Precocious Puberty (Precocious Puberty; Sexual Precocity) is a common childhood developmental abnormality that is heterogeneous and has both physiological and psychological adverse effects on the affected child. Survey data indicate that the age of menarche has changed significantly over the past century or so, with menarche occurring around 17 years of age in the early 19th century and around 13 years of age in the 20th century. Beginning in the 1870s, the age criteria for the appearance of menstruation in girls decreased in both Europe and the United States [1]. Precocious puberty is generally defined as the presentation of secondary sexual characteristics by the age of 9 years in boys and by the age of 8 years in girls [2]. It can be classified as central precocious puberty (CPP), peripheral precocious puberty (PPP), and partial precocious puberty based on the early initiation of the hypothalamic-pituitary-gonadal axis (HPGA) and clinical presentation [3]. The incidence of precocious puberty in male and female children is about 0.6%, more in females than in males, and females account for about 3/4 of all cases [4].
The rapid increase in the incidence of precocious puberty in recent years, especially idiopathic precocious puberty, may be related to the following factors: (1) with the improvement of living standards, children are generally well nourished, and growth and development tend to advance and accelerate; (2) the influence of environmental pollution and environmental endocrine disruptors or the misuse of sex hormone drugs; (3) the abuse of health products and tonic products containing hormonal components or having hormone-like effects, such as pollen (4) hereditary factors; (5) the influence of social and psychological factors such as adverse cultural media: the excessive appearance of sexual content in many audio-visual products and books and other mass media can make children’s sexual initiation early and have a certain predisposing effect on precocious sexual maturity.
1. Etiology and classification:
1.1 Central precocious puberty:
Central precocious puberty (CPP), also known as true precocious puberty, has a programmed process of hypothalamic-pituitary-gonadal axis (HPGA) initiation and maturation similar to normal puberty 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 make the gonads develop and secrete sex hormones, thus The process of internal and external genital development and secondary sexual characteristics; there are also physical changes, height growth acceleration, psychological and behavioral changes, and there may be neurological symptoms and signs.
1.1.1 Organic lesions of the central nervous system [5]: the most common of these are intracranial tumors.
(1) Intracranial tumors: such as craniopharyngioma, astrocytoma, germ cell tumor, ventricular meningioma, glioma, neurofibroma type 1, Sturge-Weber syndrome, hypothalamic malformation tumor, and various pineal tumors, of which tumors of the pineal region are the most common intracranial tumors causing CPP. Tumors of the pineal gland and pineal region include germ cell tumors, teratomas, pineal cell tumors, pineoblastomas, gangliogliomas, astrocytomas, ventricular meningiomas, and cysts or cavernous hemangiomas of the pineal region, while germ cell tumors are the most common pineal tumors;
(2) Congenital anomalies of the skull: hydrocephalus, subarachnoid cyst, ventricular septal dysplasia, foramen ovale, cranial stenosis, microcephaly, vacuolation saddle syndrome, cerebrospinal bulge, and Tay-Sachs disease;
(3) Infection or inflammation: encephalitis, meningitis, cornual tuberculosis, brain abscess, tuberous sclerosis, sarcoidosis;
(4) Other causes: after head trauma, after radiotherapy for cranial tumors, and in those with irregularly treated hypothyroidism, etc.
1.1.2 Transformation from peripheral precocious puberty: It has been proved that 20% of peripheral precocious puberty can eventually develop into CPP, and it mostly occurs after the use of sex hormone treatment.
1.1.3 If no organic pathology is found, it is called idiopathic central precocious puberty (idiopathic CPP,
ICPP). In girls, 80%-90% of central precocious puberty is idiopathic; in contrast, in boys, 80% is due to central organic pathology [6].
1.2. Peripheral precocious puberty:
Peripheral precocious puberty (PPP), also known as pseudoprecocious puberty, does not depend on the activation of the hypothalamic-pituitary-gonadal axis (HPGA), but is caused by increased secretion of extra-pituitary gonadotropins or sex hormones, or increased intake of exogenous sex hormones. In this case, only secondary sexual characteristics appear, without maturation of gonads and sexual functions, either homosexual precocious puberty (early appearance of secondary sexual characteristics of the same sex as the original sex of the child) or heterosexual precocious puberty (early appearance of secondary sexual characteristics of the opposite sex of the original sex of the child).
