Precocious puberty is a common developmental abnormality of the pediatric endocrine system. In order to standardize the diagnosis and treatment of central (true) precocious puberty, the Endocrine Genetic Metabolism Group of the Pediatrics Branch of the Chinese Medical Association conducted a special discussion and formulated the following guidelines for clinical reference.
Definition.
Precocious puberty is a developmental abnormality in which girls present secondary sexual characteristics by the age of 8 years and boys by the age of 9 years. Central precocious puberty (CPP) is caused by an early increase in the secretion and release of gonadotropin-releasing hormone (GnRH) from the hypothalamus, which leads to an early activation of gonadal axis function, resulting in gonadal development and secretion of sex hormones, resulting in the development of internal and external genitalia and the presentation of secondary sexual characteristics. CPP is also known as GnRH-dependent precocious puberty, which develops progressively until the reproductive system matures.
[Etiology]
1, organic lesions of the central nervous system.
2, transformation from peripheral precocious puberty.
3. Idiopathic CPP (ICPP) without organic lesions. About 80% to 90% of female children have ICPP; in contrast, more than 80% of male children are organic.
[Diagnosis]
The differential diagnosis of the etiology of GnRH-dependent precocious puberty should be made after determining whether it is first.
I. Diagnostic basis
1. Early appearance of secondary sexual characteristics: before the age of 8 for girls and 9 for boys.
2. Elevated serum gonadotropin levels up to puberty level.
(1) Basal value of gonadotropin: If the secondary sexual characteristics have reached the level of mid-puberty, the basal value of serum luteinizing hormone (LH) can be used as the initial screening, such as >5.0 IU/L, it can be determined that the gonadal axis has been activated, and there is no need to conduct gonadotropin-releasing hormone (GnRH) stimulation test.
(2) GnRH excitation test: This test is an important diagnostic tool for those whose gonadal axis function has been activated and whose gonadotropin basal value is not elevated.
GnRH excitation test method: GnRH (Gonarelin) 2.5 μg/kg or 100 μg/m2 is routinely injected intravenously, blood samples are taken at 0min, 30min, 60min and 90min, and serum LH and follicle stimulating hormone (FSH) concentrations are measured (120min of the classic GnRHa test method can be omitted), and synthetic GnRH analogues ( GnRHa) has a stronger stimulatory effect than the natural one, with peaks occurring at 60-120 min, but its use in routine diagnosis is not recommended.
The cut-point value of LH excitation peak for the diagnosis of CPP: depends on the gonadotropin assay used. When measured by radioimmunoassay, LH peak should be >12.0 IU/L in girls, >25.0 IU/L in boys, and LH peak/FSH peak >0.6-1.0 for the diagnosis of CPP (Note: LH peak is the highest value of LH at each time point in the excitation test) (Note: LH peak is the highest value of LH at each time point in the excitation test, FSH peak is the highest value of FSH at each time point in the excitation test); when measured by immunochemiluminescence method (ICMA), LH peak >5.0 IU/L, LH peak/FSH peak >0.6 (both sexes) can diagnose CPP; if LH peak/FSH peak >0.3, but <0.6, close clinical follow-up should be combined with repeat tests if necessary to avoid missing the diagnosis.
3, enlarged gonads: girls with ovarian volume >1m1 and multiple follicles >4mm in diameter seen under ultrasound; boys with testicular volume ≥4ml and progressive enlargement with disease duration.
4, accelerated linear growth.
5, bone age beyond age by 1 year or more.
6, elevated serum sex hormone levels to pubertal levels.
Among the above diagnostic bases, 1, 2 and 3 are the most important and must be available. However, if the duration of the disease is very short at the time of consultation, the GnRH excitation value may overlap with the prepubertal value and not reach the above diagnostic cut-off value; the same applies to ovarian size. Such children should be followed for paraphimosis progression and linear growth acceleration and the above tests should be repeated if necessary. In female children, linear growth acceleration during puberty usually occurs about 6 months to 1 year after the onset of breast development (B2 to B3 stage) and lasts for 1 to 2 years; however, there are some late cases, and even about 5% of children present one year before or in the year of menarche. In boys, accelerated growth occurs when the testicular volume is about 8 to 10 ml or one year before the change of voice, and lasts longer than in girls. The advancement of bone age only indicates the increase of sex hormone level for a period of time, which is not a specific indicator for the diagnosis of CPP. Children with short duration of disease and slow development process may not have obvious advancement of bone age, while peripheral precocious puberty may also have advancement of bone age; elevated sex hormone level cannot distinguish between central and peripheral precocious puberty.
