I. Normal pubertal development.
Adolescent development is an important period of transition from childhood to sexual maturity, eventually acquiring reproductive capacity, and is the last stage of child development and the second peak of height growth. It is characterized by the rapid development of sexual organs and secondary sexual characteristics and the acceleration of physical development, and is accompanied by corresponding changes in psychological and behavioral aspects.
The earliest sign of puberty is the enlargement of testicles, followed by the increase of androgens, secondary sex disorders and accelerated growth; the average duration of puberty for boys is 4.9 years, with a total height growth of about 25-30 CM, of which, about 1.5 years in the middle of puberty, this period is a rapid growth period, with an annual growth rate of more than 10 CM, after which the growth rate decreases sharply until it stops completely. The growth rate decreases until it stops completely. When a boy’s beard appears on his jaw, there is usually no more room for growth.
The earliest sign of puberty is the enlargement of the ovaries (which is difficult to detect in time without ultrasound and is often marked by the development of breasts), followed by an increase in estrogen, the appearance of secondary sex characteristics and accelerated growth. The average length of puberty for girls is about 4.7 years, with a total height growth of about 20-25 CM, including about 1 year in the middle of puberty, which is also a period of rapid growth, with an annual growth rate of nearly 10 CM. after the onset of menarche, the growth rate decreases sharply, and continues to grow for a total of about 4-8 CM. after two years of menarche, girls are generally no longer likely to grow taller. Some normal girls do not have an obvious rapid growth period (because rapid growth period is often also a period of rapid bone growth, therefore, the absence of rapid growth period is not necessarily a bad thing. If there is a rapid growth period, a 10 cm growth in one year and two years of bone growth is not better than a 6 cm growth in one year and only one year of bone growth).
Normal puberty initiation is an extremely complex process that is the result of the interaction of multiple hormones and many neurotransmitters. The pubertal onset process is currently considered to be the result of a networked interaction of a series of neuro-endocrine regulatory factors controlled by the central nervous system. However, the causes and mechanisms of puberty initiation are still not fully understood.
1. The gonadal stabilizer theory.
This theory suggests that the negative feedback link between the hypothalamic-pituitary-gonadal axis (HPGA) is established in the newborn and early infancy, but its inhibitory function is not yet mature. At this time, gonadotropin (Gn) is highly secreted and can resemble the level of puberty, so it is called “minipuberty”; after 1 year, the threshold of negative feedback changes, sensitivity increases, and its negative feedback effect gradually strengthens. 3 years old ~ prepubertal is highly sensitive, GnRH secretion is inhibited, and Gn is at a low level. is at a low level. On the eve of puberty, the threshold of negative feedback increases, sensitivity decreases, and GnRH secretion by the hypothalamus and Gn secretion by the pituitary gland begin to increase. After entering puberty, the frequency and amplitude of GnRH release increases significantly, and the pulsatile secretion of LH and FSH increases to promote gonadal development.
2. Central nervous control theory.
The initiation of puberty may be related to the weakening of the inhibitory mechanism of GnRH release in the hypothalamus. the balance between inhibitory and excitatory factors of GnRH release is regulated by the central nervous system. Prepubertal inhibitory amino acids such as gamma-aminobutyric acid (GABA) neurons are turgidly secreted and inhibit GnRH release; by the time puberty is initiated, their turgor decreases, reducing the inhibitory effect on GnRH release. At the same time the tension of neurons secreting excitatory factors increases, and excitatory mediators such as glutamate stimulate GnRH neurons, shifting the equilibrium point between the two in the direction of excitability and favoring GnRH release, resulting in enhanced cyclic secretion of hypothalamic GnRH, leading to pubertal development.
3. Initiation of puberty is associated with the development of GnRH secretion patterns.
It is currently believed that puberty starts to be initiated only when the hypothalamus begins to secrete GnRH pulsatilely. The rhythm of GnRH secretion is regulated by the “GnRH pulse generator” in the arcuate nucleus of the hypothalamus. This pulsatile stimulation is necessary for the maintenance of pituitary LH and FSH secretion, which begins to occur only at night, resulting in a pulsatile peak of LH and FSH secretion at night after sleep. Increased pulsatile nocturnal Gn secretion is characteristic of early puberty, when girls first have predominantly elevated FSH, followed by elevated LH. As puberty progresses, GnRH is secreted in 24-hour pulses, the frequency and peak of circadian release of LH and FSH increase, and the ratio of the two gradually transitions to LH/FSH≥1, which is an important sign that the central regulation of puberty is fully activated. At the same time, the sensitivity of the gonads to Gn also increases, presenting elevated levels of sex hormones.
4. leptin is a metabolic signal of the reproductive system.
