, etc. GnRH stimulation test should be repeated if necessary.
(3) Sex hormone levels: Sex hormone levels should not be used as a diagnostic indicator for CPP. The level of estradiol is highly variable, and low levels of estradiol cannot exclude CPP, but when estradiol levels are >367 pmol/L (100 pg/m1), a high degree of caution should be exercised for ovarian cysts or tumors.
II. Etiological diagnosis
According to the etiology CPP is subdivided into: idiopathic CPP and secondary CPP (secondary to central nervous system abnormalities, secondary to peripheral precocious puberty) (Table 1). Once the clinical diagnosis is clear, the etiological diagnosis of cPP should be made, and tests such as cranial MRI, adrenal function, and thyroid function should be performed according to the condition to understand whether it is due to central nervous system pathology or other diseases.
Congenital hypothyroidism
1. cranial imaging to rule out neurological abnormalities: CPP is more common in girls, of which 80%-90% are idiopathic CPP. but the proportion of central nervous system abnormalities in girls with CPP who develop sexually before the age of 6 is about 20%, and the younger the age, the greater the likelihood of imaging abnormalities. Although the prevalence of male precocious puberty is relatively low, 25%-90% of children have organic causes, about 2/3 of children have neurological abnormalities, and about 50% of children have CNS tumors. Therefore, cranial MRI should be routinely performed in girls with CPP younger than 6 years of age and in all male children with precocious puberty. it is controversial whether all girls with CPP between 6 and 8 years of age should undergo cranial MRI, but in children with neurological manifestations or rapidly progressive forms, cranial MRI should be performed.
2. Exclude other secondary diseases: In the diagnosis of CPP, attention should also be paid to clarify whether precocious puberty is secondary to the following diseases.
(1) Congenital adrenocortical hyperplasia This disease, mostly 21 hydroxylase deficiency, is the most common cause of peripheral precocious puberty in boys. It manifests as penile enlargement and thickening, scrotal pigmentation, and testicular volume is not large or testicular volume is not consistent with the level of penile development. Early height growth is accelerated and bone age is significantly advanced. Blood levels of 17 hydroxyprogesterone, dehydroepiandrosterone sulfate, androstenedione and testosterone are elevated. Long-term undiagnosed treatment may transform into CPP.
(2) McCune-Albright syndrome, also known as multiple osteochondrodysplasia, is most commonly seen in females and is due to a defect in the Gs gene. The syndrome is characterized by a triad of precocious puberty, cutaneous café au lait, and multiple osteochondrodysplasia. Most children may have only one or two signs and may have endocrine abnormalities of the pituitary, thyroid and adrenal glands, as well as unilateral ovarian cysts. However, the sexual development process differs from that of CPP, with vaginal bleeding, dark nipples and areolas, increased estrogen levels and low gonadotropin levels, and peripheral precocious puberty on GnRH stimulation test. With the progress of the disease, some of them can be transformed into CPP.
(3) Familial malelimited precocious puberty This disease is due to LH receptor activation mutation and is familial. The child develops testicular enlargement at the age of 2-3 years, with markedly increased testosterone levels and a significant increase in bone age, but LH does not respond to GnRH stimulation. With the progression of the disease can be transformed into CPP.
(4) Primary hypothyroidism secondary to CPP in this disease may be related to the disturbance of HPGA regulation. In hypothyroidism, hypothalamus secretion of TRH increases. Since cells secreting TSH have homology with cells secreting prolactin (PRL), LH and FSH, TRH not only promotes increased TSH secretion from pituitary gland, but also promotes PRL and LH and FSH secretion. It has also been suggested that the glycoprotein receptors of FSH and TSH are similar in structure, and that elevated TSH in low A may produce FSH-like effects. Clinical manifestations of precocious puberty, such as breast enlargement, lactation and vaginal bleeding in girls, but without linear growth acceleration and accelerated bone age growth, may occur. Severe and long-term untreated cases can be transformed into CPP.
Differential diagnosis
CPP should be distinguished from peripheral precocious puberty and incomplete precocious puberty. In particular, CPP in girls should be distinguished from simple premature breast development. Pure breast development is incomplete precocious puberty in girls, and it usually occurs in girls before 2 years old. In addition to breast development, there are no other signs of sexual development, accelerated growth and early skeletal development, and no vaginal bleeding. Serum estradiol and FSH basal values are often mildly elevated. The development of premature breast development is generally considered to be a benign and self-limiting process, but about 15% of the children will develop CPP; therefore, children with simple premature breast development should be followed up, and sex hormone levels, growth rate, and bone age progress should be routinely monitored.