The etiology of peripheral precocious puberty is diverse, and a recent study [7] showed that the most common cause is the intake of exogenous sex hormones, followed by ovarian cysts, genetic ovarian abnormalities such as McCune-Albright syndrome (MAS), congenital adrenocortical hyperplasia (CAH), adrenocortical tumors, ovarian malformations, androgen-secreting adrenocortical tumors In addition, there are also some cases of peripheral precocious puberty of unknown etiology, including ectopic GnRH-secreting chorionic gonadotropin carcinoma (such as pineal choriocarcinoma), hepatocellular carcinoma and teratoma. The different etiologies can directly affect the prognosis.
1.3. Partial precocious puberty:
It is a special type of CPP, which refers to the early appearance of secondary sexual characteristics in children, and its control mechanism also lies in the activation of hypothalamic-pituitary-gonadal axis, but the development of sexual characteristics is self-limiting; it includes simple premature breast development, simple premature pubic hair development and simple menarche.
1.3.1 Simple breast development.
The onset of breast development is the most obvious sign that estrogen is becoming active in girls, and the age of first breast development in girls has also decreased significantly over the past 20 years, with girls in the United States currently starting to develop around age 10 [1]. Simple mammoplasia is the most common type of partial precocious puberty and refers to the appearance of isolated breast development without other signs of increased endogenous estrogen secretion in girls before the age of 8 years, and its pathophysiological mechanisms are not yet clear. Serum gonadotropin and sex hormone levels are the same as in normally developing children, although some cases with elevated FSH and inhibin B cannot be excluded [8]. If it occurs within 2 years of age, it may be due to a physiologically active hypothalamic-gonadal axis, also known as “micropuberty”. It is characterized by the appearance of simple unilateral or bilateral breast development within 3 years of age, with no coloration of the areola, which may disappear spontaneously within a few months or persist until puberty; the bone age and growth rate are normal, and noninvasive ultrasonography is useful for diagnosis.
1.3.2 Early appearance of simple pubic hair.
The appearance of pubic hair is the result of increased production of androgens by the adrenal glands and is not related to the activity of the ovaries. Early appearance of pubic hair refers to the appearance of pubic hair before the age of 8 years in girls and 9 years in boys [8], with elevated blood DHEA, DHEAS, and urinary 17-ketones in affected children. It is more common in girls than boys and may be associated with the appearance of axillary hair, increased growth rate, slightly premature bone age (but no significant effect on lifetime height), mild acne, oily skin, and no other secondary sexual characteristics. The early appearance of pubic hair is often the only clinical manifestation of atypical late-onset CAH, which can also be characterized by hirsutism and should be differentiated. In addition, obese children are more likely to have premature pubic hair [9].
1.3.3 Simple menstrual primiparity.
Simple primiparous menstruation refers to the appearance of simple vaginal bleeding before the age of eight years without other signs of precocious puberty, with no overt skeletal age and gonadotropin and estrogen at prepubertal levels. The mechanism is unknown and may last for 1-6 days before stopping on its own. The diagnosis should be made by a detailed history and examination of the external genitalia to exclude other causes of vaginal bleeding such as tumors, inflammation, injuries and foreign bodies in the girl’s genital tract.
2. Diagnosis
2.1.
Diagnostic procedure: Firstly, whether precocious puberty should be determined according to clinical manifestations, then detailed medical history should be inquired, especially whether there is any history of sex hormone exposure; whether there is any history of brain surgery, trauma, inflammation, whether there is headache, visual field defects, convulsions and other symptoms; careful physical examination must be performed, such as whether there is enlargement of thyroid gland and whether there is coffee spot on the skin; and appropriate laboratory tests and imaging tests should be selected on this basis. Based on the results, we can determine whether the precocious puberty is central or peripheral, and then find out the cause.
2.2 Diagnostic basis of true precocious puberty [10]
2.2.1
Early appearance of secondary sexual characteristics: the sequence of secondary sexual characteristics development in true precocious puberty is consistent with normal development, and the children mostly have breast development or increased pubic hair growth before the age of 8 and/or first menstruation before the age of 10, and the sexual development process is continuous and progressive.
2.2.2 Gonadal enlargement.
Ultrasound showed testicular volume ≥4 ml (boys); bilateral ovarian enlargement with increased follicular diameter and unilateral ovarian volume ≥1 ml (girls); increased uterine volume was of little significance for the differential diagnosis of central precocious puberty and peripheral precocious puberty.
2.2.3
Linear growth acceleration: sudden increase in growth is the earliest symptom of precocious puberty. True precocious puberty has an early appearance of secondary sexual characteristics (by the age that meets the definition, i.e., by 8 years for girls and 9 years for boys) and progresses according to the normal developmental sequence. For example, the developmental sequence in girls is usually: breast development, sudden increase in height growth rate, pubic hair development, and menarche presentation usually 2 years after the beginning of breast development. In boys, the developmental sequence is usually: testicular and penile enlargement, sudden increase in height growth rate, pubic hair development, and generally 2 years after the beginning of testicular enlargement, voice change and seminal emission.
