I. Definition
Precocious puberty refers to the appearance of secondary sexual characteristics in boys before the age of 9 years and in girls before the age of 8 years. According to the pathogenesis and clinical manifestations, there are central (gonadotropin-releasing hormone-dependent) precocious puberty and peripheral (non-gonadotropin-releasing hormone-dependent) precocious puberty, which used to be called true precocious puberty and pseudo-precocious puberty respectively. Central precocious puberty has the same programmed process of hypothalamic-pituitary-gonadal axis (HPGA) initiation and maturation as normal pubertal development until the reproductive system matures; that is, the hypothalamus secretes and releases gonadotropin-releasing hormone (GnRH) in advance, which activates the pituitary gland to secrete gonadotropin to develop and secrete sex hormones, resulting in the development of internal and external genitalia and the presentation of secondary sexual characteristics. Peripheral precocious puberty is caused by the increase of sex steroid hormones in the body to the level of puberty due to various reasons, so only the early appearance of secondary sexual characteristics, but does not have the complete sexual development process.
Etiology
(A) Central precocious puberty.
1. Organic lesions of central nervous system, such as hypothalamus, pituitary tumor or other central nervous system lesions.
2. Transformation from peripheral precocious puberty.
3. If no organic pathology is found, it is called idiopathic CPP (ICPP).
4. Incomplete central precocious puberty, a special type of CPP, refers to children with early appearance of secondary sexual characteristics, whose control mechanism also lies in the activation of hypothalamic-pituitary-gonadal axis, but its sexual characteristics development is self-limiting; the most common type is simple early breast development, if it occurs in girls within 2 years of age, it may be due to the hypothalamic-gonadal axis being in a physiologically active state, also known as “micropuberty”.
Girls have more ICPP, accounting for more than 80%-90% of CPP; while boys have the opposite, with more than 80% being organic.
(B) Peripheral precocious puberty.
1. Classification according to the characteristics of the second sex characteristics: when the early appearance of the second sex characteristics is the same as the original sex of the child, it is called homosexual precocious puberty, and when it is opposite to the original sex, it is called heterosexual precocious puberty.
2. Classification of common causes
2.1. Girls
(1) Homosexual precocious puberty (secondary sex characteristics of girls): It is seen in hereditary ovarian abnormalities such as McCune-Albright syndrome, benign ovarian occupational lesions such as autonomic ovarian cysts, estrogen-secreting adrenocortical tumors or ovarian tumors, ectopic human chorionic gonadotropin (HCG)-secreting tumors, and exogenous estrogen intake, etc.
(2) Heterosexual precocious puberty (male secondary sexual characteristics): seen in congenital adrenocortical hyperplasia, androgen-secreting adrenocortical tumors or ovarian tumors, as well as exogenous androgen intake.
2.2, Boys
(1) Homosexual precocious puberty (male secondary sexual characteristics): seen in congenital adrenocortical hyperplasia (more common), adrenocortical tumors or testicular mesenchymal cell tumors, ectopic HCG-secreting tumors, and exogenous androgen intake, etc.
(2) Heterosexual precocious puberty (female secondary sexual characteristics): seen in estrogen-producing adrenocortical tumors or testicular tumors, ectopic HCG-secreting tumors, and exogenous estrogen intake, etc.
III. Clinical manifestations and diagnostic basis
(A) Central precocious puberty.
1. Early appearance of secondary sexual characteristics (age in accordance with the definition) and progress according to the normal developmental procedure. Girls: breast development, sudden increase in height growth rate, pubic hair development, usually presented at menarche 2 years after the beginning of breast development. Boys: testicular and penile enlargement, sudden increase in height growth rate, pubic hair development, usually 2 years after the beginning of testicular enlargement, voice change and seminal emission.
2. There is a basis for gonadal development, girls are judged by ultrasound images, boys have testicular volume ≥ 4 ml.
3. The developmental process presents a sudden increase in height growth.
4. Gonadotropins are elevated to pubertal level.
5. Early bone age may be present, but is not diagnostic specific.
The most common type of incomplete central precocious puberty is simple precocious breast development, which is characterized by early breast development without other secondary sexual characteristics, no coloration of the areola, and a non-progressive self-limiting course.
(B) Peripheral precocious puberty.
1. Early appearance of secondary sexual characteristics (at an age consistent with the definition).
2. The development of sexual characteristics does not progress according to the normal developmental program.
3. Gonadal size is at prepubertal level.
4. The gonadotropin is at the prepubertal level.
IV. Diagnostic process and auxiliary tests
(a) To determine central or peripheral precocious puberty, in addition to the initial judgment according to clinical features, the following auxiliary examinations are required.
1. Basal sex hormone measurement. Basal luteinizing hormone (LH) has screening significance, such as LH <0.1 IU/L suggests that there is no central puberty initiation, LH>3.0-5.0 IU/L can confirm that there is central puberty initiation. β-HCG and AFP should be included in the basic screening test as important clues for the diagnosis of HCG-secreting germ cell tumors. Elevated levels of estrogen and testosterone are diagnostic aids.
2. Gonadotropin-releasing hormone (GnRH) stimulation test.
(1) Method: GnRH 2.5-3.0μg/kg (maximum dose 100μg) is injected subcutaneously or intravenously, and serum LH and follicle stimulating hormone (FSH) levels are measured at 0, 30, 60 and 90min of injection.
(2) Judgment: If measured by chemiluminescence, peak excitation LH>3.3-5.0 IU/L is the threshold for determining true development, while LH/FSH ratio>0.6 can be diagnosed as central precocious puberty. Currently, it is considered that a single excitation value of 30-60 min after excitation, meeting the above criteria, can also be diagnosed.