In conclusion, the diagnosis of CPP is comprehensive, and the core issue is that it must be GnRH-dependent, and the progressive development of sexual characteristics in clinical follow-up is of great significance.
Etiological diagnosis
We should pay attention to collecting medical history related to the etiology of CPP, such as infection, central nervous system lesions and other related symptoms; all children diagnosed with CPP should exclude tumors, and MRI or CT examination of the cranial saddle area is needed; MRI has better resolution than CT for organic lesions of hypothalamus and pituitary gland.
Differential diagnosis
Although GnRH excitation test can largely distinguish central precocious puberty from peripheral precocious puberty, the following conditions should be distinguished.
1. simple precocious breast development: i.e., partial central precocious puberty (PICPP), where FSH is significantly elevated after GnRH excitation (also elevated in normal prepubertal girls after excitation), but LH is not significantly elevated (mostly <5 IU/L), and FSH/LH>1. However, it is noteworthy that PICPP is converted into CPP in the absence of any clinical precursor manifestations. therefore, the diagnosis of PICPP needs to be followed up regularly after diagnosis, especially for those with recurrent breast enlargement or persistent non-remission, and repeat the provocation test if necessary.
2, CPP transformed from non-central precocious puberty: such as congenital adrenocortical hyperplasia, McCune-Albright syndrome, etc. Attention must be paid to monitoring the occurrence of CPP during the treatment of the primary disease.
In this case, the child with congenital hypothyroidism with precocious puberty is a special type of precocious puberty, in which the basal blood LH value is elevated in the early stage, but not after GnRH excitation, and only after a longer course of the disease is it transformed into true CPP. short stature is an important feature.
[Pharmacological treatment]
The treatment of CPP is aimed at improving the adult height of the affected child, and attention should also be paid to prevent the psychological problems associated with premature maturation and early menarche. GnRH analogues (gonadotroping releasing hormone analogue (GnRHa)) are generally used to treat CPP. Diphereline; the latter is Enantone.
GnRHa can effectively inhibit LH secretion, so that the gonads suspend development and sex hormone secretion back to the prepubertal state, thus delaying the growth and fusion of epiphysis, to achieve the purpose of extending the growth years and improving the final height in adulthood as much as possible.
I. Indications for the application of GnRHa
1. In order to achieve the purpose of improving the lifelong height in adulthood, the applicable indications are children with significantly impaired growth potential and remaining growth potential, i.e. those whose bone age is significantly advanced and whose epiphyses have not yet started to fuse, as follows.
(1) Bone age: bone age ≥ 2 years of age; ≤ 11.5 years for girls and ≤ 12.5 years for boys.
(2) Predicted adult height: girls ≤ 150 cm, boys ≤ 160em, or those below their genetic target height minus 2 SD.
(3) Bone age/age > 1, bone age/height age > 1, or height SDS <-2 SDS judged by bone age.
(4) Rapid sexual development process, bone age growth / age growth > 1.
2. Indications for caution: The efficacy of improving adult height is poor in the following cases and should be used with caution: (1) girls with bone age > 11.0 years and boys > 12.0 years at the start of treatment; (2) those whose genetic target height is 2 standard deviations below the normal reference value (-2SDS). Other causes of short stature should be considered.
3. Indications that should not be applied: GnRHa treatment alone is not effective in improving height in adulthood in the following cases: (1) bone age of girls ≥ 12.0 years and boys ≥ 13.5 years; (2) 1 year after menarche in girls or after ejaculation in boys.
4, does not need to apply the indications.
(1) sexual maturation process is slow (bone age progression does not exceed age progression) does not require treatment when the impact on adult height is not significant.
(2) Although the bone age is advanced, the height growth rate is fast, making the height age greater than the bone age, and the predicted height in adulthood is not impaired. However, because the process of pubertal maturation is dynamic, the judgment of each individual should also be dynamic. Once the diagnosis of CPP is established, those whose initial assessment is deemed temporarily not to require treatment are required to periodically review their height and bone age changes, periodically re-evaluate the need for treatment, and develop treatment plans as needed.
