Basic Information
aka: precocious puberty
English name: "precociouspubertyofchildhood,prematurepuberty"
Clinic: Pediatrics, Endocrinology
Common symptoms: none
Cause
1. Organic lesions of the central nervous system.
2. Peripheral precocious puberty is transformed.
3. Idiopathic CPP (ICPP) without organic lesions. 80% to 90% of female children have ICPP; male children are the opposite, more than 80% are organic. It is speculated that this part of precocious puberty children has a great relationship with the stimulation of environmental endocrine disruptors.
clinical manifestations
Women present with breast development, enlarged labia minora, estrogen-dependent changes in vaginal mucosal cells, enlarged uterus and ovaries, appearance of pubic hair, and menarche. In men, the testicles and penis are enlarged, pubic hair appears, muscles are developed, and the voice becomes thicker. Both males and females experience accelerated growth and accelerated bone maturation, which can ultimately lead to lifetime height below target height. When accompanied by intracranial tumors and other central nervous system lesions, there may be headache, vomiting, changes in vision or other neurological symptoms and signs.
diagnosis
It should first be determined whether it is GnRH-dependent precocious puberty.
1. Secondary sexual characteristics appear in advance before the age of 8 in girls and 9 years in boys.
2. Serum gonadotropin level increased to the level of puberty.
(1) The basal value of gonadotropin If the secondary sexual characteristics have reached the level of mid-adolescence, the basal value of serum luteinizing hormone (LH) can be used as a primary screening, such as >5.0IU/L, it can be determined that the gonadal axis has been activated , no gonadotropin-releasing hormone (GnRH) challenge test is necessary.
(2) GnRH provocation test This test is an important diagnostic method for those whose gonadal axis function has been activated but the basal gonadotropin value does not increase. GnRH can increase the secretion and release of gonadotropin, and its provocative peak can be used as a diagnostic basis. The cut-poit value of LH excitation peak for diagnosis of CPP: LH peak>5.0IU/L, LH peak/FSH peak>0.6 can diagnose CPP; such as LH bee/FSH peak>0.3, but <0.6 When it is necessary, close follow-up should be combined with clinical practice, and the test should be repeated if necessary to avoid missed diagnosis.
3. In girls with enlarged gonads, the volume of the ovary is >1ml and multiple follicles with a diameter of >4mm can be seen under B-ultrasound; the volume of testis in boys is more than 4ml, and it increases progressively with the prolongation of the disease course.
4. The linear growth of height is accelerated.
5. The bone age exceeds the age by 1 year or more. 6. Serum sex hormone levels rise to puberty levels.
Among the above diagnostic criteria, 1, 2, and 3 are the most important and necessary. However, if the course of disease at the time of presentation is very short, the GnRH excitation value may overlap with the prepubertal value, and the above diagnostic cut-off value may not be reached; so does the size of the ovary. Such children should be followed up for the progression of their secondary sexual characteristics and linear growth acceleration, and the above tests should be reviewed if necessary. The linear growth acceleration of puberty in female children generally occurs 6 to 12 months after breast development begins and lasts for 1 to 2 years; but there are also later ones, and even about 5% of children appear 1 year before or at the beginning of the year of menarche. . Growth acceleration in boys occurs when the testicular volume is 8 to 10 ml or one year before voice change, and lasts longer than in girls.
Advanced bone age only indicates that the level of sex hormones has been increased for a period of time, and is not a specific indicator for the diagnosis of CPP. Children with a short course of disease and a slow developmental process may not have obvious advanced bone age, and peripheral precocious puberty may also have advanced bone age; increased sex hormone levels High inability to distinguish central and peripheral precocious puberty. In conclusion, the diagnosis of CPP is comprehensive, and the core problem is that it must be GnRH-dependent. Care must be taken to collect the medical history related to the etiology of CPP, such as infection, central nervous system lesions and other related symptoms; for all children diagnosed with CPP, tumors should be excluded, and MRI examination of the sellar area of the skull should be performed. MRI is better than CT in the resolution of hypothalamic and pituitary organic lesions.
Differential diagnosis
Although the GnRH challenge test can generally differentiate between central precocious puberty and peripheral precocious puberty, the following conditions should be identified:
1. Simple premature breast development
That is, in some central precocious puberty (PICPP), FSH is significantly increased after GnRH stimulation (it will also increase after stimulation in normal prepubertal girls), but LH is not significantly increased (mostly L), and FSH/LH>1. However, it is worth noting that in the absence of any clinical aura, PICPP will convert to CPP. Therefore, after the diagnosis of PICPP, regular follow-up is required, especially for those with repeated breast enlargement or persistent breast regression, the provocative test should be repeated if necessary.
2. CPP transformed from non-central precocious puberty
Such as congenital adrenal hyperplasia, McCune-Albright syndrome, etc., the occurrence of CPP must be monitored during the treatment of the primary disease.
3. Precocious puberty associated with congenital hypothyroidism
It is a special type of precocious puberty. The basal blood LH value of children in the early stage is increased, but it does not increase after GnRH stimulation. Short stature is an important characteristic.
treat
1. The purpose of drug treatment of CPP is to improve the height of children in adulthood as the core, and attention should also be paid to preventing psychological problems caused by precocious puberty and early menarche. Generally, GnRH analogs (GnRHa) are used to treat CPP. The sustained-release GnRHa preparations currently available for children in China include triptorelin and leuprolide acetate. GnRHa can effectively inhibit the secretion of LH, suspend the development of the gonads, and return the secretion of sex hormones to the prepubertal state, thereby delaying the growth and fusion of the epiphysis, so as to prolong the growth period and improve the final adult height as much as possible.