If the peak of excitation is dominated by elevated FSH and low LH/FSH ratio, combined with the clinical situation, it may be early stage of simple premature breast development or central precocious puberty, the latter requires regular follow-up and repeat examination if necessary.
3. Utero-ovarian ultrasound. Unilateral ovarian volume ≥1-3 ml and multiple follicles ≥4 mm in diameter can be considered as having entered pubertal development; uterine length >3.4-4 cm can be considered as having entered pubertal development, and endometrial shadow is visible suggesting a meaningful increase in estrogen. However, ultrasound findings alone cannot be used as a basis for CPP diagnosis.
4. Bone age. It is an important basis for predicting adult height, but is not specific for identifying central and peripheral.
(II) Etiological diagnosis.
1. Etiological diagnosis of central precocious puberty: brain CT or MRI examination (focusing on the saddle area) is required after the diagnosis of central precocious puberty, especially in the following cases.
(1) All boys with a confirmed diagnosis of CPP.
(2) Girls with onset under 6 years of age.
(3) Those with rapid sexual maturation process or other manifestations of central lesions.
2. Diagnosis of the etiology of peripheral precocious puberty: further endocrine examination according to specific clinical features and after the initial screening of endocrine hormones, and imaging of gonads, adrenal glands or other related organs as needed. Complex examinations may be dispensed with if there is a clear history of exogenous sex steroid hormone intake, as appropriate.
V. Treatment
(i) Central precocious puberty.
The therapeutic goals are to inhibit premature or rapid sexual development and to prevent or slow down the social or psychological problems associated with precocious puberty (e.g. early menarche) in the child or parents; improving adult height loss due to early bone age is also an important goal. However, not all ICPP requires treatment.
GnRH analogs (GnRHa) are the main current treatment option, and currently the commonly used preparations are treprostinil and leuprolide in extended-release form.
1. Indications for application with the aim of improving adult height.
(1) Bone age 2 years or more above age, but need to be ≤11.5 years for girls and ≤12.5 years for boys.
(2) Predicted adult height: <150cm for girls and <160cm for boys.
(3) Or height SDS <-2SD judged by bone age (judged by normal population reference values or genetic target height).
(4) Rapid developmental progression with bone age growth/age growth > 1.
2. Indications that do not require treatment.
(1) Slow sexual maturation (bone age progression does not exceed age progression) with insignificant effect on adult height.
(2) Although the bone age is advanced, but the height growth rate is also fast, and the predicted adult height is not impaired. Because pubertal development is a dynamic process, the above indicators need to be dynamically observed for each individual. For those who do not need treatment for the time being, regular review and evaluation are needed to adjust the treatment plan.
GnRHa dose: the first dose of 80-100μg/kg, the maximum amount of 3.75mg; subsequent injections every 4 weeks, weight ≥ 30kg, treprostinum every 4 weeks intramuscular injection 3-3.75mg. already menarche 2 weeks after the first dose should be intensified once. However, it should be emphasized that the maintenance dose should be individualized, depending on the suppression of gonadal axis function (including sexual characteristics, sex hormone levels and bone age progression), and the dose may be higher in boys. The interval between injections may be shortened or the dose increased, as appropriate, for those with poor gonadal axis suppression despite the above treatment. Different GnRHa extended-release agents are effective, and the choice of product depends on physician dosing practices and patient acceptance (e.g., greater acceptance of intramuscular or subcutaneous injections) or local product availability.
Treatment monitoring and decision to discontinue: Measure height and gonadal development every 3-6 months during treatment (pubic hair progression is not indicative of gonadal suppression); repeat GnRH stimulation test at the end of 3-6 months of the first dose; peak LH at prepubertal levels suggests appropriate dose. For girls, basal serum estradiol (E2) and ultrasound of the uterus and ovaries should be reviewed periodically; for boys, basal serum testosterone concentration should be reviewed to determine the status of gonadal axis suppression. Bone age should be reviewed every 6 months to predict the improvement of adult height in combination with height growth. In cases of poor efficacy, careful assessment of the cause and adjustment of the treatment regimen are required. Vaginal bleeding may occur after the first injection, or if bleeding is seen again in those with menarche, but should be carefully evaluated if bleeding continues with subsequent injections. The duration of treatment for the purpose of improving adult height should be at least 2 years and should be individualized.
It is generally recommended to discontinue the drug at age 11.0 years, or at 12.0 years of bone age, when maximum adult height can be expected, with more significant improvement in adult height in those who start treatment earlier (<6 years). However, bone age is not the absolute single best parameter to base on and there are still individual differences.
Simple premature breast development has a self-limiting course and generally does not require pharmacological treatment, but regular follow-up should be emphasized, and a small percentage of children may turn into central precocious puberty, especially after the age of 4 years.
The combination of recombinant human growth hormone (rhGH) has been shown to improve growth rate or adult height in small samples, but there is still a lack of data from large, randomized controlled studies, so it is not recommended for routine combination, especially for girls >12 years of age and boys >14 years of age.
Patients with CPP with central organic lesions should be treated with the appropriate etiology according to the nature of the lesion. Malformations are developmental abnormalities that do not require surgery in the absence of increased cranial pressure or other central nervous system manifestations and should remain on the ICPP drug regimen. The same is true for subarachnoid cysts.
(B) Peripheral precocious puberty.
The treatment is based on different etiologies, such as surgery for various tumors and cortisol replacement therapy for congenital adrenocortical hyperplasia.