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.
1.Definition
Precocious puberty is a developmental disorder in which girls present secondary sexual characteristics before the age of 8 and boys before the age of 9. CPP is also known as GnRH-dependent precocious puberty, the process of which is progressive until the reproductive system is mature.
2.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.
3.Diagnosis
The diagnosis of GnRH-dependent precocious puberty should be determined first, followed by the differential diagnosis of the etiology.
Diagnostic basis
(1) Early appearance of secondary sexual characteristics: before 8 years old in girls and before 9 years old in boys.
(2) Elevated serum gonadotropin levels up to puberty level.
a. 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 activated, and there is no need to conduct gonadotropin-releasing hormone (GnRH) stimulation test.
b. GnRH excitation test: This test is an important diagnostic tool for those whose gonadal axis function has been initiated but whose gonadotropin basal value is not elevated, GnRH can increase gonadotropin secretion and its excitation peak can be used as a diagnostic basis.
c. 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 mln, and 60 min to measure serum LH and follicle-stimulating hormone (FSH) concentrations (120 min of the classic GnRHa test method can be omitted). The excitation effect 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.
(3) The cut-point value of LH excitation peak for the diagnosis of CPP: depends on the gonadotropin assay method 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 1m1, and multiple follicles >4mm in diameter are visible; testicular volume ≥4ml in boys, and progressive increase with disease duration.
(4) Accelerated linear growth.
(5) Bone age exceeds 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 cases of late onset of linear growth acceleration, even in about 5% of children who 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 on clinical follow-up is important.
Etiological diagnosis
The history related to the etiology of CPP, such as infections, central nervous system lesions and other related symptoms, must be collected; tumors should be excluded in all children diagnosed with CPP, and MRI or CT of the cranial saddle area is required; MRI has better resolution than CT for organic lesions of the hypothalamus and pituitary gland.
Differential diagnosis
Although GnRH excitation test can broadly 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 (it is also elevated after excitation in normal prepubertal girls), but LH is not significantly elevated (mostly 1. However, it is noteworthy that PICPP converts to CPP in the absence of any clinical precursor manifestations. therefore, regular follow-up is needed after the diagnosis of PICPP, especially for those with recurrent or persistent breast enlargement, 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.
(3) Congenital hypothyroidism with precocious puberty is a special type of precocious puberty, in which the basal value of blood LH is elevated in the early stage of the child, but not after GnRH excitation, and only after a longer course of the disease is it transformed into real CPP. short stature is its important feature.
4.Medication
The treatment of CPP is aimed at improving the adult height of the child, and attention should also be paid to prevent the psychological problems associated with premature maturation and early menarche. GnRH analogue (gonadotroping releasing hormone analogue, GnRHa) is 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 DecapeptyI Dep and Diphereline; the latter is Enantone.
GnRHa can effectively inhibit the secretion of LH, causing the gonads to suspend development and the secretion of sex hormones to return to the prepubertal state, thus delaying the growth and fusion of the epiphysis and achieving the purpose of extending the growth years and improving the final height in adulthood as much as possible.
Indications for the use of GnRHa
(1) For the purpose of improving lifelong height in adulthood, the indications are for 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 less than 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 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) girls > 11.5 years of age and boys > 12.5 years of age at the time of Kepi 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: a. girls ≥ 11.5 years old and boys ≥ 13.5 years old at bone age; b. girls after menarche or boys 1 year after ejaculation.
(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 to be temporarily unneeded for 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.
GnRHa application method
(1) Dose: 80-100μg/kg for the first dose, and then intensify once after 2 weeks, and then once every 4 weeks (not 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), and those with 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 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 range, 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. suppression. In girls, ultrasound of the uterus and ovaries should be repeated at the same time.
(3) Course of treatment: In order to improve adult height, the course of GnRHa generally takes at least 2 years, and girls should stop treatment when they are 12.0-12.5 years old, at which time it is often difficult to continue to improve adult height if the course of treatment is extended. For those who started 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 can be restarted, and should be followed regularly.
Post-discontinuation monitoring
Recovery of height, weight and paraphilia, as well as recovery of gonadal axis function, should be reviewed every 6 months after the end of treatment. Girls usually present with menarche within 2 years after stopping treatment.
Management 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 after 1 to 2 years of treatment.