As early as the 70s Frisch et al. found that one of the key factors for puberty initiation and menarche is to reach a critical weight and fat reserves to a certain threshold. Recent studies on leptin have confirmed that it is not only a regulator of body fat metabolism, but also a metabolic signal of the neuroendocrine reproductive system, which is associated with puberty development. As a “permissive factor” rather than a stimulating factor of puberty development, Leptin, together with other peptides involved in the regulation of nutrient metabolism, such as neuropeptide Y, angiotensin and ghrelin, is closely related to the regulation of the reproductive axis through a complex network of regulation, and becomes a central signal for puberty initiation.
Numerous studies have shown that leptin levels increase before FSH, LH and sex hormones in both boys and girls before they enter puberty. The onset of puberty requires the involvement of leptin, but there are significant differences between the two. In boys, leptin levels rise and peak during the G2 phase and fall to a low point during the G5 phase. Leptin was negatively correlated with FSH, LH, and T. Leptin levels decreased with rising testosterone, mainly because rising testosterone directly inhibited leptin production in adipose tissue. This suggests that leptin is no longer a necessary factor in the full course of pubertal development in boys after stimulating their initial development. In contrast, in girls, leptin levels gradually increase from stage B1 to B5, and remain at a high level as estrogen levels rise, reaching a peak at stage B5. Leptin was positively correlated with FSH, LH and E2. This means that leptin not only helps girls to complete pubertal development, but also has a role in maintaining normal reproductive function in the future.
5. Insulin-like growth factor-1 (IGF-1) is an important signal for puberty initiation.
Experimentally, it was demonstrated that the secretion of GnRH increased after adding IGF-1 to hypothalamic cells of isolated rats in culture medium. Therefore, it is proposed that IGF-1 may be a metabolic signal for puberty initiation. Measurements of IGF-1 in children and adolescents aged 1-18 years showed that IGF-1 increased gradually with age, peaking at 13 years in girls and 15 years in boys, consistent with their peak age of pubertal development. In recent years, cell biology studies have demonstrated that ovarian granulosa cells and follicular membrane cells are the sites of IGF-1 production and IGF-1 receptors and their effects. IGF-1 plays an important role in the proliferation, differentiation and sex hormone synthesis of ovarian cells in concert with gonadotropins.
As early as 1955, it was shown that the initial development of the breast during puberty was caused by GH. The mammary gland contains receptors for GH and IGF-1, and GH increases the expression of IGF-1 mRNA in the mammary gland. IGF-1 alone has a mild effect on murine breast development, but the addition of E2 has a significant effect. However, the effect of E2 on mammary development was after IGF-1 production. It can be seen that GH and IGF-1 play a major role in pubertal breast development, but the complete development of breast requires the combined effect of both and E2.
6. First appearance of adrenocortical function.
During the “peri-pubertal” period, there is a significant increase in the adrenocortical androgens, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S), followed by a gradual increase in androstenedione. It is therefore hypothesized that the unleashing of the adrenal cortex may be a precursor to the maturation of the HPGA axis. It was once thought that adrenocortical androgen synthesis was increased by the production of opioid melanocortinogen (POMC) by pituitary pro-corticotropic cells and the secretion of adrenocortical androgen-stimulating hormone (CASH) by the pituitary gland, which stimulates the maturation of the adrenocortical reticular zone or alters its enzymatic activity (increased activity of 17α hydroxylase and 17-20 lyase). However, it is currently believed that the unleashing of adrenocortical function is not related to the developmental maturation of the HPGA axis.
Second, the definition about precocious puberty.
There are not only inter-individual differences in the age of pubertal development initiation, developmental speed, maturation age and developmental degree, but also obvious inter-racial and gender differences. There are also differences between individuals of the same race, sex, and similar living environment. There are many factors that affect pubertal development, such as genetic, nutritional, emotional, environmental and social factors, and diseases.
According to statistics from some European and American countries, the age of puberty has been advancing about 3-4 months every 10 years for the past 100 years. Domestic data also show that the age of menarche is earlier for girls, for example, the average age of menarche in Beijing was 14.5 years in 1963; 12.4 years in 1984; and 12.1 years in 2004, the latest data. In Shanghai, the average age of menarche was 14.1 years in 1978 and 12.5 years in 1989. 1993 survey data in Hong Kong showed that 10% of girls had breast development at the age of 7 years, which should not be called premature at the age of 7-8 years; 50% of girls had menarche at the age of 12.5 years, which is 6 months earlier than that reported in the study 30 years ago. Therefore the definition of precocious puberty should be adjusted according to different generations and regions in order to be appropriate.
It has been proposed that precocious puberty is defined as any secondary sexual sign appearing at an age lower than the mean age of appearance of that sign for normal adolescents in that region – 2.5 SD (standard deviation). At present, textbooks generally stipulate that girls appear second sexual characteristics before the age of 8, and menstruation begins before the age of 10; boys appear second sexual characteristics before the age of 9-10, accompanied by excessive physical development, called precocious puberty.