Treatment of CPP
I. Etiological treatment
For secondary CPP, simultaneous etiological treatment should be emphasized. CPP with central nervous system lesions can be considered for surgery or radiotherapy, such as tumors in the saddle area especially those with neurological symptoms mostly require surgery; however, cautious treatment is appropriate for intracranial tumors with non-progressive damage or congenital anomalies, such as hypothalamic malformation tumors or arachnoid cysts. CPP secondary to other diseases should be treated simultaneously for the original disease.
II. GnRHa treatment
The aim of treatment for idiopathic CPP is to inhibit the process of sexual development, delay excessive skeletal maturation and improve the final adult height, and avoid psychological and behavioral problems. At present, GnRHa is commonly used in the treatment of CPP at home and abroad, and has achieved better clinical results.
1, the scope of treatment: CPP treatment should first clarify the scope of treatment, not all children with CPP need GnRHa treatment. gnRHa treatment indications.
(1) CPP (fast progressive): children with precocious puberty have significantly accelerated skeletal maturation and secondary sex characteristics (more than linear growth acceleration);
(2) Impaired predicted adult height: predicted adult height < 3rd percentile or < genetic target height, skeletal height < 2 standard deviations of height (one 2s);
(3) Fast-progressing puberty: those who begin to develop sexually after the age defined by precocious puberty, but have rapid sexual developmental progression and skeletal maturation that can affect final adult height;
(4) The appearance of psychological behavioral problems directly related to precocious puberty. < span="">Children with slowly progressive precocious puberty and those with CPP whose bone age is advanced but whose growth rate is higher than normal and whose predicted adult height is not significantly impaired do not require immediate treatment and should be reviewed periodically for changes in height and bone age to assess the need for treatment at any time.
It should be noted that the Bayley.Pinneau method is commonly used for height prediction at home and abroad, but data show that this method may overestimate the predicted height of children with precocious puberty.
2, GnRHa drug type: GnRHa is a long-acting synthetic hormone made by replacing the 6th amino acid in the natural GnRH molecule, namely glycine, with D-tryptophan, D-serine, D-histidine or D-leucine. Several drugs such as Triptorelin, Leuprorelin, Buserelin, Goserelin and Histrelin are currently available and are 15-200 times more potent than natural GnRH. Formulations are available as 3.75 mg extended-release (intramuscular or subcutaneous injection every 4 weeks), 11.25 mg
(injected every 3 months), and 11.25 mg long-acting extended-release (injected every 3 months). In China, the 3.75 mg formulations of treprostinil and leuprolide are most commonly used.
The mechanism of action of GnRHa is to bind to the GnRH receptors of the anterior pituitary gonadotropic cells, which can briefly increase the transient release of LH and FSH (“ignition effect”), and then cause the corresponding receptors of the pituitary target cells to be down-regulated, inhibiting the pituitary. The gonadal axis, so that LH, FSH and gonadal hormone secretion is reduced, thereby controlling the process of sexual development and delaying skeletal maturation.
3, GnRHa treatment program: about GnRHa dose and dosing program, there is a lack of uniform standards at home and abroad. The first dose of 3.75 mg of slow-release is recommended in China, and thereafter the dose is 80-100ug/(kg・4 weeks), or the usual dose of 3.75 mg is used and injected once every 4 weeks. Appropriate adjustments can be made according to the suppression of gonadal axis function. The choice of dose varies between drug formulations. The literature reports that the dose of treprostinil is 60-160ug/(kg・4 weeks); the therapeutic dose of leuprolide is 30-180ug/(kg・4 weeks) and even up to 350ug/(kg・4 weeks).
The application of GnRHa in the treatment of children with CPP emphasizes the principle of individualization. Drugs approved by the State Food and Drug Administration for CPP should be used, and individualized treatment plans should be adopted according to the type of drug, dosage form and injection method. Formulations can be selected according to local drug availability and physician’s experience with medication.
GnRHa injections every 4 weeks can adequately suppress HPGA function in most children with CPP. Individual children with poor control may require a shorter dosing interval or more than the standard dose, but caution is advised and attention should be paid to further evaluation of the diagnosis and condition.
4.Treatment monitoring: During GnRHa treatment, sexual development, growth rate, height standard deviation score (HtSDS), and hormone levels should be monitored every 3 months; bone age should be monitored once every 6 months. Gonadotropin and sex hormone levels can be monitored during treatment, either arbitrarily or after stimulation, to assess gonadal axis suppression, but there is no consensus on the monitoring method.