2.2.4 Bone age is more than 1 year earlier.
2.3 Diagnostic basis of peripheral precocious puberty.
2.3.1 Early appearance of secondary sexual characteristics (age in accordance with the definition).
2.3.2 Development of sexual characteristics does not progress according to the normal developmental program.
2.3.3 Gonad size is at prepubertal level.
2.3.4 Gonadotropins at prepubertal levels.
2.3.5 McCune-Albright syndrome has typical clinical manifestations, mostly in girls but rarely in boys, and is often associated with cutaneous café-au-lait spots and cystic hyperplasia of bone fibers.
2.4 Ancillary tests: To determine true precocious puberty and pseudoprecocious puberty, in addition to the basic clinical features, special ancillary tests are required.
2.4.1 Basal sex hormone measurement: Basal luteinizing hormone (LH) has screening significance, such as LH < 0.1 IU/L suggests that central puberty has not yet been initiated, and LH > 3.0-5.0 IU/L can confirm that central puberty has been initiated [11]. β-HCG and AFP are currently used as important clues for the diagnosis of HCG-secreting germ cell tumors. Elevated levels of estrogen and testosterone are diagnostic aids.
2.4.2 Gonadotropin-releasing hormone (GnRH) stimulation test: This test is of diagnostic importance in patients whose gonadal axis is activated but whose basal gonadotropin values are not elevated; GnRH increases gonadotropin secretion and release, and its stimulation peak can be used as a diagnostic basis.
(1) Method: GnRH is administered subcutaneously or intravenously at 2.5-3.0 μg/kg (maximum dose 100 μg) and blood is drawn at 0, 30, 60 and 90 min after injection to determine serum LH and follicle stimulating hormone (FSH) levels.
(2) Judgment: If measured by chemiluminescence, peak excitation LH>3.3-5.0 IU/L is the threshold for judging true sexual development, while LH/FSH ratio>0.6 can be diagnosed as central precocious puberty. It is also considered that a single excitation value of 30-60 min after excitation, meeting the above criteria, can also be diagnosed [12].
If the peak excitation is dominated by elevated FSH and a low LH/FSH ratio, combined with the clinical picture it may be simple premature breast development or the early stage of central precocious puberty, the latter requiring regular follow-up and repeat examination if necessary. In peripheral precocious puberty, the response to GnRH excitation test is low and serum FSH and LH excitation values are not different from basal values, suggesting that the pituitary gland does not respond to GnRH. It is also important to distinguish normal pubertal girls, whose response to GnRH excitation test is dominated by elevated FSH.
2.4.3 Ultrasound of the uterus and ovaries: unilateral ovarian volume ≥1 ml and multiple follicles ≥4 mm in diameter are seen, indicating that the ovaries have entered pubertal development; uterine length >3.4-4 cm can also be considered to have entered pubertal development, and the visible endometrial shadow suggests that estrogen is meaningfully elevated. However, ultrasound findings alone cannot be used as a basis for the diagnosis of CPP.
2.4.4 Bone age: It is an important basis for predicting adult height, but it is not specific for identifying central and peripheral precocious puberty. True precocious puberty 95% of bone age is early; pseudoprecocious puberty bone age is generally consistent with age.
The current diagnostic basis is mainly the sex hormone provocation test, but it has limitations due to its expensive, time-consuming and unnecessary pain to patients due to the need for multiple intravenous blood draws; simple clinical tests, such as blood or urine tests, and the lack of molecular markers are currently the bottleneck of clinical diagnosis and evaluation of PP; in recent years, there are studies to help diagnosis through the determination of specific urinary metabolites and prognostic assessment, such as urinary levels of 5-hydroxytryptophan, 5-hydroxytryptophan, 5-indoleacetic acid, and indoleacetic acid have very significant alterations in true precocious puberty [13].
2.5 Etiological diagnosis.
2.5.1
Etiological diagnosis of central precocious puberty: cranial CT or MRI examination (with emphasis on the saddle area) is required after the diagnosis of central precocious puberty, especially for all boys diagnosed with CPP, girls with onset under 6 years of age and those with rapid sexual maturation process or other manifestations of central pathology.
2.5.2
Diagnosis of the etiology of peripheral precocious puberty: further endocrine examination is performed according to specific clinical features and after the initial screening of endocrine hormones, and imaging of gonads, adrenal glands or other related organs is performed as needed. Complex examinations may be dispensed with if there is a clear history of exogenous sex steroid hormone intake, as appropriate.
