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, precocious puberty is divided into central precocious puberty (gonadotropin-releasing hormone-dependent) and peripheral precocious puberty (non-gonadotropin-releasing hormone-dependent), which used to be called true precocious puberty and pseudo-precocious puberty respectively. Central precocious puberty (CPP) has a programmed process of initiation and maturation of the hypothalamic-pituitary-gonadal axis (HPGA) similar to normal pubertal development until the maturation of the reproductive system; 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 This results 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, therefore, only the early appearance of secondary sexual characteristics, but does not have a complete sexual development process.
Etiology
1. 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) Idiopathic central precocious puberty (ICPP), if no organic pathology is found.
(4) Incomplete central precocious puberty, a special type of CPP, refers to the early appearance of secondary sexual characteristics in the affected child, and its control mechanism also lies in the activation of the hypothalamic-pituitary-gonadal axis, but its sexual characteristics development is self-limiting; the most common type is simple premature 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 are more likely to have ICPP, accounting for more than 80%-90% of CPP; while boys are the opposite, with more than 80% being organic.
2. 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
a. Girls
(1) Homosexual precocious puberty (second sex sign in 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.
(2) Heterosexual precocious puberty (secondary sexual characteristics in males): seen in congenital adrenocortical hyperplasia, androgen-secreting adrenocortical tumors or ovarian tumors, and exogenous androgen intake, etc.
b. 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.
Clinical manifestations and diagnostic basis
1. Central precocious puberty.
(1) Early appearance of secondary sexual characteristics (age in accordance with the definition) and progression according to normal developmental procedures, girls: breast development, sudden increase in height growth rate, pubic hair development, generally presented at menarche 2 years after the beginning of breast development. Boys: testicular and penile enlargement, sudden increase in the rate of height growth, pubic hair development, generally 2 years after the beginning of testicular enlargement presents the change of voice and spermatorrhea.
(2) There is a basis for gonadal development, girls are judged by ultrasound images, and boys have testicular volume ≥ 4 ml.
(3) The developmental process presents a sudden increase in height growth.
(4) Gonadotropins are elevated to pubertal levels.
(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 coloring of the areola, and a non-progressive self-limiting course, with the breast fading naturally after several months.
2. Peripheral precocious sexual development.
(1) Early appearance of secondary sexual characteristics (age according to the definition).
(2) The development of sexual characteristics does not progress according to the normal developmental procedure.
(3) Gonadal size is at prepubertal level.
(4) Gonadotropin at prepubertal level.
IV. Diagnostic process and auxiliary tests
1. To determine central or peripheral precocious puberty, in addition to the initial judgment according to clinical characteristics, 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 indicates that there is no central puberty initiation, and LH >3.0-5.0 IU/L can confirm 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.
a. 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.
b. Judgment: If measured by chemiluminescence, peak LH > 3.3-5.0 IU/L is the cut-off point 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 condition, it may be early stage of simple premature breast development or central precocious puberty, and 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 the diagnosis of CPP.
(4) Bone age. It is an important basis for predicting adult height, but is not specific for identifying central and peripheral.
2.Etiology diagnosis.
(1) Etiological diagnosis of central precocious puberty: brain CT or MRI examination (focus on saddle area) is required after the diagnosis of central precocious puberty, especially for the following cases.
a. All boys with a confirmed diagnosis of CPP.
b. Girls with onset under 6 years of age.
c. 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
1. Central precocious puberty.
The goal of treatment is to suppress 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 formulations are treprostinil and leuprolide in extended-release form.
(1) Indications for application with the aim of improving adult height.
a. Bone age 2 years or more above age, but need to be ≤11.5 years for girls and ≤12.5 years for boys.
b. Predicted adult height: <150cm for girls and <160cm for boys.
c, or height SDS <-2SD judged by bone age (judged by normal population reference values or genetic target height).
d. Rapid developmental progression with bone age growth/age growth > 1.
(2) Indications that do not require treatment.
a.Slow sexual maturation process (bone age progression does not exceed age progression) and the impact on adult height is not significant.
b. Although the bone age is advanced, but the height growth rate is also fast, and the predicted adult height is not impaired. Because youth 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.
(3) 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 3-3.75mg. 2 weeks after the first dose of menarche 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 in cases of poor gonadal axis suppression despite the above treatment. Different GnRHa extended-release agents are effective, and the choice of product is determined by physician dosing practices and patient acceptance (e.g., more acceptable intramuscular or subcutaneous injections) or local product availability.
(4) Treatment monitoring and discontinuation decisions: height and gonadal development should be measured every 3-6 months during treatment (pubic hair progression is not indicative of gonadal suppression); GnRH stimulation tests should be repeated at the end of the first 3-6 months, with peak LH at prepubertal levels suggesting an 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 six months to predict the improvement of adult height in conjunction with height growth. For those with poor efficacy, the reasons need to be carefully evaluated and the treatment regimen adjusted. 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 a bone age of 12.0 years, 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 an 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 4 years of age.
(5) Some patients in GnRHa treatment have significant growth deceleration, and data from small samples show that the combined application of recombinant human growth hormone (rhGH) can improve growth rate or adult height, but there is still a lack of data from large, randomized controlled studies, so the routine combined application is not recommended, especially for girls with bone age >12 years and boys with bone age >14 years.
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 still be treated according to the ICPP pharmacologic regimen. The same is true for subarachnoid cysts.
2. Peripheral precocious puberty.
The treatment is based on different etiologies, such as surgery for various tumors and cortisol replacement therapy for congenital adrenocortical hyperplasia.