Children with CPP who have a clear diagnosis and do not require special treatment for the time being should still be monitored regularly for changes in growth rate and bone age and evaluated, and GnRHa therapy can be considered if necessary. Indicators of effective treatment: normal or decreased growth rate; retraction of breast tissue or no continued enlargement; reduced or no continued enlargement of testicular volume in boys; delayed progression of bone age; HPGA in a suppressed state.
Care should be taken to carefully assess the diagnosis and exclude other diseases if the following conditions occur during treatment (1) Vaginal bleeding occurs during GnRHa treatment. Some children with CPP may have vaginal bleeding after the first GnRHa injection, which is related to the “ignition effect” of GnRHa. Vaginal bleeding in the later stages of treatment may be related to poor HPGA suppression, but the correct diagnosis should be re-evaluated to exclude tumors and other diseases; (2) a significant decrease in growth rate (≤2SDS); and (3) rapid progression of bone age. In addition, the appearance or progression of pubic hair usually represents incipient adrenal function and does not necessarily imply treatment failure. the inhibitory effect of GnRHa treatment on HPGA is well recognized, but there are mixed reports on the benefit of GnRHa treatment to improve lifetime height and height in CPP. Foreign studies have shown a greater height benefit in girls with precocious puberty who started treatment with GnRHa before the age of 6 years. However, studies with long-term follow-up to lifetime height have also found no significant correlation between lifetime height or post-treatment height benefit and age. During GnRHa treatment, children showed a decrease in growth rate after six months of treatment and especially after one year of treatment, and some children even showed a significant growth deceleration. The specific mechanism of growth deceleration is unknown, but it may be that GnRHa interferes with and inhibits related growth regulatory levels, including alterations in the growth hormone insulin-like growth factor 1 (GH/IGFl) axis; local alterations in the growth plate due to premature exposure to estrogen; and the effect of GnRHa on the growth factor receptor pathway. Because of the lack of data from long-term controlled clinical studies in large samples, routine combination therapy with recombinant human growth hormone (rhGH) is not recommended. The application of rhGH can be considered for those with severe height impairment in predicted adults, but close monitoring is required.
5. Timing of GnRHa discontinuation: depends on the purpose of treatment. To improve adult height for the purpose of treatment is generally appropriate to continue for more than 2 years; bone age 12-13 years (girls 12 years, boys 13 years).
Discontinuation of the drug may take into account the wishes of the child and his parents, as appropriate, and requires careful assessment by the physician. However, there is a lack of appropriate fixed indicators for discontinuation, such as bone age, age, growth rate, duration of treatment, height, and genetic target height. Bone age is not an appropriate single indicator for discontinuation; bone age of 12 years can occur in children with CPP at different ages, and the use of bone age to evaluate the benefit of height after treatment is not reliable.
The treatment regimen for GnRHa should be individualized, and discontinuation of the drug should take into account height satisfaction, compliance, quality of life, and the need for concurrent development of sexual development with that of the same age.
6, safety monitoring: GnRHa treatment during the occasional rash, flushing, headache, but usually transient and mild, does not affect the treatment. 10-15% of children can appear local reactions, allergic reactions are very rare. Some children may experience a small amount of vaginal bleeding 3-7 days after the first GnRHa treatment, which is related to the “ignition effect” of GnRHa leading to a transient increase in estrogen levels, follicular growth and vesicle formation. The safety of long-term treatment is good.
(1) Reproductive system function The literature reports that GnRHa treatment does not affect ovarian function and reproductive function. HPGA function recovered rapidly after discontinuation of the drug, gonadotropin as well as estrogen levels increased, and uterus and ovaries resumed development. First menstruation can occur 2-61 months (mean 12-16 months) after discontinuation and regular menstrual cycles occur in 60%-90% of patients, with no significant differences from normal girls, and no reports of infertility have been seen. A recent cross-sectional study with a large sample showed that adult fertility in GnRHa-treated CPP patients was similar to that of normal controls, and natural conception was similar to normal. In contrast, untreated CPP patients are more likely to have fertility problems in adulthood and require ovulation promotion or assisted reproductive technology at a significantly higher rate than normal controls and GnRHa-treated CPP patients.
(2) Body mass index (BMI) It has been shown that early development or precocious puberty in girls is associated with overweight and obesity. In some girls with CPP, BMI was higher than the normal mean at the beginning of diagnosis and treatment, and long-term GnRHa treatment did not aggravate the obesity trend, and there was no significant change in SDS or percentile of BMI.