(1) Application indications of GnRHa
1) In order to achieve the goal of improving lifelong height in adulthood, the applicable indications are children with significantly impaired growth potential and remaining growth potential at the same time, that is, those with significantly advanced bone age but the epiphysis has not yet begun to fuse, the specific recommendations are as follows: ① bone age ≥ age 2 years old; girls ≤ 11.5 years old, boys ≤ 12.5 years old. 2) Predicted adult height for girls <150 cm, boy age > 1, bone age/height age > 1, or height SDS age growth determined by bone age > 1. 2) The indications used with caution have poor efficacy in improving adult height. It should be used with caution in the following situations: 1. Girls with bone age > 11.5 years old and boys > 12.5 years old when starting treatment. ②If the genetic target height is less than 2 standard deviations from the normal reference value, other causes of short stature should be considered. 3) Indications that should not be used GnRHa alone has no significant effect on improving adult height in the following situations: ① skeletal age girls ≥ 12.5 years old, boys ≥ 13.5 years old; ② girls after menarche or 1 year after boy nocturnal emission. 4) Indications that do not need to be used ① If the process of sexual maturation is slow (the progress of bone age does not exceed the progress of age), if the effect on adult height is not large, treatment is not required. ②Although the bone age is advanced, the height growth rate is fast, making the height age larger than the bone age, and predicting that the height in adulthood will not be damaged. However, since the process of puberty and maturation is dynamic, the judgment of each individual should also be dynamic. once the diagnosis of CPP is established, the changes in height and bone age should be regularly reviewed for those who are considered to be temporarily unnecessary for treatment at the initial assessment. If necessary, develop a treatment plan as needed.
(2) Application method of GnRHa
1) The first dose is 80-100 μg/kg, and it is boosted once after 2 weeks, and then once every 4 weeks (not more than 5 weeks), and the dose is 60-80 μg/kg. Including sexual characteristics, sex hormone levels and bone age progression), those with poor inhibition can refer to the first dose. In order to accurately understand the progress of bone age, clinicians should evaluate and compare the bone age before and after treatment, and should not make judgments based on the report of the radiology department alone. 2) Monitoring during treatment During treatment, check secondary sexual characteristics and measure height every 2 to 3 months; review the GnRH provocation test at the end of 3 months after the first dose, if the LH provocation value is in prepubertal value, the dose is appropriate; Girls only need to periodically review the basal serum estradiol (E:) concentration or vaginal smear (maturity index), while boys should review the basal serum testosterone level to judge the suppression of gonadal axis function. The bone age is reviewed every 6 to 12 months, and the uterus and ovary B-ultrasound in girls are reviewed at the same time. 3) Course of treatment In order to improve adult height, the course of GnRHa generally takes at least 2 years. Girls should stop treatment when the bone age is 12.0 to 12.5 years old. At this time, it is often difficult to continue to improve adult height if the course of treatment is prolonged. 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 puberty initiation age (≥8 years old), the drug can be stopped when the predicted height can reach the genetic target height, so that the gonadal axis function can be restarted. Should be tracked regularly.
(3) Monitoring after drug withdrawal
After the treatment, the height, weight, recovery of secondary sexual characteristics and the recovery of gonadal axis function should be reviewed every six months. Girls generally experience menarche within 2 years of stopping treatment.
(4) Treatment of growth retardation in GnRHa treatment
In the first half year of GnRHa treatment, the growth rate did not change significantly compared with that before treatment. After half a year, it generally fell back to the growth rate of prepubertal (about 5cm/year). Some children had a growth rate of less than 4cm/year after 1 to 2 years of treatment. Continued treatment of GnRHa at this time will be difficult to improve their adult height, especially when the bone age is ≥12.0 years old (female) or 13.5 years old (male). Reducing the dose of GnRHa does not improve growth, but rather risks accelerating bone age. In recent years, the combination of GnRHa and recombinant human growth hormone (rhGH) has been used internationally to overcome growth retardation. The growth potential has been exhausted, and even with the addition of rhGH, the growth improvement is often not significant. The use of rhGH should strictly follow the application indications, generally only when the child's predicted adult height cannot reach the target height; GH should be used in a pharmacological treatment dose [0.15-0.20U/(kg·d)], and the application process needs to be used. Close monitoring of side effects (contraindications to rhGH use and monitoring of side effects during treatment with other growth retarding diseases).
2. Treatment of the cause
For non-idiopathic CPP, simultaneous etiological treatment should be emphasized (such as surgical treatment of sellar tumors, cortisol should be given at the same time for congenital adrenal hyperplasia complicated with CPP, etc.). However, in children with hypothalamic hamartoma and arachnoid cyst, if there is no manifestation of increased intracranial pressure, the operation will be postponed, and only ICPP will be treated.
In conclusion, precocious puberty is a sexual developmental disorder with multiple etiologies, and the identification of the etiology is crucial. Central organic disease should be excluded after GnRH-dependent precocious puberty is identified, especially in boys and those with onset under 6 years of age (both sexes). For idiopathic CPP, GnRHa treatment can be considered as the first choice, but the application indications should be reasonably grasped, and the balance of growth/maturity should be monitored, judged, and mastered during treatment, so as to achieve the purpose of improving adult height. In the course of treatment, attention should also be paid to avoiding exposure to substances with estrogenic effects, eating lightly, exercising more, and avoiding obesity.