Three, the classification of precocious puberty.
1. GnRH-dependent precocious puberty: also known as central precocious puberty or true precocious puberty.
It is the real initiation of HPGA, not only has the early appearance of the second sex characteristics, at the same time has the early development and maturity of sexual function, all are same-sex precocious puberty. Its developmental procedure is the same as normal puberty development, and its maturation process is progressive until it finally develops into an individual with fertility.
2.Non-GnRH-dependent precocious puberty: also known as peripheral precocious puberty or pseudo-precocious puberty.
There is only the appearance of some secondary sexual characteristics, without the development and maturation of gonads and sexual functions, that is, without the initiation of gonadal axis. It can be homosexual precocious puberty or heterosexual precocious puberty.
3, incomplete central precocious puberty: also known as normal variant puberty or partial precocious puberty. It refers to the early appearance of some secondary sexual characteristics alone, which is due to the partial initiation of HPGA and is generally self-limiting.
Including: simple early development of breast; simple early development of pubic hair; simple early appearance of menarche, etc.
4, puberty in order to raise early: girls before the age of 8 years old to appear sexual development is considered precocious sexual development. But girls we take breast development as the initial development signs, compared with boys to testicular enlargement as development signs, is not very scientific. Ideally, it would be more reasonable for girls to take ovarian development as the first sign, because sex hormones will increase only after ovarian development, and only after that will there be breast development, but the ovaries are in the abdominal cavity, so it is impossible to know in advance without ultrasound. The time between breast development and menarche varies greatly from person to person, ranging from 4-5 years to less than a year. Regardless of boys or girls, signs of development only appear before puberty, and if the predicted adult height is low, the diagnosis of early pubertal development can be made and medical intervention can be performed.
IV. Idiopathic central precocious puberty (ICPP).
It is a common cause of true precocious puberty in children, accounting for about 80-90% of precocious puberty in girls and 40-50% of precocious puberty in boys. It is significantly more common in girls than in boys, and is mostly episodic in girls, while boys generally have a familial tendency and may be sex-linked inherited.
(i) Clinical features.
ICPP is an abnormal manifestation of growth and development, and its sexual development process is progressive and follows the normal sexual development pattern, but the whole sexual maturation process is advanced in time. In addition to the early appearance of secondary sexual characteristics, it is accompanied by accelerated height and weight growth, rapid skeletal maturation and early epiphyseal fusion, which affects the final height.
The speed of progression from breast development to menarche in children with ICPP can be divided into three types, namely, rapidly progressive, slowly progressive and delayed. Rapidly progressive patients tend to have their first menstrual period about 1.5 years after breast development or even in a shorter period of time, and as the disease progresses, skeletal maturation accelerates and fuses earlier, which obviously affects their final height; slowly progressive patients have a slower developmental rate, and the tendency of accelerated skeletal growth and earlier maturation is more moderate, which has relatively less adverse effects on their final height; delayed growth patients have earlier sexual development, but their skeletal In the delayed growth type, the sexual development is advanced, but the linear growth of the skeleton is relatively delayed, and there may be obstacles in the skeletal growth process, and the final height of such children is obviously short, even less than 150 cm.
Although children with this disorder do not have neurological manifestations, some authors have reported extensive EEG abnormalities in children with this disorder. Other authors have reported postmortem findings of hypothalamic malformations in children diagnosed with ICPP during life. Therefore, the diagnosis of ICPP should be made with caution, and the etiology should be sought whenever possible, excluding organic lesions, and should be followed up periodically.
(II) The adverse effects of precocious puberty in children on their physical and mental development.
1. Due to premature maturation, the period of skeletal growth will be shortened and the epiphysis will close prematurely, which will affect their final height.
2. Although the affected children start to mature sexually, their actual age and psychological maturity are not consistent with this, which can easily cause psychological disorders in children, but almost no spontaneous sexual behavior will appear early.
3. It has been reported that the increased incidence of tumors in estrogen-sensitive target organs, such as the breast, in adulthood may be related to the high sensitivity of individuals to estrogen.
(III) The pathogenesis of ICPP its occurrence mechanism is not completely clear
It is believed that the early onset of puberty is influenced by the multifactorial and multilevel network excitation process of the hypothalamus “GnRH pulse generator”, and the imbalance between inhibitory and excitatory factors, which together initiate the schedule of the biological clock of sexual development.
In recent years, studies on ICPP girls have shown that the changes in blood leptin levels with puberty in ICPP girls are similar to those in normal adolescent girls. This suggests that leptin plays a similar role in the initiation of precocious puberty. It was also found that the changes in blood IGF-1 in ICPP girls paralleled the pubertal development process, and that the function of GH-IGF-1 axis was activated at the same time as the function of gonadal axis was activated in ICPP patients, and blood insulin levels were also significantly increased, with an increase in BMI and the presence of insulin resistance.
