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. CPP is also known as GnRH-dependent precocious puberty, which develops progressively until the development of the reproductive system is mature.
[Etiology]
1, Organic lesions of the central nervous system.
2. Peripheral precocious puberty is transformed.
3. Idiopathic CPP (ICPP) without organic lesions. About 80% to 90% of female children have ICPP; male children, on the contrary, more than 80% are organic.
[Diagnosis]
The differential diagnosis of the etiology of GnRH-dependent precocious puberty should be made 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 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 its 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.
–The method of GnRH excitation test: GnRH (Gonarelin) is routinely administered intravenously at 2, 5μg/kg or 100μg/m2, blood samples are taken at 0min, 30min60min and 90min, and serum LH and follicle stimulating hormone (FSH) concentrations are measured (120min of the classical 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, and 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 refers to the LH at each time point in the excitation test). The highest value, FSH peak refers to 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, should be combined with close clinical follow-up, repeat the test 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 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 must be available. 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 some late cases, and even about 5% of children present one year before or during the first year of menarche. In boys, the growth acceleration occurs when the testicular volume is about 8-10 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 summary, 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
The history related to the etiology of CPP must be collected, 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 required; 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 to CPP in the absence of any clinical precursor manifestations. 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: 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 precocious puberty and early menarche. GnRH analogues (gonadotropingreleasinghormoneanalogue, GnRHa) are generally used for the treatment of CPP, and the slow-release GnRHa preparations currently available for children in China are Triptorelin and Leuprorelin acetate; the former, such as DecapeptyIDep and Diphereline; the latter is Enantone.
GnRHa can effectively inhibit LH secretion, so that the gonads suspend development, sex hormone secretion back to the prepubertal state, thus delaying the growth and fusion of epiphysis, as far as possible to achieve the purpose of extending the growth years and improving the final adult height.
I. Indications for the application of GnRHa
1.To achieve the purpose of improving the lifelong height in adulthood
Indications for the application of GnRHa are children with significantly impaired growth potential and residual growth potential at the same time, i.e. those with significantly advanced bone age and whose epiphyses have not yet begun to fuse, as suggested below.
(1) Bone age: bone age ≥ 2 years of age; girls ≤ 11,5 years of age, boys ≤ 12,5 years of age.
(2) Predicted adult height: girls ≤150cm, 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 when the following conditions exist and should be used with caution as appropriate.
(1) Bone age >11,5 years for girls and >12,5 years for boys 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 those with the following conditions.
(1) Bone age of girls ≥ 12,0 years, boys ≥ 13,5 years;
(2) 1 year after menarche in girls or after ejaculation in boys.
4, do 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 small.
(2) Although the bone age is advanced, but 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 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 (no more than 5 weeks), with a dose of 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), and those with poor suppression can refer to the first dose, with the maximum amount of 3,75mg/time. In order to know exactly the bone age progression, clinicians should personally evaluate and compare the bone age before and after treatment, and it is not appropriate to make judgments based on radiology reports alone.
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, it means the dose is appropriate; thereafter, only the basal serum estradiol (E2) concentration or vaginal smear (maturity index) should be reviewed regularly for girls, and the basal serum testosterone level should be reviewed for boys to judge the function of gonadal axis. 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 old 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 followed up regularly.
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 5cm/year), and the growth rate of some children is <4cm/year after 1 to 2 years of treatment, at which time it will be difficult to improve their height in adulthood if GnRHa treatment is continued, 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 or 5 years (female) or 15 years (male), growth improvement is often not significant even with rhGH because the growth potential of the bone growth plate has been depleted.
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/(kg-d)], 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 summary, 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 growth/maturation balance should be monitored, judged, and mastered during treatment in order to achieve improvement in adult height.