Etiology of precocious puberty
1.Organic lesions of central nervous system. Dong Qing, Department of Neonatology, Taian Central Hospital
2, peripheral precocious puberty is transformed.
3. Idiopathic CPP (ICPP) without organic lesions. In female children, 80% to 90% are ICPP; in male children, on the contrary, more than 80% are organic. It is speculated that this part of children with precocious puberty is strongly related to the stimulation of environmental endocrine disruptors.
Clinical manifestations of precocious puberty
Females show breast development, enlargement of labia minora, estrogen-dependent changes in vaginal mucosa cells, enlargement of uterus and ovaries, appearance of pubic hair, and first menstruation. Males show enlarged testicles and penis, appearance of pubic hair, developed muscles, and thickened voice. Both men and women have accelerated growth and accelerated bone maturation, which can eventually lead to lifelong height below the target height. In the presence of central nervous system lesions such as intracranial tumors, headache, vomiting, vision changes or other neurological signs and symptoms may be present.
Diagnosis of precocious puberty
It should be determined first whether it is GnRH-dependent precocious puberty.
1. Early appearance of secondary sexual characteristics
Before 8 years old for girls and before 9 years old for boys.
2.Serum gonadotropin level increases to puberty level
(1) Basal gonadotropin values
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 stimulation test
This test is an important diagnostic tool for those whose gonadal axis is activated but whose basal gonadotropin value is not elevated. GnRH can increase gonadotropin secretion and its excitation peak can be used as a diagnostic basis.
The cut-poit value of LH excitation peak for the diagnosis of CPP: LH peak > 5.0 IU/L, LH peak/FSH peak > O.6 can diagnose CPP; if LH bee/FSH peak > O.3, but < 0.6, it should be combined with close clinical follow-up and repeat the test if necessary to avoid missing the diagnosis.
3. Enlarged gonads. In girls, ovarian volume >lml and multiple follicles >4mm in diameter are seen under ultrasound; in boys, testicular volume ≥4ml and progressive enlargement with prolonged disease duration.
4. Linear growth acceleration of height.
5.Bone age exceeds age by 1 year or more.
6.Serum sex hormone level is elevated to puberty 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 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 if necessary, the above tests should be repeated.
The above tests should be repeated if necessary. In females, linear growth acceleration during puberty usually occurs 6 to 12 months after the onset of breast development and lasts for 1 to 2 years; however, there are cases where it occurs later, even in about 5% of children, one year before or during the year of menarche. In boys, accelerated growth occurs when the testicular volume is 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 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 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.
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 be excluded from tumors and require MRI of the saddle area of the skull, which is better than CT in resolving organic lesions of the hypothalamus and pituitary gland.
Differential diagnosis of precocious puberty
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
That is, 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 (most L) and FSH/LH>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 breast enlargement or persistent non-receding, repeat the provocation test if necessary.
2. CPP transformed from non-central precocious puberty
Such as congenital adrenocortical 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 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 true CPP. short stature is its important feature.
Treatment of precocious puberty
1.Medication
The treatment of CPP is aimed at improving the adult height of the affected children, and attention should also be paid to prevent the psychological problems brought about by precocious puberty and early menarche. The GnRH analogue (GnRHa) is generally used for the treatment of CPP, and the slow-release GnRHa preparations currently available for children in China are treprostin and leuprolide acetate.
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.
(1) Indications for the application of GnRHa
1) For the purpose of improving lifelong height in adulthood, the applicable indications are 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 ≥ 2 years of age; girls ≤ 11.5 years of age, boys ≤ 12.5 years of age. ②predicted adult height <150cm in girls, age >1 in boys, bone age/height age >l, or height SDS age growth >1 judged by bone age.
2) Indications for caution to improve the efficacy of adult height are poor and should be used with discretion in the following cases: ①Bone age >11.5 years for girls and >12.5 years for boys at the start of treatment. (2) If the genetic target height is 2 standard deviations below the normal reference value, 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 girls ≥ 12.5 years old at bone age and boys ≥ 13.5 years old; ② girls after menarche or boys 1 year after ejaculation.
4) Indications that do not need to be applied: ① the slow process of sexual maturation (bone age progression does not exceed age progression) does not require treatment 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. Once the diagnosis of CPP is established, those who are not considered to need treatment for the time being should be reviewed regularly for changes in height and bone age, and the need for treatment should be re-evaluated periodically to develop a treatment plan as needed.
(2)GnRHa application method
1) Dose: 80-100μg/kg for the first dose, reinforced once after 2 weeks, then once every 4 weeks (no more than 5 weeks) at a dose of 60-80μg/kg, the dose needs to be individualized, according to the suppression of gonadal axis function (including sexual characteristics, sex hormone levels and bone age progression), and the first dose can be referred to for those with poor suppression. In order to know exactly how the bone age progresses, 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 (E:) 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 were repeated to determine the suppression of gonadal axis function. In girls, ultrasound of the uterus and ovaries was also repeated.
3) Course of treatment: In order to improve adult height, the course of GnRHa generally requires at least 2 years, girls at the age of 12.0 to 12.5 years should stop treatment, such as extending the course of treatment at this time is often difficult to continue to improve adult height. 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 can stop the drug, so that their gonadal axis function to restart, should be followed up regularly.
(3) Post-discontinuation monitoring: Height, weight and recovery of paraphimosis and gonadal axis function should be reviewed every 6 months after the end of treatment. Girls usually present menarche within 2 years after stopping treatment.
(4) GnRHa treatment in the treatment of growth deceleration: GnRHa treatment for the first six months of growth rate and treatment before the change is not obvious, half a year later generally fall back to the growth rate of pre-puberty (5cm / year or so), some children in the treatment of 1 to 2 years after the growth rate <4cm / year, at this time GnRHa continue treatment will be difficult to improve their adult height, especially the bone age has ≥ 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 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), 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 cannot reach its target height; GH should be used at pharmacological therapeutic doses [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).
2. Etiological treatment
For non-specific CPP, simultaneous etiological treatment should be emphasized (e.g., surgical treatment of saddle area tumors, simultaneous administration of cortisol for congenital adrenocortical hyperplasia combined with CPP, etc.). 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. During treatment, attention should also be paid to avoiding exposure to substances with estrogenic effects as much as possible, eating a light diet, exercising more, avoiding obesity, etc.