(iv) Discussion of diagnostic criteria for ICPP.
1, Secondary sexual characteristics appeared before 8 years of age in girls and 9-10 years of age in boys (as determined by Tanner criteria).
2.Bone age exceeds the actual age by more than 1 year.
3, Growth rate increase >6-7cm/year.
4, elevated pituitary gonadotropin and sex hormone levels up to pubertal level; GnRH stimulation test supports the diagnosis of central precocious puberty (GnRH stimulation test: static injection of GnRH 100μg /M2, maximum amount 100μg, according to LH/FSH ratio ≥0.6~1, LH basal or peak value, >15IU/L in females, >25IU/L in males (RIA), has (diagnostic significance).
5. Ultrasound examination of the uterus and ovaries is consistent with the manifestation of precocious puberty (observation of ovarian volume >1 ml, the number and size of follicles in the ovaries, and generally when the number of follicles ≥4 mm in diameter in either ovary reaches 4 or more, the HPGA function can be considered to have been initiated).
6. Exclude central organic lesions and other endocrine disorders.
V. Incomplete central precocious puberty.
(I) Simple premature breast development.
Breast development does not fully represent true pubertal development. Pure premature breast development (PT) refers to isolated breast development that occurs before the age of 8 years in girls.
1. Clinical features.
(1) The age of onset is small, and it is more common in girls aged 6 months-2 years.
②Breasts are mostly in stage B2 or B3, symmetrical or only unilateral development, without nipple and areola development and without darkening of areola pigmentation.
There is no overgrowth or bone age overgrowth, the vulva remains infantile, and there is no pubic or axillary hair growth.
④There may be family history.
2. Pathogenesis.
①Related to the physiological characteristics of “mini puberty”.
If the GnRH stimulation test is performed, it shows that FSH is the dominant response and stimulates the ovaries to secrete a small amount of estrogen temporarily.
(iii) Increased serum sex hormone binding globulin leads to a decrease in biologically active, unbound, free state testosterone. Other authors suggest that it may be related to increased secretion of DHEA, which is converted into increased estrogen in immature breast tissue by cytosolic means, thereby altering the estrogen/androgen ratio in breast tissue and contributing to breast development.
(4) The influence of environmental estrogens, such as E substances in meat; phytoestrogens, such as isoflavones and soy estrol.
3. Prognosis: It is currently believed that this disorder is not entirely a self-limiting disease with no effect on puberty. Although most patients do not progress further or can remit on their own. However, some patients with PT can be transformed into CPP without any aura. Some authors have followed up 100 cases of children with simple premature breast development, 14 of which developed into CPP. Therefore, children diagnosed with PT need to be followed up regularly every 3 months, if accompanied by accelerated growth rate and rapid increase in bone age; GnRH excitation test changes from mainly elevated peak FSH to LH/FSH ≥ 0.7 If the GnRH excitation test changes from a predominantly elevated peak FSH to LH/FSH ≥ 0.7, the child should be alerted to the transformation to central precocious puberty.
Therefore, it is inferred that premature breast development and central precocious puberty are different manifestations with the continuous activation of hypothalamic GnRH neurons. This is mainly due to the inconsistent response of LH and FSH to GnRH neurons, and only high-frequency GnRH pulses are excited to promote LH secretion. The clinical course of central precocious puberty may be the transition from the predominance of FSH secretion to the predominance of LH secretion.
(ii) Early appearance of simple pubic hair.
This syndrome refers to the presentation of pubic hair before the age of 8 years in girls and before the age of 9 years in boys, mostly in girls. In addition to pubic hair development II, it may be accompanied by mild acne, oily skin or the appearance of axillary hair, without other secondary sexual characteristics.
Precocious pubic hair and early development are the result of early adrenocortical function and are associated with dysfunction of P450C17, increased synthesis of androgens by the adrenal glands, and elevated blood DHEA, DHEA-S and urinary 17 ketones. Adrenocortical maturation is independent of HPGA maturation. Basal levels of testosterone and LH are in a prepubertal state and are not accompanied by a maturational response to GnRH stimulation, and no LH pulse secretion occurs.
Premature pubic hair is also often the only clinical manifestation of atypical late-onset CAH, but is usually accompanied by significantly earlier bone age. It is important to note that girls with premature pubic hair are at increased risk of developing polycystic ovary syndrome after puberty.
(iii) Premature menarche alone.
The mechanism is unknown. The onset of menstruation in girls aged 1-9 years can last for 1-6 years and stop on its own, without other signs of precocious puberty. Pubertal development begins at a normal age. Other causes of vaginal bleeding should be excluded, such as misuse of contraceptives, ovarian cysts, tumors in the girl’s genital tract, inflammation, injury and vaginal foreign bodies.