Second, GnRHa application methods
1.Dose: 80-100μg/kg for the first dose, and then intensify once after 2 weeks, and once every 4 weeks (not more than 5 weeks), the dose is 60-80μg/kg, the dose should be individualized, according to the suppression of gonadal axis function (including sexual characteristics, sex hormone level and bone age progression), poor suppression can be referred to the first dose, the maximum amount is 3.75 mg/time. In order to know exactly the bone age progression, the clinician should personally evaluate and compare the bone age before and after the treatment, and should not make judgment only based on the radiology report.
2.Monitoring during treatment: check the secondary sexual characteristics and measure height every 2-3 months during treatment; review the GnRH excitation test at the end of 3 months after the first dose, if the LH excitation value is in the prepubertal value, then the dose is appropriate; thereafter, only the basal serum estradiol (E2) concentration or vaginal smear (maturity index) should be reviewed periodically for girls, and the basal serum testosterone level should be reviewed for boys to determine the gonadal axis function. The basal serum testosterone levels were repeated in boys to determine the suppression of gonadal axis function. In girls, ultrasound of the uterus and ovaries should be repeated at the same time.
3, the course of treatment: in order to improve adult height, the course of GnRHa generally need at least 2 years, girls in the bone age of 12.0 ~ 12.5 years should stop treatment, at this time, such as extending the course of treatment is often difficult to continue to improve the height of adulthood. For those who start treatment at a younger age, if their age has caught up with the bone age, and the bone age has reached the normal pubertal initiation age (≥ 8 years), the predicted height can reach the genetic target height can stop the drug, so that its gonadal axis function restart, should be regularly followed.
Third, the monitoring after discontinuation of the drug
The height, weight and recovery of paraphilias as well as the recovery of gonadal axis function should be reviewed every six months after the end of treatment. Girls usually present menarche within 2 years after stopping treatment.
Fourth, the treatment of growth deceleration in GnRHa treatment
The growth rate of the first six months of GnRHa treatment does not change significantly compared with that before treatment, and after six months, it generally falls back to the growth rate of pre-puberty (about 5 cm/year), and the growth rate of some children is <4 cm/year after 1 to 2 years of treatment, at which time it will be difficult to improve their adult height with continued GnRHa treatment, especially when the bone age is ≥12.0 years old (female) or 13.5 years old (male). Reducing the dose of GnRHa treatment does not result in improved growth, but rather risks accelerating bone age growth. In recent years, GnRHa and recombinant human growth hormone (rhGH) have been used internationally to overcome growth deceleration, but it should be noted that in children with bone age ≥13.5 years (female) or 15 years (male), the growth potential of the bone growth plate has been depleted, and growth improvement is often not significant even with the addition of rhGH.
The use of rhGH should be strictly indicated and generally used only when the child’s predicted adult height does not reach its target height; GH should be administered at a pharmacological therapeutic dose [0.15-0.20 U/(k g?d)], and side effects should be closely monitored during application (contraindications to the use of rhGH and monitoring of side effects during treatment are the same as for other growth retardation disorders).
[Etiological treatment]
For non-specific CPP, concurrent etiologic treatment should be emphasized (e.g., surgical treatment of saddle area tumors, concurrent administration of cortisol for congenital adrenocortical hyperplasia combined with CPP, etc.). However, in children with hypothalamic malformation tumors and arachnoid cysts, if there is no elevated cranial pressure, surgery should be deferred and only ICPP should be treated.
In conclusion, precocious puberty is a multi-causal abnormality of sexual development, and the identification of the cause is crucial. The identification of GnRH-dependent precocious puberty should exclude central organic pathology, especially in boys and in those with onset under 6 years of age (both sexes). GnRHa treatment can be considered as the first choice for idiopathic CPP, but the indications for its application need to be reasonably controlled, and the balance of growth/maturation should be monitored, judged, and mastered during treatment in order to achieve improvement in adult height.
Post-reading summary.
In recent years, the specialty of pediatric endocrinology and metabolism has developed rapidly, and many diseases are gradually recognized by everyone. CPP, as a major disease of sexual developmental abnormalities in pediatric endocrine diseases, has gradually increased in incidence with the changes of the general social environment, and everyone’s awareness of it has gradually deepened.
This guideline is very timely, because
1. the level of awareness of CPP among pediatricians in China is uneven.
2. treatment is often not standardized and tends to expand
3, drug treatment is expensive, and GnRHa is the only therapeutic drug with positive efficacy for the treatment of true precocious puberty. The guidelines are silent on the treatment of true precocious puberty with herbal medicine.