Girls with CPP who were significantly overweight had an increased risk of type 2 diabetes and cardiovascular disease compared to normal girls, but not due to GnRHa treatment. Early development, especially the onset of menarche before age 12 years, increases the risk of obesity, type 2 diabetes, cardiovascular disease, and certain cancers in adulthood.
(3) Polycystic ovary syndrome (PCOS) There are conflicting reports in the literature regarding the occurrence of hyperandrogenism and PCOS after GnRHa treatment in girls with CPP.
Some studies have shown that GnRHa treatment may increase the incidence of hyperandrogenism and PCOS in CPP patients. However, some studies concluded that the manifestation of hyperandrogenism after CPP treatment was higher than that of the control group, but not statistically significant. Rapid weight gain in infancy is associated with early age at menarche and ovarian hyperandrogenism. In contrast, the latest cross-sectional study with a large sample showed that the hyperandrogenic status of CPP patients was not related to the presence or absence of GnRHa treatment, and that untreated CPP patients were more likely to develop symptoms caused by hyperandrogenism in adulthood, such as acne and hirsutism, with irregular menstruation.
A pelvic ultrasound study of girls with precocious puberty found that the uterus and ovaries were usually enlarged at the time of diagnosis in girls with CPP; 3 months after starting treatment, the volume of the uterus and ovaries could be reduced to the normal range; after stopping treatment, the volume of the uterus and ovaries remained in the normal range and no features of polycystic ovaries were found. A study with a mean follow-up of 12 years after discontinuation of GnRHa treatment found no increase in the incidence of PCOS in girls after CPP treatment compared to healthy women.
In the general population, the incidence of PCOS was 5-10%, while the incidence of PCOS in girls on CPP was 0-12%. The study concluded. Premature adrenal function and insulin resistance in childhood are potential risk factors for PCOS, and it is uncertain whether these risk factors ultimately increase the risk of PCOS when present in conjunction with CPP. Precocious puberty has also been suggested to be the first manifestation in some patients with PCOS.
(4) bone mineral density (BMD) Children with CPP often have increased BMD values at the time of diagnosis. During GnRHa treatment, the acquisition of bone minerals is limited due to suppression of ovarian function, but BMD values do not change or decrease slightly, and bone mineral content is restored soon after treatment is stopped.
(5) Lipid metabolism It has been documented that fasting insulin, triglyceride, LDL and cholesterol levels are elevated at the time of diagnosis in girls with CPP, while insulin sensitivity and HDL/total cholesterol levels are decreased. Moreover, the earlier the age of onset of sexual development, the more pronounced the above abnormalities in lipid metabolism. The abnormalities of lipid metabolism may become more obvious in some patients during the treatment, but there is also literature showing that the above changes may be related to obesity itself.
(6) Psychosocial impact Epidemiological studies show that early development is more likely to cause functional manifestations (such as stomach pain, headache, joint pain, etc.), depressive symptoms, sexual contact and other psychological behavior problems. Girls are more prone to alcohol abuse, overweight, and sexual behavior. Boys, on the other hand, are more prone to risk-taking or criminal behaviors such as drug use. However, the effect of applying GnRHa treatment on psychosocial behavior in children with precocious puberty is not certain.
7.Application of GnRHa in non-CPP areas The following conditions are not recommended for routine application of GnRHa.
(1) The long-term effects of chemotherapy for malignancy can cause infertility. However, the application of GnRHa during chemotherapy in children is not recommended to protect gonadal function.
(2) GnRHa alone has limited effect on improving eventual adult height in idiopathic short stature in children with normal age onset of sexual development and in children younger than fetal age, and is not recommended.
(3) The efficacy of GnRHa alone or in combination with rhGH treatment in congenital adrenocortical hyperplasia predicting severely impaired height requires further studies in large samples.
GnRH antagonists
GnRH antagonists act directly on GnRH receptors in the pituitary gland and should have a good future because they do not have an “ignition effect” and the inhibitory effect on the gonadal axis can be quickly restored after discontinuation of the drug. It is still under development.
In conclusion, the diagnosis of CPP should be based on the age of onset, symptoms, signs, laboratory and imaging examinations of the child according to the steps of clinical diagnosis, etiological diagnosis and differential diagnosis, among which etiological diagnosis is particularly important. The treatment of GnRHa should be strictly controlled, individualized, and closely monitored during the treatment process to ensure the effectiveness and safety of the medication.