3 Treatment:
3.1 Treatment of central precocious puberty:
The goals of treatment are, in order of priority, to detect and eliminate the cause of precocious puberty, to detect and treat intracranial tumors, to inhibit premature or rapid sexual development, and to prevent or alleviate social or psychological problems associated with precocious puberty in the child or parents; improving adult height loss due to premature bone age and reducing the high incidence of breast cancer due to premature breast development are also important goals. However, not all cases of partial precocious puberty require treatment.
3.1.1 GnRH analogs (GnRHa)
GnRH analogs are currently preferred. GnRHa effectively inhibits pituitary gonadotropin secretion and decreases GnRH receptor activity, thereby promoting a return to prepubertal levels of gonadal suppression and improving clinical symptoms. It improves the lifelong height of the child, and most experiments have shown that it is most effective in children before the age of 6 years [10]. The currently available sustained-release GnRHa formulations for use in children in China are treprostinil acetate and leuprolide acetate.
3.1.1.1 Indications for application [14].
(1) Bone age 2 or more years older than age, but need to be ≤11.5 years for girls and ≤12.5 years for boys.
(2) Predicted adult height: <150 cm for girls and <160 cm 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 gain/age gain > 1.
3.1.1.2 Indications for caution.
(1) Bone age >11.5 years for girls and >12.5 years for boys at the start of treatment;
(2) Genetic target height 2 standard deviations below the normal reference value (-2SDS). 3.1.1.3 Indications for inappropriate use.
(1) Bone age ≥ 12.5 years for girls and ≥ 13.5 years for boys;
(2) >1 year after menarche in girls or after ejaculation in boys.
(3) Children with excitation peak LH < 4.0 U/L.
3.1.1.4 Indications for which application is not required.
(1) Treatment is not required in those with slow sexual maturation progression (bone age progression not beyond age progression) when it has little effect on adult height.
(2) Although the bone age is advanced, the height growth rate is rapid, making the height age greater than the bone age, and the predicted height in adulthood is not impaired. However, once the diagnosis of CPP is established, all those whose initial assessment is deemed not to require treatment for the time being need to regularly review their height and bone age changes, periodically re-evaluate the need for treatment, and develop treatment plans as needed.
3.1.1.5 GnRHa dose.
GnRHa monthly formulations (1 injection per month) have been widely used in the treatment of clinical true precocious puberty, which provides a stable release of the drug, improves short-term and long-term efficacy, and has fewer associated side effects.The March dose formulation of GnRHa (March dose of treprostinil 11.25 mg),previously used in clinical treatment, is more effective than GnRHa monthly formulations in improving the effectiveness of treatment and patient compliance [15], thus improving the quality of life of the child. In China, the guidelines state that the initial treatment regimen is 80-100 μg/kg for the first dose, with a maximum of 3.75 mg; thereafter, injections are given every 4 weeks, and for those weighing ≥30 kg, treprostinil is given 3-3.75 mg intramuscularly every 4 weeks. 2 weeks after the first dose in those with menarche, a booster dose is recommended. 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. Common side effects are vaginal bleeding (more common after the first dose), nausea, and vascular reactions.
3.1.1.6
Treatment monitoring and decision to discontinue: height and sex characteristics are measured every 3-6 months during treatment (pubic hair progression is not indicative of gonadal suppression); GnRH stimulation test is repeated at the end of 3-6 months of the first dose, and peak LH at prepubertal levels indicates 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 6 months to predict the improvement of adult height in conjunction with height growth. The reasons for poor results need to be carefully evaluated and the treatment plan adjusted. The duration of treatment for the purpose of improving adult height should be at least 2 years, but the exact duration of treatment 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 an absolute single best based parameter and there is still individual variation. < p="">
Recent studies have shown that gonadotropin analogs combined with letrozole tablets (Letrozole) can achieve good results in the treatment of CPP, especially in precocious puberty due to MAS syndrome, and can effectively improve the final height of the child [16]. 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 proportion of children may turn into central precocious puberty, especially after the age of 4 years.
3.1.2. Application of traditional Chinese medicine.
3.1.2.1 Treatment of precocious puberty from kidney theory.
Cai Depei et al [17] found that children with precocious puberty have fear of heat, thirst, irritability, constipation, etc. According to the identification of Chinese medicine as the evidence of yin deficiency and fire, it is attributed to the Chinese herbal medicine that nourishes kidney yin and diarrhea the phase fire, such as Shengdi, Guiban, Huangbai, Zhimu, etc. The Chinese medicine can be used for the short duration of the disease and the milder children, which is more effective, not only can make the sexual signs subside, but also can significantly delay the skeletal maturation. Fu Xu-Mei [18] reported that the proposed method of nourishing Yin and nourishing the kidney, as well as clearing the liver fire, was based on Zhi Bai Di Huang Tang, and the child’s diet was controlled with light food. The shortest duration of medication was 1 week and the longest was 2 months, and good results were achieved.
