Ye Xiaoqin, Department of Pediatrics, Bengbu Third People’s Hospital, Pediatrics Branch of the Chinese Medical Association, Endocrine Genetic Metabolism Group
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 held 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 before the age of 8 years and boys before 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 activates the gonadal axis in advance and leads to gonadal development and secretion of sex hormones, resulting in the development of internal and external genitalia and the presentation of secondary sexual characteristics.
I. Diagnosis basis
1. Early appearance of secondary sexual characteristics: before the age of 8 for girls and 9 for boys.
2. The level of serum gonadotropin increases to the level of puberty.
(1) Basal gonadotropin value: If the secondary sexual characteristics have reached the level of mid-puberty, the basal serum luteinizing hormone (LH) value can be used as the initial screening, such as >5.0 IU/L, it can be determined that the gonadal axis has been launched, 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 initiated but whose basal gonadotropin value is not elevated, GnRH can increase the release of gonadotropin secretion, and its excitation peak can be used as a diagnostic basis.
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 assay (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 follow-up should be combined with clinical follow-up and repeat the test if necessary to avoid missing the diagnosis. < p="">
3. enlarged gonads: in girls, ovarian volume >1m1 and multiple follicles >4mm in diameter are seen on ultrasound; in boys, testicular volume is ≥4ml and increases progressively with the duration of the disease.
4. Accelerated linear growth.
5. Bone age exceeds age by 1 year or more.
6. Serum sex hormone levels are elevated to pubertal levels.
Among the above diagnostic bases, 1, 2 and 3 are the most important and necessary. However, if the duration of the disease at the time of consultation is very short, 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 cases of late onset, 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.
Second, the etiological diagnosis must pay attention to the collection of medical history related to the etiology of CPP.
MRI has better resolution than CT for organic lesions of hypothalamus and pituitary gland.
Although GnRH excitation test can generally distinguish central precocious puberty from peripheral precocious puberty, the following conditions should be distinguished.
1. simple premature 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 <5iu/l) and fsh/lh>1. However, it is noteworthy that PICPP can be converted to CPP in the absence of any clinical precursors. therefore, the diagnosis of PICPP needs to be followed up regularly after diagnosis, especially in cases of recurrent breast enlargement or persistent non-remission, with repeat provocation tests if necessary.
2. CPP transformed from non-central precocious puberty: e.g. congenital adrenocortical hyperplasia, McCune-Albright syndrome, etc. It is necessary to monitor the occurrence of CPP during the treatment of the primary disease.
The early children with congenital hypothyroidism with precocious puberty are a special type of precocious puberty, in which the basal blood LH is elevated, but not after GnRH stimulation, and only after a longer course of the disease is it transformed into true CPP.
[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, and achieving the purpose of extending the growth years and improving the final adult height as much as possible.
IV. Indications for the application of GnRHa
1. In order to improve the lifelong height in adulthood, the applicable indications are children with significantly impaired growth potential and residual growth potential, i.e. those with significantly advanced bone age and whose epiphyses have not yet begun to fuse, as follows: (1) bone age: bone age ≥ 2 years; girls ≤ 11.5 years, boys ≤ 12.5 years. (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 <-2SDS judged by bone age.(4) Rapid sexual development process, bone age growth/age growth > 1.
2. Indications for caution: The following conditions have poor efficacy in improving adult height and should be used with caution: (1) bone age >11.5 years for girls and >12.5 years for boys at the start of treatment; (2) genetic target height is 2 standard deviations below the normal reference value (-2SDS). Other causes of short stature should be considered.
3. Indications for inappropriate use: GnRHa treatment alone is not effective in improving height in adulthood if (1) the bone age is ≥ 12.5 years for girls and ≥ 13.5 years for boys; (2) after menarche in girls or 1 year after ejaculation in boys.
4. indications that do not need to be applied: (1) sexual maturation process is slow (bone age progression does not exceed age progression) does not need to be treated when it has little effect on adult height. (2) Although the bone age is advanced, the height growth rate is fast, so that the height age is 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 should be reviewed regularly for changes in their height and bone age, and the need for treatment should be re-evaluated periodically to develop a treatment plan as needed.
V. GnRHa application methods
1. Dose: 80-100μg/kg for the first dose, and intensify once after 2 weeks, then once every 4 weeks (not more than 5 weeks), the dose is 60-80μg/kg, the dose needs to be individualized, according to the suppression of gonadal axis function (including sexual characteristics, sex hormone levels and bone age progression), poor suppression can refer to the first dose, the maximum amount is 3.75 mg/time. In order to know exactly how the bone age progresses, the clinician should personally evaluate and compare the bone age before and after treatment, and it is not advisable to make a judgment based on the radiology report alone.
Therapeutic monitoring: check the secondary sexual characteristics and measure the height every 2-3 months during the 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 was also repeated.
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 old should consider stopping 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 the gonadal axis function to restart, should be followed up regularly.
VI. Post-discontinuation monitoring
The height, weight and recovery of paraphilias and gonadal axis function should be reviewed every six months after the end of treatment. Girls usually present menarche within 2 years after stopping treatment.
Seven, GnRHa treatment in the treatment of growth deceleration
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 (female) or 13.5 years (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 thrust)], and side effects should be closely monitored during application (contraindications to rhGH application and monitoring of side effects during treatment are the same as for other growth retardation diseases).
[Etiological treatment].
For non-specific CPP, simultaneous etiologic treatment should be emphasized (e.g., surgical treatment of saddle area tumors, simultaneous administration of cortisol for congenital adrenocortical hyperplasia combined with CPP). 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 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.
