[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 reproductive system matures.
[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; 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 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, GnRH can increase the release of gonadotropin secretion and its excitation peak can be used as a diagnostic basis.
___GnRH excitation test method: routinely use GnRH (Gonarelin) 2.5 μg/kg or 100μg/m2 intravenously, take blood samples at 0min, 30mln, 60min, and measure serum LH and follicle stimulating hormone (FSH) concentrations (120min of the classic GnRHa test method can be omitted), the synthetic GnRH analog (GnRHa) The stimulatory effect of the synthetic GnRH analogue (GnRHa) is stronger than that of the natural one, with the peak 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 and >25.0 IU/L in boys, and LH peak/FSH peak >0.6-1.0 for the diagnosis of CPP; when measured by immunochemiluminescence assay (ICMA) LH peak > 5.0 IU / L, LH peak / FSH peak > 0, 6 (both sexes) can be diagnosed CPP; such as LH peak / FSH peak > 0, 3, but < 0, 6, should be combined with close clinical follow-up, repeat the test if necessary, so as not to miss 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 prolonged disease course.
4, Linear growth was accelerated.
5.Bone age exceeds age by 1 year or more.
6.Serum sex hormone level is elevated to pubertal level.
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 the 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
It is important to collect 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 saddle area of the skull is needed; MRI has better resolution than CT for organic lesions of hypothalamus and pituitary gland.
Differential diagnosis
Although GnRH excitation test can largely identify central precocious puberty and peripheral precocious puberty, the following conditions should be identified.
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 improve the lifelong height in adulthood, the applicable indications are children with significantly impaired growth potential and remaining 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 time of Kibi 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 in the following cases: (1) girls ≥11.5 years old and boys ≥13.5 years old at bone age; (2) girls after menarche or boys 1 year after ejaculation.
4, does not need to apply the indications: (1) sexual maturation process is slow (bone age progression does not exceed the age progression) does not need to be treated when the impact on adult height is not significant. (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 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 method
1. Dose: 80-100μg/kg for the first dose, and intensify once after 2 weeks, then once every 4 weeks (no more than 5 weeks), at a dose of 60-80μg/kg, the dose should be individualized, according to the suppression of gonadal axis function (including sexual characteristics, sex hormone levels and bone age progression), poor suppression can be referred to the first dose, the maximum amount of 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 should not make judgments based on radiology reports alone.
2.Monitoring during treatment: 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 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 the gonadal axis function to 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 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 rhGH application and monitoring of side effects during treatment are the same as for other growth retardation disorders).
[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.