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 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. In female children, about 80% to 90% are ICPP; in 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 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 initiated but whose basal gonadotropin value is not elevated.
(3) GnRH excitation test method: GnRH (Gonarelin) is routinely administered intravenously at 2.5 μg/kg or 100 μg/m2, and blood samples are taken at 0 min, 30 min and 60 min to measure serum LH and follicle stimulating hormone (FSH) concentrations (the 120 min classical test for GnRHa can be omitted). The stimulatory effect of the synthetic GnRH analogue (GnRHa) is stronger than the natural one, with a peak 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 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.
3, enlarged gonads: girls with ovarian volume >1 ml and multiple follicles >4 mm in diameter seen under ultrasound; boys with testicular volume ≥4 ml and progressive enlargement with prolonged disease course.
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 is very short at the time of consultation, the GnRH excitation test may overlap with the prepubertal values and not reach the above diagnostic cut-off values; 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 8-10 ml or one year before the change of voice, and lasts longer than in girls. Premature bone age only indicates the increase of sex hormone level for a period of time, and is not a specific indicator for the diagnosis of CPP. Children with short duration of disease and slow developmental process may not have obvious pre-mature bone age, while peripheral precocious puberty may also have pre-mature bone age; elevated sex hormone level cannot distinguish between central and peripheral precocious puberty.
Etiological diagnosis
All children diagnosed with CPP should be excluded from the diagnosis of tumor, and MRI or CT examination of the saddle area of the skull should be performed; MRI is better than CT in resolving 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 converts to 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 that persists, and repeat the provocation test if necessary.
2. CPP transformed from non-central precocious puberty such as congenital adrenocortical hyperplasia and McCune-Albright syndrome must be monitored 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 excitation, and only after a longer course of the disease is it transformed into true CPP. short stature is its important feature.
[Pharmacological treatment]
The treatment of CPP is aimed at improving the adult height of the child, and attention should be paid to prevent the psychological problems associated with premature maturation and early menarche. GnRH analogues (gonadotropin releasing hormone analogue, 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 is Decapetyl Dep and Diphereline; the latter is Enant. 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.
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 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 <150 cm for girls and <160 cm for boys, or less than their genetic target height minus 2 SD. (3) Bone age/age > 1, bone age/height age > 1, or height SDS judged by bone age < -2 SDS.(4) Rapid sexual development process with 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 that should not be applied: GnRHa treatment alone is not effective in improving height in adulthood in the following cases: (1) bone age ≥ 12.5 years for girls and ≥ 13.5 years for boys; (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 progress does not exceed the age of progression) of those who do not have a significant impact on the height of adulthood, do not need treatment. (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.
Second, GnRHa application methods
1. Dose: 80~100 μg/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 60~80 μg/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, the maximum amount is 3.75 mg/time. In order to know exactly the bone age progression, clinicians 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 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, the dose is appropriate; thereafter, only the basal serum estradiol (E2) concentration or vaginal smear (maturation index) should be reviewed periodically for girls, and the basal serum testosterone level should be reviewed for boys to determine the gonadal axis function. In boys, basal serum testosterone levels are repeated 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 their bone age, and their bone age has reached the normal age of puberty initiation (≥ 8 years), the predicted height can reach the genetic target height when the drug can be discontinued, so that their 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 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 prepubertal period (about 5 cm/year), and the growth rate of some children is < 4 cm/year after 1~2 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 growth. In recent years, the combination of GnRHa and recombinant human growth hormone (rhGH) has 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 even with the addition of rhGH, growth improvement is often not significant.
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, concomitant etiologic treatment should be emphasized (e.g., surgical treatment of saddle area tumors, concomitant 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 may be considered as the first choice for idiopathic CPP, but the indications for its application need to be rationalized and the growth/maturation balance should be monitored, judged and mastered during treatment in order to achieve improvement in adult height.