(Written by Minlian Du, reviewed by Muti Wang)
Experts who participated in the discussion and review of this guideline: Muti Wang, Minlian Du, Yongnian Shen, Xiaoping Lu, Zhongqi Zhang, Bitao Wang, Zhichao Zhu, Yanling Yang, Goli Liu, Tang Li, Xuefan Gu, Shuixian Shen, Wei Wang, Li Liu, Feng Xiong
Post-reading summary.
The specialty of pediatric endocrinology and metabolism has developed rapidly in recent years, and many diseases are gradually recognized. CPP, as a major disease of sexual developmental abnormalities in pediatric endocrine diseases, has gradually increased in incidence and awareness with the changes of the general social environment.
The development of this guideline is very meaningful to guide clinical treatment because.
1. the level of awareness of CPP among pediatric specialists in China is uneven
2. treatment is often not standardized and tends to be amplified
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 monitoring and follow-up.
4. In terms of clinical diagnosis, there is another point that is not mentioned in the guideline but has been used as a basis for diagnosis, namely: “The appearance of menarche before the age of 10 in females can be used as a basis for the diagnosis of precocious puberty”.
For the diagnosis of bone age, the GP chart method which is widely used in China has limited accuracy. It is better to adopt TW3 scoring method and make annual height prediction if possible (as the height prediction can only be made by the bone age, age and height at that time, the adult height can be predicted according to the normal growth and development law. 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 to 5 years to less than a year, so it should not be absolutized.
If the age of development exceeds the standard age for diagnosis of precocious puberty, but signs of development appear before the age of 10 for girls and 11 for boys, the diagnosis of early pubertal development can be made if the predicted adult height is low, and medical intervention can be performed.
5. Treatment: For the indications of GnRHa application, the guidelines describe in detail for the first time the indications of caution, contraindication and no treatment required. The indications listed in the guidelines are common to the treatment of CPP, although relatively conservative, special circumstances can be appropriate to relax the indicators of bone age, but relaxation of the indicators of bone age is 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 reinforcement is more necessary.
In some scientific research observation projects about precocious puberty treatment, in order to facilitate the observation of treatment results, it is recommended that for children with true precocious puberty weighing more than 20KG, all GnRHa doses are full injections, and below 20KG, all half injections. Recently, some domestic experts have also suggested (especially in some large hospitals, where refined treatment is difficult to achieve due to the large number of patients) that for the treatment of true precocious puberty, “regardless of age and weight, all GnRHa injections are full, and the dose is not reduced in the middle of the treatment”. Although this can reduce the burden of doctors and the pain of review and examination costs for those who receive treatment, it may cause excessive inhibition or non-strengthening of those with excessive bone age and weight may cause insufficient inhibition. It is also true that some pediatric endocrinologists, represented by Europe, currently recommend the use of high doses of GnRHa to inhibit bone growth as much as possible and the combination of growth hormone when growth decelerates. However, the European medical security system is perfect, parents do not need to bear the cost, and the European GnRHa has 3.75mg, 7.5mg, and 11.5mg dosage form (3 months long-acting dosage form, not convenient dose adjustment), while the domestic is only 3.75mg and 1.87mg two dosage form, for weight, bone age is larger, the sexual development of vigorous people, not to strengthen the possibility of affected control effect. At the same time, there are also children’s endocrinologists, represented by Japan, who recommend strict regular review and refinement of GnRHa dose adjustment at the right time. Refined treatment, although review may require more detail and more effort on the part of the physician, often leads to better treatment results. After all, lifelong effects on children and adolescents are possible in terms of lifetime high results, and the main goal of parental treatment is often to improve lifetime high. I actively recommend that it is best to refine the treatment! GnRHa treatment at the beginning, because sexual development is in a more vigorous stage, GnRHa treatment often requires a larger dose or the first dose to strengthen. After sexual development is somewhat controlled, the dosage of GnRHa mostly needs to be reduced appropriately (of course, factors such as different body weights need to be taken into account), in addition, if the initial high dose, height growth may be inhibited excessively.
The duration of treatment should not be too short, because the initial period of GnRHa use, there is a short period of time to promote sexual development and promote bone age growth, after which there is a slow decline of 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 can play a longer role (long-acting) principle is to do made into disintegration time frame of different microcapsules, microcapsules maximum release time of no more than 28 days, excessive extension of injection time is not appropriate!
6, the long-term nature of the treatment, the need for a detailed assessment in advance, the development of a thorough long-term planning. As this treatment is a long-term process, a detailed assessment is needed beforehand, especially after a detailed assessment of bone age, to make a prediction of adult height. It is important to know how much height can be grown without treatment in order to know whether treatment is needed or to develop a more reasonable treatment plan. Nowadays, there are many doctors who do not evaluate in detail before treatment and lack a long-term plan. “Use it first, and add growth hormone if you grow slowly.” If the predicted adult height is relatively normal before using the drug, after using GnRHa, even if it cannot significantly improve the adult height, at least it should be able to prevent the predicted adult height from decreasing due to premature maturity and too rapid progression of bone age, otherwise it is less meaningful to use GnRHa. Why use growth hormone when the predicted adult height is more normal? What needs to be done is probably to adjust the dose of GnRHa when appropriate after a detailed examination. In the case of older bone age, where the predicted adult height is too low and the time for growth hormone is already limited, the earlier the combination of growth hormone is needed, the less the chance of treatment will be if the waiting time is too long. In addition, the use of drugs need to have the corresponding indications, discontinuation of drugs also need to have the corresponding indicators of discontinuation, before treatment, but also consider what kind of program, can be earlier to achieve the indicators of discontinuation.
7, the “first dose of GnRH stimulation test at the end of 3 months” can only be used as one of the indicators of whether the treatment is effective, and can not be used as the best dose adjustment indicators. Because the higher the dose, the greater the possibility of effective control.