This guideline focuses on diagnostic criteria and treatment detection follow-up.
4. In terms of clinical diagnosis, there is another point that is not raised in the guideline, but has been used as a diagnostic basis at present, namely: “The appearance of menarche before the age of 10 in females can be used as a diagnostic basis for precocious puberty”.
In fact, there is a problem of bone age diagnosis in it. The GP chart method widely used in China has limited accuracy, and it is better to adopt TW3 scoring method and make annual height prediction if you have the conditions (as the height prediction can only be made by the bone age, age and height at that time, and the adult height is predicted according to the law of normal growth and development. Children with true precocious puberty cannot grow according to the normal growth pattern, so the reliability of height prediction is limited. (However, it can at least provide a reference for the development of the initial treatment plan and be used for pre- and post-treatment comparison). Although the guidelines emphasize that “clinicians should personally assess and compare bone age before and after treatment, and should not make judgments based on radiology reports alone.” However, many physicians are too busy to make personal assessment, which is obviously detrimental to the timely adjustment of medication dosage.
There is also the issue of measured values in the guidelines, where GnRH excitation values may overlap with prepubertal values and not reach the above diagnostic cut-off values, as does ovarian size. This requires dynamic observation and comprehensive analysis at the time of diagnosis, and advancement of bone age is not a specific indicator for the diagnosis of CPP.
One thing to note in the differential diagnosis is simple breast development, which can easily be misdiagnosed and lead to expanded treatment.
In addition, the diagnosis of precocious puberty can only be made when sexual development occurs before the age of 8 years in girls. However, it is not very scientific for girls to use breast development as the first sign of development, compared to boys who use testicular enlargement as a sign of development. Ideally, it would be more reasonable for girls to use ovarian development as the first sign, because sex hormones increase only after ovarian development, and then breast development occurs, but the ovaries are in the abdominal cavity and cannot be known in advance without ultrasound. The time between breast development and menarche varies greatly from person to person, ranging from 4-5 years to less than a year.
Developmental age exceeds the standard age for diagnosis of precocious puberty, but signs of development appear before 10 for girls and 11 for boys, and if the predicted adult height is low, the diagnosis of early pubertal development can be made and medical intervention can be performed.
5, treatment, for GnRHa application indications, the guidelines for the first time described in detail the indications of caution, inappropriate and do not need treatment. The indications listed in the guidelines are for the common indications of CPP treatment, although relatively conservative, special circumstances can be appropriate to relax the bone age indicators, but relaxation of bone age indicators are generally appropriate to not more than 0.5 years, if the bone age is too large, the use of GnRHa, at least for the improvement of lifelong height is not significant.
For the management of growth deceleration in treatment, detailed principles of management are indicated. The indications for the use of rhGH must be strictly controlled, and the combination of rhGH + GnRHa therapy is expensive.
The dose of GnRHa treatment is a difficult issue and needs to be individualized, i.e. the dosage may be different from patient to patient and from period to period. In particular, it needs to be reviewed regularly during the first six months of treatment. Height growth, control of sexual development, ultrasound, and sex hormone levels should be reviewed in the first month after treatment and every 3 months thereafter, and bone age should be reviewed every 6 months so that the dose can be adjusted when appropriate. If the dose is too large, the growth will be too slow and will not help much to improve adult height, and if the dose is too small, it will be difficult to control during puberty and will not achieve the treatment purpose.
For those with older bone age, the first dose of strengthening is more necessary.
Treatment time should not be too short, because the use of GnRHa at the beginning, there is a short period of time to promote sexual development and promote the role of bone age growth, after which there is a slow decline in sex hormones, the first six months of treatment, the inhibition of bone age growth is often not significant. In the first six months of treatment, the inhibition of bone age growth is often not significant. Besides, any treatment needs to have a purpose, and too short a time is not very meaningful.
The reason why GnRHa works for a longer period of time (long-acting) is that it is made into microcapsules with different disintegration time frames, and the longest release time of microcapsules is no more than 28 (Daphylline) or 33 (Inhibiton) days, so it is inappropriate to extend the injection time excessively!
In the guidelines, “the first dose of GnRH stimulation test at the end of 3 months” can only be used as one of the indicators of the effectiveness of treatment, and not as the best dose adjustment indicators. The higher the dose, the greater the likelihood of effective control.