3.1.2.2 Treatment of precocious puberty from the liver
Currently, most doctors use Danjuania Prosperity San, Chaihu Dredging Liver San, Gentian Diarrhea Liver Tang, or their additions and subtractions. Xia Wei [19] treated partial precocious puberty with Chai Hu Shu Liver San with addition and subtraction, and the formula Chai Hu, Scutellaria baicalensis, Radix Angelicae Sinensis, Yu Jin, Radix Aromaticus, Radix Paeoniae Alba, Radix Shengdi, Radix et Rhizoma ganoderma, and Radix Glycyrrhizae had an overall efficiency of 90%. Jin Chuan-sang [20] treated true precocious puberty with the formula of Jia Wei Yi Yao San (Chai Hu, Radix Angelicae Sinensis, Radix Paeoniae Alba, Xia Ku Cao and Yan Hu Suo). It is taken with water decoction for 1 month as a course of treatment and is more effective. Some people have also adopted the treatment of true precocious puberty with the addition and subtraction of prolotherapy, decoction in water, each course of medication for 3 weeks, stopping for 1 week.
FSH and LH were reduced to normal level, and the side effects were less.
3.2 Treatment of peripheral precocious puberty:
According to different etiologies, such as surgery for various tumors and cortisol replacement therapy for congenital adrenocortical hyperplasia, etc.
3.2.1 Surgical treatment: it is applied to adrenal, ovarian and testicular tumors, and current studies have shown that radiotherapy and chemotherapy can also be administered according to the situation, which can achieve better results, but no definitive conclusion has been reached [8].
3.2.2 Drug therapy
3.2.2.1 Progestin therapy
In addition to inhibiting the secretion of pituitary gonadotropins, it can also inhibit the synthesis of sex hormones by inhibiting several enzymes of the synthesis pathway of steroids. For the treatment of testicular tumors and MAS syndrome [21], progesterone is commonly used, and the conventional dose is 10-50 mg by intramuscular injection every 2 weeks. The dose is adjusted according to clinical symptoms. Adverse effects include edema, chronic headache, increased body mass, skin cyanosis, and hyperalgesia.
3.2.2.2 Anti-androgen drugs: Including androgen receptor blockers and androgen synthesis inhibitors.
(1) Androgen receptor blockers: such as spironolactone and cyproterone, both of which can compete with androgens for androgen receptors in peripheral tissues to achieve anti-androgen effects. Ciproterone also partially inhibits gonadotropin secretion at the pituitary level due to its progesterone-like effect. The dose is 100mg/d of spironolactone and 50-100mg/d of cyproterone, divided into two to three oral doses. Adverse effects include gastrointestinal reactions and gynecomastia. Ciclopirogesterone can also cause hypoadrenocorticism, so attention should be paid to monitoring adrenocortical function.
(2) Androgen synthesis inhibitors: such as ketoconazole. The dose is 200mg/d, divided into 2~3 oral doses. The main adverse effect is liver damage. Other adverse effects include gastrointestinal reactions, reversible transaminase elevation, and hyperalgesia.
3.2.2.3 Anti-estrogen drugs: including estrogen receptor modulators and estrogen synthesis inhibitors. (1) Estrogen receptor modulators.
Such as tamoxifen, which belongs to the family of selective estrogen receptor modulators. The dose is 10~20mg/d in 2~3 oral doses. Adverse effects include hepatic impairment and hirsutism. Other estrogen receptor blockers such as flovisetron are theoretically effective, but there is no clinical experience.
(2) Estrogen synthesis inhibitors: i.e., aromatase inhibitors. Effective in treating PPP and McCune-Albright syndrome in boys or girls. Commonly used drugs include anastrozole (1mg/d) and letrozole tablets (2.5mg/d).
3.2.3. Etiological treatment: treatment of hypothyroidism with thyroxine; pseudoprematurity due to congenital adrenocortical hyperplasia requires lifelong adrenocorticotropic hormone replacement therapy, with glucocorticoids preferred to hydrocortisone and salt corticosteroids preferred to 9a fludrocortisone, and regular testing of cortisol, ACTH testosterone, progesterone, urinary 17KS and plasma renin activity is required during treatment to guide drug dose adjustment .